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  • 51.
    Lahesmaa, Minna
    et al.
    Univ Turku, Turku PET Ctr, Turku, Finland;Turku Univ Hosp, Turku PET Ctr, Turku, Finland.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Abo Akad Univ, Turku PET Ctr, Turku, Finland.
    Gnad, Thorsten
    Univ Bonn, Inst Pharmacol & Toxicol, Bonn, Germany.
    Oikonen, Vesa
    Univ Turku, Turku PET Ctr, Turku, Finland.
    Bucci, Marco
    Univ Turku, Turku PET Ctr, Turku, Finland.
    Hirvonen, Jussi
    Univ Turku, Turku PET Ctr, Turku, Finland;Univ Turku, Dept Radiol, Turku, Finland.
    Koskensalo, Kalle
    Univ Turku, Turku PET Ctr, Turku, Finland;Turku Univ Hosp, Turku PET Ctr, Turku, Finland.
    Teuho, Jarmo
    Turku Univ Hosp, Turku PET Ctr, Turku, Finland.
    Niemi, Tarja
    Turku Univ Hosp, Dept Plast & Gen Surg, Turku, Finland.
    Taittonen, Markku
    Turku Univ Hosp, Dept Anesthesiol, Turku, Finland.
    Lahdenpohja, Salla
    Univ Turku, Turku PET Ctr, Turku, Finland.
    Din, Mueez U.
    Univ Turku, Turku PET Ctr, Turku, Finland.
    Haaparanta-Solin, Merja
    Univ Turku, Turku PET Ctr, Turku, Finland;Univ Turku, Med Res Labs, Turku, Finland.
    Pfeifer, Alexander
    Univ Bonn, Inst Pharmacol & Toxicol, Bonn, Germany.
    Virtanen, Kirsi A.
    Univ Turku, Turku PET Ctr, Turku, Finland;Turku Univ Hosp, Turku PET Ctr, Turku, Finland.
    Nuutila, Pirjo
    Univ Turku, Turku PET Ctr, Turku, Finland;Turku Univ Hosp, Dept Endocrinol, Turku, Finland.
    Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of Brown Adipose Tissue2018Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, nr 7, s. 1226-1236Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with upregulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and to decrease cardiometabolic risk factors. These effects may be mediated partly via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography radioligand [F-18]FMPEP-d(2) and measured BAT activation in parallel with the glucose analog [F-18]fluorodeoxyglucose. Activation by cold exposure markedly increased CB1R density and glucose uptake in the BAT of lean men. Similarly, 3-receptor agonism increased CB1R density in the BAT of rats. In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes. Our results highlight that CB1Rs are significant for human BAT activity, and the CB1Rs provide a novel therapeutic target for BAT activation in humans.

  • 52.
    Lai, En Yin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Patzak, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vascular reactivity in arterioles from normal and alloxan-diabetic mice: studies on single perfused islets2007Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, nr 1, s. 107-112Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pancreatic islets possess an autonomous mechanism of blood flow regulation, independent of that of the exocrine pancreas. To study islet vascular regulation without confounding effects of the exocrine blood vessels, we have developed a technique enabling us to isolate single pancreatic islets and then to perfuse them using their endogenous vasculature for distribution of the medium. This made it possible to directly study the vascular reactivity of islet arterioles to different substances. We confirmed that control of islet blood flow is mainly located at the precapillary level. As expected, administration of angiotensin II and L-nitro-arginine methyl ester contracted islet arterioles, whereas nitric oxide and adenosine dilated them. D-glucose, the main insulin secretagogue, had a selective dilating effect on smooth muscle in islet arterioles but not in glomerular afferent arterioles. The response to glucose was amplified in islet arterioles from diabetic animals, indicating enhanced islet blood perfusion in diabetes. This newly developed technique for perfusing isolated pancreatic islets will provide new insights into islet perfusion control and its possible contributions to the pathogenesis of type 2 diabetes.

  • 53.
    Lau, Joey
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Mattsson, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Nyqvist, Daniel
    Köhler, Martin
    Berggren, Per-Olof
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Implantation site-dependent dysfunction of transplanted pancreatic islets2007Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, nr 6, s. 1544-1550Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE—Clinical islet transplantations are performed through infusion of islets via the portal vein into the liver. This study aimed at characterizing the influence of the implantation microenvironment on islet graft metabolism and function.

    RESEARCH DESIGN AND METHODS—Islets were transplanted into their normal environment, i.e., the pancreas, or intraportally into the liver of mice. One month posttransplantation, the transplanted islets were retrieved and investigated for changes in function and gene expression.

    RESULTS—Insulin content, glucose-stimulated insulin release, (pro)insulin biosynthesis, and glucose oxidation rate were markedly decreased in islets retrieved from the liver, both when compared with islets transplanted into the pancreas and endogenous islets. Islets transplanted into the pancreas showed normal insulin content, (pro)insulin biosynthesis, and glucose oxidation rate but increased basal insulin secretion and impaired glucose stimulation index. Gene expression data for retrieved islets showed downregulation of pancreatic and duodenal homeobox gene-1, GLUT-2, glucokinase, mitochondrial glycerol-phosphate dehydrogenase, and pyruvate carboxylase, preferentially in intraportally transplanted islets.

    CONCLUSIONS—Islets transplanted into their normal microenvironment, i.e., the pancreas, display gene expression changes when compared with endogenous islets but only moderate changes in metabolic functions. In contrast, site-specific properties of the liver markedly impaired the metabolic functions of intraportally transplanted islets.

  • 54. Leproult, Rachel
    et al.
    Holmbäck, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Van Canter, Eve
    Circadian Misalignment Augments Markers of Insulin Resistance and Inflammation, Independently of Sleep Loss2014Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 6, s. 1860-1869Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Shift workers, who are exposed to irregular sleep schedules resulting in sleep deprivation and misalignment of circadian rhythms, have an increased risk of diabetes relative to day workers. In healthy adults, sleep restriction without circadian misalignment promotes insulin resistance. To determine whether the misalignment of circadian rhythms that typically occurs in shift work involves intrinsic adverse metabolic effects independently of sleep loss, a parallel group design was used to study 26 healthy adults. Both interventions involved 3 inpatient days with 10-h bedtimes, followed by 8 inpatient days of sleep restriction to 5 h with fixed nocturnal bedtimes (circadian alignment) or with bedtimes delayed by 8.5 h on 4 of the 8 days (circadian misalignment). Daily total sleep time (SD) during the intervention was nearly identical in the aligned and misaligned conditions (4 h 48 min [5 min] vs. 4 h 45 min [6 min]). In both groups, insulin sensitivity (SI) significantly decreased after sleep restriction, without a compensatory increase in insulin secretion, and inflammation increased. In male participants exposed to circadian misalignment, the reduction in SI and the increase in inflammation both doubled compared with those who maintained regular nocturnal bedtimes. Circadian misalignment that occurs in shift work may increase diabetes risk and inflammation, independently of sleep loss.

  • 55. Lin, Chia-Wei
    et al.
    Yan, Feifei
    Shimamura, Satoko
    Barg, Sebastian
    Shyng, Show-Ling
    Membrane phosphoinositides control insulin secretion through their effects on ATP-sensitive K+ channel activity.2005Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, nr 10, s. 2852-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ATP-sensitive K(+) channels (K(ATP) channels) of pancreatic beta-cells play key roles in glucose-stimulated insulin secretion by linking metabolic signals to cell excitability. Membrane phosphoinositides, in particular phosphatidylinositol 4,5-bisphosphates (PIP(2)), stimulate K(ATP) channels and decrease channel sensitivity to ATP inhibition; as such, they have been postulated as critical regulators of K(ATP) channels and hence of insulin secretion in beta-cells. Here, we tested this hypothesis by manipulating the interactions between K(ATP) channels and membrane phospholipids in a beta-cell line, INS-1, and assessing how the manipulations affect membrane excitability and insulin secretion. We demonstrate that disruption of channel interactions with PIP(2) by overexpressing PIP(2)-insensitive channel subunits leads to membrane depolarization and elevated basal level insulin secretion at low glucose concentrations. By contrast, facilitation of channel interactions with PIP(2) by upregulating PIP(2) levels via overexpression of a lipid kinase, phosphatidylinositol 4-phosphate 5 kinase, decreases the ATP sensitivity of endogenous K(ATP) channels by approximately 26-fold and renders INS-1 cells hyperpolarized, unable to secrete insulin properly in the face of high glucose. Our results establish an important role of the interaction between membrane phosphoinositides and K(ATP) channels in regulating insulin secretion.

  • 56.
    Lundberg, Marcus
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Krogvold, Lars
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
    Kuric, Enida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Dahl-Jörgensen, Knut
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
    Skog, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 10, s. 3104-3110Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A primary insult to the pancreatic islets of Langerhans, leading to the activation of innate immunity, has been suggested as an important step in the inflammatory process in type 1 diabetes (T1D). The aim of this study was to examine whether interferon (IFN)-stimulated genes (ISGs) are overexpressed in human T1D islets affected with insulitis. By using laser capture microdissection and a quantitative PCR array, 23 of 84 examined ISGs were found to be overexpressed by at least fivefold in insulitic islets from living patients with recent-onset T1D, participating in the Diabetes Virus Detection (DiViD) study, compared with islets from organ donors without diabetes. Most of the overexpressed ISGs, including GBP1, TLR3, OAS1, EIF2AK2, HLA-E, IFI6, and STAT1, showed higher expression in the islet core compared with the peri-islet area containing the surrounding immune cells. In contrast, the T-cell attractant chemokine CXCL10 showed an almost 10-fold higher expression in the peri-islet area than in the islet, possibly partly explaining the localization of T cells mainly to this region. In conclusion, insulitic islets from recent-onset T1D subjects show overexpression of ISGs, with an expression pattern similar to that seen in islets infected with virus or exposed to IFN-gamma/interleukin-1 beta or IFN-alpha.

  • 57.
    Ma, Jiantao
    et al.
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Tufts Univ, Nutr Data Sci, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA.
    Nano, Jana
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol, Neuherberg, Germany;German Ctr Diabet Res, Munich, Germany.
    Ding, Jingzhong
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA.
    Zheng, Yinan
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Hennein, Rachel
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    Liu, Chunyu
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Boston Univ, Dept Biostat, Boston, MA 02215 USA.
    Speliotes, Elizabeth K.
    Univ Michigan, Sch Med, Ann Arbor, MI USA.
    Huan, Tianxiao
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    Song, Ci
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    Mendelson, Michael M.
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA;Harvard Med Sch, Dept Cardiol, Boston Childrens Hosp, Boston, MA 02115 USA.
    Joehanes, Roby
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    Long, Michelle T.
    Boston Univ, Sch Med, Dept Med, Gastroenterol Sect, Boston, MA 02118 USA.
    Liang, Liming
    Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Smith, Jennifer A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Reynolds, Lindsay M.
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA.
    Ghanbari, Mohsen
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Mashhad Univ Med Sci, Sch Med, Dept Genet, Mashhad, Razavi Khorasan, Iran.
    Muka, Taulant
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    van Meurs, Joyce B. J.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands.
    Alferink, Louise J. M.
    Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands.
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands;Imperial Coll London, Dept Biostat & Epidemiol, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, London, England.
    Ratliff, Scott
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Zhao, Wei
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Bielak, Lawrence
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Kardia, Sharon L. R.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Peyser, Patricia A.
    Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA.
    Ning, Hongyan
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    VanWagner, Lisa B.
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA;Northwestern Univ, Dept Med, Feinberg Sch Med, Div Gastroenterol & Hepatol, Chicago, IL 60611 USA.
    Lloyd-Jones, Donald M.
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Carr, John Jeffrey
    Vanderbilt Univ, Med Ctr, Dept Radiol & Radiol Sci, Nashville, TN 37232 USA.
    Greenland, Philip
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Lichtenstein, Alice H.
    Tufts Univ, USDA, Human Nutr Res Ctr Aging, Cardiovasc Nutr Lab, Boston, MA 02111 USA.
    Hu, Frank B.
    Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.
    Liu, Yongmei
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA.
    Hou, Lifang
    Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA.
    Murad, Sarwa Darwish
    Erasmus MC, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands.
    Levy, Daniel
    NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
    A Peripheral Blood DNA Methylation Signature of Hepatic Fat Reveals a Potential Causal Pathway for Nonalcoholic Fatty Liver Disease2019Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, nr 5, s. 1073-1083Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate <0.05 (corresponding P = 6.9 x 10(-6)) with replication at Bonferroni-corrected P < 8.6 x 10(-4). Mendelian randomization analyses supported the association of hypomethylation of cg08309687 (LINC00649) with NAFLD (P = 2.5 x 10(-4)). Hypomethylation of the same CpG was also associated with risk for new-onset T2D (P = 0.005). Our study demonstrates that a peripheral blood-derived DNA methylation signature is robustly associated with hepatic fat accumulation. The hepatic fat-associated CpGs may represent attractive biomarkers for T2D. Future studies are warranted to explore mechanisms and to examine DNA methylation signatures of NAFLD across racial/ethnic groups.

  • 58.
    Manning, Alisa
    et al.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Highland, Heather M.
    Univ Texas MD Anderson Canc Ctr, Human Genet Ctr, Houston, TX 77030 USA.;Univ Texas Hlth Sci Ctr Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA.;Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Gasser, Jessica
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Sim, Xueling
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Tukiainen, Taru
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Fontanillas, Pierre
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;23andMe, Mountain View, CA USA..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Rivas, Manuel A.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Mahajan, Anubha
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Locke, Adam E.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Cingolani, Pablo
    McGill Univ, Sch Comp Sci, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Pers, Tune H.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Boston Childrens Hosp, Div Endocrinol & Genet, Boston, MA USA.;Boston Childrens Hosp, Div Genom, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes, Boston, MA USA.;Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark..
    Vinuela, Ana
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland.;Univ Geneva, Inst Genet & Genom Geneva, Geneva, Switzerland..
    Brown, Andrew A.
    Wellcome Trust Sanger Inst, Hinxton, England.;Oslo Univ Hosp, Norwegian Ctr Mental Disorders Res, Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Ctr Psychosis Res, Div Mental Hlth & Addict, Oslo, Norway..
    Wu, Ying
    Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC USA..
    Flannick, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA..
    Fuchsberger, Christian
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Gamazon, Eric R.
    Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA.;Univ Amsterdam, Acad Med Ctr, Amsterdam, Netherlands..
    Gaulton, Kyle J.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA..
    Im, Hae Kyung
    Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Teslovich, Tanya M.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Blackwell, Thomas W.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Bork-Jensen, Jette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Burtt, Noel P.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Chen, Yuhui
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Green, Todd
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Hartl, Christopher
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Kang, Hyun Min
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Kumar, Ashish
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Basel, Swiss Trop & Publ Hlth Inst, Chron Dis Epidemiol Unit, Basel, Switzerland..
    Ladenvall, Claes
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Ma, Clement
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Moutsianas, Loukas
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Pearson, Richard D.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Perry, John R. B.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England.;Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Rayner, N. William
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England..
    Robertson, Neil R.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Scott, Laura J.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    van de Bunt, Martijn
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Eriksson, Johan G.
    Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Univ Helsinki, Unit Gen Practice, Cent Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Vaasa Cent Hosp, Vaasa, Finland.;Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Tampere, Dept Clin Chem, Fimlab Labs, Sch Med, Tampere, Finland..
    Jula, Antti
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Koskinen, Seppo
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Lehtimaki, Terho
    Palotie, Aarno
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    Jacobs, Suzanne B. R.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Wessel, Jennifer
    Fairbanks Sch Publ Hlth, Dept Epidemiol, Indianapolis, IN USA.;Indiana Univ Sch Med, Dept Med, Indianapolis, IN 46202 USA..
    Chu, Audrey Y.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Goodarzi, Mark O.
    Cedars Sinai Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA.;Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA..
    Blancher, Christine
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Buck, Gemma
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Buck, David
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Chines, Peter S.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Gabriel, Stacey
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Gjesing, Anette P.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Groves, Christopher J.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hollensted, Mette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Huyghe, Jeroen R.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jackson, Anne U.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Jun, Goo
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Justesen, Johanne Marie
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Murphy, Jacquelyn
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Neville, Matt
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Onofrio, Robert
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Small, Kerrin S.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Stringham, Heather M.
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Trakalo, Joseph
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, High Throughput Genom,Oxford Genom Ctr, Oxford, England..
    Banks, Eric
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Carey, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Carneiro, Mauricio O.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    DePristo, Mark
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Farjoun, Yossi
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Fennell, Timothy
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Goldstein, Jacqueline I.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Grant, George
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    de Angelis, Martin Hrabe
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Expt Genet, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Tech Univ Munich, Sch Life Sci Weihenstephan, Inst Expt Genet, Freising Weihenstephan, Germany..
    Maguire, Jared
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Neale, Benjamin M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Poplin, Ryan
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Purcell, Shaun
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Psychiat, New York, NY 10029 USA..
    Schwarzmayr, Thomas
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Shakir, Khalid
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA..
    Smith, Joshua D.
    Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA..
    Strom, Tim M.
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Neuherberg, Germany..
    Wieland, Thomas
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Lindstrom, Jaana
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland..
    Brandslund, Ivan
    Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark.;Vejle Hosp, Dept Clin Biochem, Vejle, Denmark..
    Christensen, Cramer
    Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark..
    Surdulescu, Gabriela L.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Lakka, Timo A.
    Univ Eastern FinIand, Inst Biomed, Dept Physiol, Kuopio, Finland.;Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Doney, Alex S. F.
    Ninewells Hosp & Med Sch, Med Res Inst, Div Cardiovasc & Diabet Med, Dundee, Scotland..
    Nilsson, Peter
    Lund Univ, Fac Med, Dept Clin Sci, Malmo, Sweden..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England..
    Varga, Tibor V.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden.;Lund Univ, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Franks, Paul W.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden.;Lund Univ, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Rolandsson, Olov
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Rosengren, Anders H.
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Farook, Vidya S.
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Thameem, Farook
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Puppala, Sobha
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Kumar, Satish
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Lehman, Donna M.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Jenkinson, Christopher P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA.;South Texas Vet Hlth Care Syst, Res & Dev Serv, San Antonio, TX USA..
    Curran, Joanne E.
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Hale, Daniel Esten
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    Fowler, Sharon P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Arya, Rector
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    DeFronzo, Ralph A.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Abboud, Hanna E.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hicks, Pamela J.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Palmer, Nicholette D.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Ng, Maggie C. Y.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA..
    Bowden, Donald W.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Freedman, Barry I.
    Wake Forest Sch Med, Dept Internal Med, Sect Nephrol, Winston Salem, NC USA..
    Esko, Tonu
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Narisu, Narisu
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Bonnycastle, Lori L.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Swift, Amy
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Pasko, Dorota
    Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    Wood, Andrew R.
    Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    Fadista, Joao
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Pollin, Toni I.
    Univ Maryland, Dept Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA..
    Barzilai, Nir
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA..
    Atzmon, Gil
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA.;Univ Haifa, Fac Nat Sci, Haifa, Israel..
    Glaser, Benjamin
    Hadassah Hebrew Univ, Endocrinol & Metab Serv, Med Ctr, Jerusalem, Israel..
    Thorand, Barbara
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Dept Genet Epidemiol, Munich, Germany..
    Peters, Annette
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Partner Site Munich Heart Alliance, Herz Kreislauf Forsch DZHK, Deutsch Zentrum, Munich, Germany..
    Roden, Michael
    Heinrich Heine Univ, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;Partner Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Dept Genet Epidemiol, Munich, Germany.;Partner Site Munich Heart Alliance, Herz Kreislauf Forsch DZHK, Deutsch Zentrum, Munich, Germany.;Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany..
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Kriebel, Jennifer
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Illig, Thomas
    German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany.;Hannover Med Sch, Inst Human Genet, Hannover, Germany..
    Grallert, Harald
    German Ctr Diabet Res DZD, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Gieger, Christian
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Meisinger, Christa
    German Res Ctr Environm Hlth, Inst Epidemiol 2, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Lannfelt, L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Musani, Solomon K.
    Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA..
    Griswold, Michael
    Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA..
    Taylor, Herman A., Jr.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Wilson, Gregory, Sr.
    Jackson State Univ, Coll Publ Serv, Jackson, MS USA..
    Correa, Adolfo
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Oksa, Heikki
    Pirkanmaa Hosp Dist, Tampere, Finland..
    Scott, William R.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Afzal, Uzma
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Tan, Sian-Tsung
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Loh, Marie
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Univ Oulu, Inst Hlth Sci, Oulu, Finland.;ASTAR, Translat Lab Genet Med, Singapore, Singapore..
    Chambers, John C.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England..
    Sehmi, Jobanpreet
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Kooner, Jaspal Singh
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Lehne, Benjamin
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Cho, Yoon Shin
    Hallym Univ, Dept Biomed Sci, Chunchon, South Korea..
    Lee, Jong-Young
    Minist Hlth & Welf, Seoul, South Korea..
    Han, Bok-Ghee
    Korea Natl Res Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea..
    Karajamaki, Annemari
    Vaasa Hlth Care Ctr, Vaasa, Finland.;Vaasa Cent Hosp, Dept Primary Hlth Care, Vaasa, Finland..
    Qi, Qibin
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA..
    Qi, Lu
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Huang, Jinyan
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Hu, Frank B.
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Melander, Olle
    Lund Univ, Dept Clin Sci, Hypertens & Cardiovasc Dis, Malmo, Sweden..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci, Diabet & Cardiovasc Dis Genet Epidemiol, Malmo, Sweden..
    Below, Jennifer E.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Aguilar, David
    Baylor Coll Med, Cardiovasc Div, Houston, TX 77030 USA..
    Wong, Tien Yin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Liu, Jianjun
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore..
    Khor, Chiea-Chuen
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Paediat, Singapore, Singapore..
    Chia, Kee Seng
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Lim, Wei Yen
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Cheng, Ching-Yu
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch Singapore, Ctr Quantitat Med, Off Clin Sci, Singapore, Singapore..
    Chan, Edmund
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore..
    Tai, E. Shyong
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore.;Duke NUS Grad Med Sch Singapore, Cardiovasc Metab Disorders Program, Singapore, Singapore..
    Aung, Tin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Linneberg, Allan
    Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Isomaa, Bo
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Social Serv & Hlth Care, Pietarsaari, Finland..
    Meitinger, Thomas
    German Res Ctr Environm Hlth, Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Neuherberg, Germany.;Partner Site Munich Heart Alliance, Herz Kreislauf Forsch DZHK, Deutsch Zentrum, Munich, Germany..
    Tuomi, Tiinamaija
    Folkhalsan Res Ctr, Helsinki, Finland.;Helsinki Univ Cent Hosp, Dept Endocrinol, Helsinki, Finland..
    Hakaste, Liisa
    Folkhalsan Res Ctr, Helsinki, Finland..
    Kravic, Jasmina
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Lauritzen, Torsten
    Aarhus Univ, Dept Publ Hlth, Sect Gen Practice, Aarhus, Denmark..
    Deloukas, Panos
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England..
    Stirrups, Kathleen E.
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Univ Cambridge, Dept Haematol, Cambridge, England..
    Owen, Katharine R.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Farmer, Andrew J.
    Univ Oxford, Dept Primary Care Hlth Sci, Oxford, England..
    Frayling, Timothy M.
    Univ Exeter, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    O'Rahilly, Stephen P.
    Univ Cambridge, Inst Metab Sci, Med Res Labs, Cambridge, England..
    Walker, Mark
    Univ Newcastle, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Levy, Jonathan C.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hodgkiss, Dylan
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Hattersley, Andrew T.
    Univ Exeter, Sch Med, Exeter, Devon, England..
    Kuulasmaa, Teemu
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland..
    Stancakova, Alena
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England.;Univ Cambridge, Inst Metab Sci, Med Res Labs, Cambridge, England..
    Bharadwaj, Dwaipayan
    CSIR Inst Genom & Integrat Biol, Funct Genom Unit, New Delhi, India..
    Chan, Juliana
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    Chandak, Giriraj R.
    CSIR Ctr Cellular Mol Biol, Hyderabad, Andhra Pradesh, India..
    Daly, Mark J.
    Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Donnelly, Peter J.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Ebrahim, Shah B.
    Ctr Chron Dis Control, New Delhi, India. Imperial Coll London, MRC, PHE Ctr Environm & Hlth, London, England..
    Elliott, Paul
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Fingerlin, Tasha
    Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA..
    Froguel, Philippe
    CNRS, Inst Biol Lille, Genom & Mol Physiol, Lille, France..
    Hu, Cheng
    Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Jia, Weiping
    Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Ma, Ronald C. W.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    McVean, Gilean
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Park, Taesung
    Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea.;Seoul Natl Univ, Dept Stat, Seoul, South Korea.;Univ Cambridge, Dept Publ Hlth & Primary Care, Inst Publ Hlth, Cambridge, England..
    Prabhakaran, Dorairaj
    Ctr Chron Dis Control, New Delhi, India. Imperial Coll London, MRC, PHE Ctr Environm & Hlth, London, England..
    Sandhu, Manjinder
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Inst Publ Hlth, Cambridge, England..
    Scott, James
    Imperial Coll London, Natl Heart & Lung Inst, Cardiovasc Sci, London, England..
    Sladek, Rob
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Dept Med, Div Endocrinol & Metab, Montreal, PQ, Canada..
    Tandon, Nikhil
    All India Inst Med Sci, Dept Endocrinol & Metab, New Delhi, India..
    Teo, Yik Ying
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Inst Life Sci, Singapore, Singapore.;Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, England..
    Watanabe, Richard M.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Diabet & Obes Res Inst, Los Angeles, CA USA..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Dept Med, Helsinki, Finland.;Univ Helsinki, Abdominal Ctr, Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Minerva Fdn, Inst Med Res, Helsinki, Finland..
    Kesaniemi, Y. Antero
    Univ Oulu, Inst Clin Med, Fac Med, Oulu, Finland..
    Uusitupa, Matti
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Rauramaa, Rainer
    Fdn Res Hlth Exercise & Nutr, Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Palmer, Colin N. A.
    Ninewells Hosp & Med Sch, Med Res Inst, Pat Macpherson Ctr Pharmacogenet & Pharmacogenom, Dundee, Scotland..
    Prokopenko, Inga
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Morris, Andrew D.
    Ninewells Hosp & Med Sch, Clin Res Ctr, Div Mol Med, Dundee, Scotland..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA..
    Collins, Francis S.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden.;Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.;Dasman Diabet Inst, Dasman, Kuwait..
    Karpe, Fredrik
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Groop, Leif
    Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Diabet & Endocrinol Unit, Malmo, Sweden..
    Jorgensen, Torben
    Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Kuusisto, Johanna
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Abecasis, GonOalo
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Bell, Graeme I.
    Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA.;Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA..
    Blangero, John
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Cox, Nancy J.
    Univ Chicago, Dept Med, Sect Genet Med, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Duggirala, Ravindranath
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Seielstad, Mark
    Univ Calif San Francisco, Dept Lab Med, Inst Human Genet, San Francisco, CA 94143 USA.;Blood Syst Res Inst, San Francisco, CA USA..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
    Ripatti, Samuli
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Helsinki, Hjelt Inst, Helsinki, Finland..
    Hanis, Craig L.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Florez, Jose C.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA..
    Mohlke, Karen L.
    Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC USA..
    Meigs, James B.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA..
    Laakso, Markku
    Univ Eastern Finland, Fac Hlth Sci, Inst Clin Med, Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Morris, Andrew P.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Boehnke, Michael
    Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Altshuler, David
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA.;MIT, Dept Biol, Cambridge, MA USA..
    McCarthy, Mark I.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Gloyn, Anna L.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Lindgren, Cecilia M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA.;Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Big Data Inst, Oxford, England..
    A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk2017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 7, s. 2019-2032Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

  • 59.
    Mattsson, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Nordin, Astrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Andersson, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Evidence of Functional Impairment of Syngeneically Transplanted Mouse Pancreatic Islets Retrieved from the Liver2004Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 53, nr 4, s. 948-954Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A drawback in pancreatic islet transplantation is the large number of islets needed to obtain insulin independence in patients with diabetes. This most likely reflects extensive posttransplantation islet cell death and functional impairment of the remaining endocrine cells. We aimed to develop an experimental method to retrieve transplanted islets from the mouse liver, which would enable comparisons of transplanted and endogenous islets and provide valuable information on functional changes induced by intraportal transplantation. Transplanted islets were obtained by retrograde perfusion of the liver with collagenase. The identity of retrieved tissue as transplanted islets was confirmed by intravital staining, immunohistochemistry, and electron microscopy. The retrieved islets, irrespective of whether they had resided in diabetic or nondiabetic recipients, had a markedly lower insulin content and glucose-stimulated insulin release when compared with isolated endogenous islets. The glucose oxidation rate was also markedly lower in the retrieved islets, suggesting mitochondrial dysfunction. These disturbances in insulin content, insulin release, and glucose oxidation rate were not reversed by a few days of culture after retrieval. The results implicate changes in islet function after intraportal transplantation. Such dysfunction may contribute to the high number of islets needed for successful transplantation in diabetic individuals.

  • 60.
    Mojtaba Ghiasi, Seyed
    et al.
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Dahlby, Tina
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Hede Andersen, Caroline
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Haataja, Leena
    Univ Michigan, Div Metab Endocrinol & Diabet, Med Ctr, Ann Arbor, MI USA.
    Petersen, Sólrun
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Omar-Hmeadi, Muhmmad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Yang, Mingyu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pihl, Celina
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Emilie Bresson, Sophie
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Saad Khilji, Muhammad
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Klindt, Kristian
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Cheta, Oana
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Perone, Marcelo J
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark;Polo Cient Tecnol, Max Planck Soc, Partner Inst, CONICET,Inst Invest Biomed Buenos Aires IBioBA, Buenos Aires, DF, Argentina.
    Tyrberg, Björn
    AstraZeneca, IMED Biotech Unit, Translat Sci Cardiovasc Renal & Metab, Gothenburg, Sweden.
    Prats, Clara
    Univ Copenhagen, Dept Biomed Sci, Ctr Hlth Ageing, Copenhagen, Denmark.
    Barg, Sebastian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Arvan, Peter
    Univ Michigan, Div Metab Endocrinol & Diabet, Med Ctr, Ann Arbor, MI USA.
    Mandrup-Poulsen, Thomas
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    Tomasz Marzec, Michal
    Univ Copenhagen, Dept Biomed Sci, Copenhagen, Denmark.
    The Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 is Essential for Proinsulin Handling2019Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, nr 4, s. 747-760Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is under-investigated. Here, we have explored the importance of glucose regulated protein 94 (GRP94), a prominent ER chaperone known to fold insulin-like growth factors, in proinsulin handling within β-cells. We found that GRP94 co-immunoprecipitated with proinsulin and that inhibition of GRP94 function and/or expression reduced glucose-dependent insulin secretion, shortened proinsulin half-life and lowered intracellular proinsulin and insulin levels. This phenotype was accompanied by post-ER proinsulin misprocessing and higher numbers of enlarged insulin granules that contained amorphic material with reduced immunogold staining for mature insulin. Insulin granule exocytosis was two-fold accelerated but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in β-cells selectively activated Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from T2D patients. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.

  • 61.
    Mokhtari, Dariush
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Myers, Jason W
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    MAPK kinase kinase-1 is essential for cytokine-induced c-Jun NH2-terminal kinase and nuclear factor-kappaB activation in human pancreatic islet cells2008Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 57, nr 7, s. 1896-1904Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: The transcription factor nuclear factor-kappaB (NF-kappaB) and the mitogen-activated protein kinases (MAPKs) c-Jun NH(2)-terminal kinase (JNK) 1/2 are known to play decisive roles in cytokine-induced damage of rodent beta-cells. The upstream events by which these factors are activated in response to cytokines are, however, uncharacterized. The aim of the present investigation was to elucidate a putative role of the MAPK kinase kinase-1 (MEKK-1) in cytokine-induced signaling. RESEARCH DESIGN AND METHODS: To establish a functional role of MEKK-1, the effects of transient MEKK-1 overexpression in betaTC-6 cells, achieved by lipofection and cell sorting, and MEKK-1 downregulation in betaTC-6 cells and human islet cells, achieved by diced-small interfering RNA treatment, were studied. RESULTS: We observed that overexpression of wild-type MEKK-1, but not of a kinase dead MEKK-1 mutant, resulted in potentiation of cytokine-induced JNK activation, inhibitor of kappaB (IkappaB) degradation, and cell death. Downregulation of MEKK-1 in human islet cells provoked opposite effects, i.e., attenuation of cytokine-induced JNK and MKK4 activation, IkappaB stability, and a less pronounced NF-kappaB translocation. betaTC-6 cells with a downregulated MEKK-1 expression displayed also a weaker cytokine-induced iNOS expression and lower cell death rates. Also primary mouse islet cells with downregulated MEKK-1 expression were protected against cytokine-induced cell death. CONCLUSIONS: MEKK-1 mediates cytokine-induced JNK- and NF-kappaB activation, and this event is necessary for iNOS expression and cell death.

  • 62.
    Nano, Rita
    et al.
    IRCCS San Raffaele Sci Inst, Diabet Res Inst, Milan, Italy.
    Kerr-Conte, Julie A.
    Univ Lille, CHU Lille, Fac Med, European Genom Inst Diabet,INSERM, Lille, France.
    Bosco, Domenico
    Hop Univ Geneve, Geneva, Switzerland.
    Karlsson, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Lavallard, Vanessa
    Hop Univ Geneve, Geneva, Switzerland.
    Melzi, Raffaella
    IRCCS San Raffaele Sci Inst, Diabet Res Inst, Milan, Italy.
    Gmyr, Valery
    Univ Lille, CHU Lille, Fac Med, European Genom Inst Diabet,INSERM, Lille, France.
    Mercalli, Alessia
    IRCCS San Raffaele Sci Inst, Diabet Res Inst, Milan, Italy.
    Berney, Thierry
    Hop Univ Geneve, Geneva, Switzerland.
    Pattou, Francois
    Univ Lille, CHU Lille, Fac Med, European Genom Inst Diabet,INSERM, Lille, France.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Piemonti, Lorenzo
    IRCCS San Raffaele Sci Inst, Diabet Res Inst, Milan, Italy.
    Islets for Research: Nothing Is Perfect, but We Can Do Better2019Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, nr 8, s. 1541-1543Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In December 2018, Diabetes and Diabetologia began requiring authors of papers reporting data obtained from studies on human islets to report critical characteristics of the human islets used for research. The islet community was asked to provide feedback on it. Here is the contribution by the European Consortium for Islet Transplantation.

  • 63. Naslund, Erik
    et al.
    Hellström, Per M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Gastroenterologi/hepatologi.
    Elucidating the Mechanisms Behind the Restoration of Euglycemia After Gastric Bypass Surgery2013Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, nr 4, s. 1012-1013Artikel i tidskrift (Övrigt vetenskapligt)
  • 64. Nielsen, Jens H
    et al.
    Galsgaard, ED
    Møldrup, A
    Friedrichsen, BN
    Billestrup, N
    Hansen, JA
    Lee, YC
    Carlsson, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Regulation of the beta cell mass by hormones and growth factors2001Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 50, nr Suppl . 1, s. 25-29Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Substantial new information has accumulated on molecular mechanisms of pancreas development, regulation of beta-cell gene expression, and the role of growth factors in the differentiation, growth, and regeneration of beta-cells. The present review focuses on some recent studies on the mechanism of action of cytokines such as growth hormone (GH) and prolactin (PRL) in beta-cell proliferation and gene expression-in particular, the role of signal transducers and activators of transcription (STAT) proteins. The implication of the discovery of suppressors of cytokine signaling (SOCS) proteins for the interaction between stimulatory and inhibitory cytokines, including GH, PRL, leptin, and the proinflammatory cytokines interleukin-1 and interferon-gamma, in beta-cell survival is not yet clear. Recent studies indicate a role of cell adhesion molecules and the delta-like protein preadipocyte factor 1/fetal antigen 1 (Pref-1/FA-1) in cytokine-induced beta-cell growth and development. Surprisingly, glucagon-like peptide-1 (GLP-1) was recently found to stimulate not only insulin secretion but also beta-cell replication and differentiation, which may present a new perspective in treatment of type 2 diabetes. Together with the intriguing reports on positive effects of insulin on both beta-cell growth and function, a picture is emerging of an integrated network of signaling events acting in concert to control beta-cell mass adaptation to insulin demand.

  • 65.
    Nowak, Christoph
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Protein Biomarkers for Insulin Resistance and Type 2 Diabetes Risk in Two Large Community Cohorts2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 1, s. 276-284Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 ± 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist [IL-1ra], hepatocyte growth factor, fatty acid-binding protein 4, and tissue plasminogen activator [t-PA]) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio [HR] 1.28, 95% CI 1.03-1.59) and t-PA (HR 1.30, 1.02-1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02-1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62-0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI -0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA.

  • 66.
    Olerud, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Johansson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lawler, Jack
    Harvard University.
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Improved vascular engraftment and graft function after inhibition of the angiostatic factor thrombospondin-1 in mouse pancreatic islets2008Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 57, nr 7, s. 1870-1877Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Insufficient development of a new intra-islet capillary network after transplantation may be one contributing factor to the failure of islet grafts in clinical transplantation. The present study tested the hypothesis that the angiostatic factor thrombospondin-1 (TSP-1), which is normally present in islets, restricts intra-islet vascular expansion posttransplantation. RESEARCH DESIGN AND METHODS: Pancreatic islets of TSP-1-deficient (TSP-1(-/-)) mice or wild-type islets transfected with siRNA for TSP-1 were transplanted beneath the renal capsule of syngeneic or immunocompromised recipient mice. RESULTS: Both genetically TSP-1(-/-) islets and TSP-1 siRNA-transfected islet cells demonstrated an increased vascular density when compared with control islets 1 month after transplantation. This was also reflected in a markedly increased blood perfusion and oxygenation of the grafts. The functional importance of the improved vascular engraftment was analyzed by comparing glucose-stimulated insulin release from islet cells transfected with either TSP-1 siRNA or scramble siRNA before implantation. These experiments showed that the increased revascularization of grafts composed of TSP-1 siRNA-transfected islet cells correlated to increments in both their first and second phase of glucose-stimulated insulin secretion. CONCLUSIONS: Our findings demonstrate that inhibition of TSP-1 in islets intended for transplantation may be a feasible strategy to improve islet graft revascularization and function.

  • 67.
    Olsson, Richard
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    A low oxygenated subpopulation of pancreatic islets constitutes a functional reserve of endocrine cells2011Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 8, s. 2068-2075Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE The blood perfusion of pancreatic islets is highly variable and tightly regulated by the blood glucose concentration. Thus, oxygen levels are considered crucial for islet metabolism and function. Although islet oxygenation has been extensively studied in vitro, little is known about it in vivo. The current study aimed to investigate the oxygenation of the endocrine pancreas in vivo.

    RESEARCH DESIGN AND METHODS The reductive metabolism of 2-nitroimidazoles, such as pimonidazole, has previously been extensively used in studies of oxygen metabolism both in vitro and in vivo. At tissue oxygen levels <10 mmHg, pimonidazole accumulates intracellularly and may thereafter be detected by means of immunohistochemistry. Islet oxygenation was investigated in normal, 60% partially pancreatectomized, as well as whole-pancreas–transplanted rats. Moreover, leucine-dependent protein biosynthesis was performed using autoradiography to correlate islet oxygenation with metabolic activity.

    RESULTS In vivo, 20–25% of all islets in normal rats showed low oxygenation (pO2 <10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low-oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Moreover, oxygenation was related to metabolism, since well-oxygenated islets in vivo had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis.

    CONCLUSIONS The current study suggests a novel subpopulation of dormant low-oxygenated islets, which seems to constitute a functional reserve of endocrine cells. This study establishes a novel perspective on the use of the endocrine pancreas in glucose homeostasis.

  • 68.
    Olsson, Richard
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Olerud, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Pettersson, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Increased Numbers of Low-Oxygenated Pancreatic Islets After Intraportal Islet Transplantation2011Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 9, s. 2350-2353Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE-No previous study has measured the oxygenation of intraportally transplanted islets, although recent data suggest that insufficient engraftment may result in hypoxia and loss of islet cells. RESEARCH DESIGN AND METHODS-After intraportal infusion into syngeneic mice, islet oxygenation was investigated in 1-day-old, 1-month-old, or 3-month-old grafts and compared with renal subcapsular grafts and native islets. Animals received an intravenous injection of pimonidazole for immunohistochemical detection of low-oxygenated islet cells (pO(2) <10 mmHg), and caspase-3 immunostaining was performed to assess apoptosis rates in adjacent tissue sections. RESULTS-In the native pancreas of nontransplanted animals, similar to 30% of the islets stained positive for pimonidazole. In 1-day-old and 1-month-old grafts, the percentage of pimonidazole-positive islets in the liver was twice that of native islets, whereas this increase was abolished in 3-month-old grafts. Beneath the renal capsule, pimonidazole accumulation was, however, similar to native islets at all time points. Apoptosis rates were markedly increased in 1-day-old intrahepatic grafts compared with corresponding renal islet grafts, which were slightly increased compared with native islets. One month posttransplantation renal subcapsular grafts had similar frequencies of apoptosis as native islets, whereas apoptosis in intraportally implanted islets was still high. In the liver, islet graft vascular density increased between 1 and 3 months posttransplantation, and apoptosis rates simultaneously dropped to values similar to those observed in native islets. CONCLUSIONS-The vascular engraflment of intraportally transplanted islets is markedly delayed compared with renal islet grafts. The prolonged ischemia of intraportally transplanted islets may favor an alternative implantation site.

  • 69. Onozato, Maristela L
    et al.
    Tojo, Akihiro
    Leiper, James
    Fujita, Toshiro
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Wilcox, Christopher S
    Expression of NG,NG-dimethylarginine dimethylaminohydrolase and protein arginine N-methyltransferase isoforms in diabetic rat kidney: effects of angiotensin II receptor blockers2008Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 57, nr 1, s. 172-180Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The nitric oxide (NO) synthase inhibitor, asymmetric dimethylarginine (ADMA) is generated by protein arginine N-methyltransferase (PRMT)-1 and is metabolized by NG, NG-dimethylarginine dimethylaminohydrolase (DDAH). We tested the hypothesis that increased serum ADMA (SADMA) in the streptozotocin (STZ)-induced rat model of diabetes mellitus (DM) is mediated by an angiotensin receptor blocker– sensitive change in DDAH or PRMT expression.

    Research design and Methods: Data were compared from 4 groups of rats: sham injected controls; untreated STZ- DM at 4 weeks; STZ-DM rats administered the angiotensin II receptor blocker telmisartan for 2 weeks; control rats administered telmisartan for 2 weeks.

    Results: Immunostaining and Western blotting of microdissected nephron segments localized DDAH I in the proximal tubules and DDAH II in the glomeruli, afferent arterioles, macula densa and distal nephron. Renal angiotensin II and SADMA increased with DM but were normalized by 2 weeks of telmisartan. DDAH I expression was decreased in DM kidneys while DDAH II expression was increased. These changes were reversed by telmisartan which also reduced expression of PRMT-1 and -5. Telmisartan increased expressions of DDAH I but decreased DDAH II in Ang II-stimulated kidney slices ex-vivo.

    Conclusion: Renal angiotensin II and SADMA are increased in insulinopenic DM. They are normalized by an angiotensin II receptor blocker which increases the renal expression of DDAH I, decreases PRMT-1 and increases renal NO metabolites.

  • 70.
    Palm, Fredrik
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Buerk, Donald G.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hansell, Peter
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Liss, Per
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi. Radiologi.
    Reduced nitric oxide concentration in the renal cortex of streptozotocin-induced diabetic rats: effects on renal oxygenation and microcirculation2005Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, nr 11, s. 3282-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nitric oxide (NO) regulates vascular tone and mitochondrial respiration. We investigated the hypothesis that there is reduced NO concentration in the renal cortex of diabetic rats that mediates reduced renal cortical blood perfusion and oxygen tension (P O2). Streptozotocin-induced diabetic and control rats were injected with l-arginine followed by Nomega-nitro-L-arginine-metyl-ester (L-NAME). NO and P O2 were measured using microsensors, and local blood flow was recorded by laser-Doppler flowmetry. Plasma arginine and asymmetric dimethylarginine (ADMA) were analyzed by high-performance liquid chromatography. L-Arginine increased cortical NO concentrations more in diabetic animals, whereas changes in blood flow were similar. Cortical P O2 was unaffected by L-arginine in both groups. L-NAME decreased NO in control animals by 87 +/- 15 nmol/l compared with 45 +/- 7 nmol/l in diabetic animals. L-NAME decreased blood perfusion more in diabetic animals, but it only affected P O2 in control animals. Plasma arginine was significantly lower in diabetic animals (79.7 +/- 6.7 vs. 127.9 +/- 3.9 mmol/l), whereas ADMA was unchanged. A larger increase in renal cortical NO concentration after l-arginine injection, a smaller decrease in NO after L-NAME, and reduced plasma arginine suggest substrate limitation for NO formation in the renal cortex of diabetic animals. This demonstrates a new mechanism for diabetes-induced alteration in renal oxygen metabolism and local blood flow regulation.

  • 71. Renström, Erik
    et al.
    Barg, Sebastian
    Thévenod, Frank
    Rorsman, Patrik
    Sulfonylurea-mediated stimulation of insulin exocytosis via an ATP-sensitive K+ channel-independent action.2002Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 51 Suppl 1, s. S33-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several reports indicate that hypoglycemic sulfonylureas augment Ca(2+)-dependent insulin secretion via mechanisms other than inhibition of the ATP-sensitive K(+) channel. The effect involves a 65-kd protein in the granule membrane and culminates in intragranular acidification. Lowering of granule pH is necessary for the insulin granule to gain release competence. Proton pumping into the granule is driven by a v-type H(+)-ATPase, but requires simultaneous Cl(-) uptake into the granule via metabolically regulated ClC-3 Cl(-) channels to maintain electroneutrality. Here we discuss the possibility that modulation of granule ClC-3 channels represents the mechanism whereby sulfonylureas directly potentiate the beta-cell exocytotic machinery.

  • 72.
    Ricordi, Camillo
    et al.
    Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA..
    Goldstein, Julia S.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Balamurugan, A. N.
    Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN USA.;Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA.;Univ Louisville, Dept Surg, Islet Cell Lab, Cardiovasc Innovat Inst, Louisville, KY 40292 USA..
    Szot, Gregory L.
    Univ Calif San Francisco, Dept Surg, San Francisco, CA USA..
    Kin, Tatsuya
    Univ Alberta, Clin Islet Transplant Program, Edmonton, AB, Canada.;Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada..
    Liu, Chengyang
    Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA.;Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Czarniecki, Christine W.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Barbaro, Barbara
    Univ Illinois Hosp & Hlth Sci Syst, Div Transplantat, Chicago, IL USA..
    Bridges, Nancy D.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Cano, Jose
    Emory Univ, Dept Surg, Emory Transplant Ctr, Div Transplantat, Atlanta, GA 30322 USA..
    Clarke, William R.
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Eggerman, Thomas L.
    NIDDK, NIH, Bethesda, MD 20892 USA..
    Hunsicker, Lawrence G.
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Kaufman, Dixon B.
    Northwestern Univ, Feinberg Sch Med, Comprehens Transplant Ctr, Chicago, IL 60611 USA.;Univ Wisconsin, Madison, WI USA..
    Khan, Aisha
    Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA..
    Lafontant, David-Erick
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Linetsky, Elina
    Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA..
    Luo, Xunrong
    Northwestern Univ, Feinberg Sch Med, Comprehens Transplant Ctr, Chicago, IL 60611 USA..
    Markmann, James F.
    Harvard Med Sch, Massachusetts Gen Hosp, Div Transplant Surg, Boston, MA USA..
    Naji, Ali
    Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA.;Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Oberholzer, Jose
    Univ Illinois Hosp & Hlth Sci Syst, Div Transplantat, Chicago, IL USA..
    Turgeon, Nicole A.
    Emory Univ, Dept Surg, Emory Transplant Ctr, Div Transplantat, Atlanta, GA 30322 USA..
    Brandhorst, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Friberg, Andrew S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Lei, Ji
    Harvard Med Sch, Massachusetts Gen Hosp, Div Transplant Surg, Boston, MA USA..
    Wang, Ling-jia
    Northwestern Univ, Feinberg Sch Med, Comprehens Transplant Ctr, Chicago, IL 60611 USA..
    Wilhelm, Joshua J.
    Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN USA.;Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Willits, Jamie
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Zhang, Xiaomin
    Northwestern Univ, Feinberg Sch Med, Comprehens Transplant Ctr, Chicago, IL 60611 USA..
    Hering, Bernhard J.
    Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN USA.;Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Posselt, Andrew M.
    Univ Calif San Francisco, Dept Surg, San Francisco, CA USA..
    Stock, Peter G.
    Univ Calif San Francisco, Dept Surg, San Francisco, CA USA..
    Shapiro, A. M. James
    Univ Alberta, Clin Islet Transplant Program, Edmonton, AB, Canada.;Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada..
    National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 11, s. 3418-3428Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.

  • 73. Rijzewijk, Luuk J
    et al.
    van der Meer, Rutger W
    Lubberink, Mark
    Department of Nuclear Medicine & PET Research, VU University Medical Center, Amsterdam, the Netherlands.
    Lamb, Hildo J
    Romijn, Johannes A
    de Roos, Albert
    Twisk, Jos W
    Heine, Robert J
    Lammertsma, Adriaan A
    Smit, Johannes W A
    Diamant, Michaela
    Liver fat content in type 2 diabetes: relationship with hepatic perfusion and substrate metabolism.2010Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 11, s. 2747-2754Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE:

    Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have indicated that increased liver fat may impair hepatic perfusion and metabolism. The aim of the current study was to assess hepatic parenchymal perfusion, together with glucose and fatty acid metabolism, in relation to hepatic triglyceride content.

    RESEARCH DESIGN AND METHODS:

    Fifty-nine men with well controlled type 2 diabetes and 18 age-matched healthy normoglycemic men were studied using positron emission tomography to assess hepatic tissue perfusion, insulin-stimulated glucose, and fasting fatty acid metabolism, respectively, in relation to hepatic triglyceride content, quantified by proton magnetic resonance spectroscopy. Patients were divided into two groups with hepatic triglyceride content below (type 2 diabetes-low) or above (type 2 diabetes-high) the median of 8.6%.

    RESULTS:

    Type 2 diabetes-high patients had the highest BMI and A1C and lowest whole-body insulin sensitivity (ANOVA, all P < 0.001). Compared with control subjects and type 2 diabetes-low patients, type 2 diabetes-high patients had the lowest hepatic parenchymal perfusion (P = 0.004) and insulin-stimulated hepatic glucose uptake (P = 0.013). The observed decrease in hepatic fatty acid influx rate constant, however, only reached borderline significance (P = 0.088). In type 2 diabetic patients, hepatic parenchymal perfusion (r = -0.360, P = 0.007) and hepatic fatty acid influx rate constant (r = -0.407, P = 0.007) correlated inversely with hepatic triglyceride content. In a pooled analysis, hepatic fat correlated with hepatic glucose uptake (r = -0.329, P = 0.004).

    CONCLUSIONS:

    In conclusion, type 2 diabetic patients with increased hepatic triglyceride content showed decreased hepatic parenchymal perfusion and hepatic insulin mediated glucose uptake, suggesting a potential modulating effect of hepatic fat on hepatic physiology.

  • 74.
    Risérus, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Sprecher, Dennis
    Johnson, Tony
    Olson, Eric
    Hirschberg, Sandra
    Liu, Aixue
    Fang, Zeke
    Hegde, Priti
    Richards, Duncan
    Sarov-Blat, Leli
    Strum, Jay C
    Basu, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Cheeseman, Jane
    Fielding, Barbara A
    Humphreys, Sandy M
    Danoff, Theodore
    Moore, Niall R
    Murgatroyd, Peter
    O'Rahilly, Stephen
    Sutton, Pauline
    Willson, Tim
    Hassall, David
    Frayn, Keith N
    Karpe, Fredrik
    Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men2008Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 57, nr 2, s. 332-339Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIEVE-Pharmacological use of peroxisome proliferator-activated receptor (PPAR)delta agonists and transgenic overexpression of PPAR delta in mice suggest amelioration of features of the metabolic syndrome through enhanced fat oxidation in skeletal muscle. We hypothesize a similar mechanism operates in humans. RESEARCH DESIGN AND METHODS-The PPAR delta agonist (10 mg o.d. GW501516), a comparator PPAR alpha agonist (20 mu g o.d. GW590735)), and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress. RESULTS-Treatment with GW501516 showed statistically significant reductions in fasting plasma triglycerides (-30%), apolipoprotein B (-26%), LDL cholesterol (-23%), and insulin (-11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P < 0.05) and 30% reduction in urinary isoprostanes (P = 0.01) were also observed. Except for a lowering of triglycerides (-30%, P < 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO, directly originating from the fat content of the meal was increased (P < 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b (CPT1b) was also significantly increased. CONCLUSIONS-The PPAR delta agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle.

  • 75.
    Roest, Pauline A.M.
    et al.
    Department of Embryology and Anatomy, Leiden University.
    Molin, Daniël G. M.
    Department of Embryology and Anatomy, Leiden University.
    Schalkwijk, Casper G.
    Department of Embryology and Anatomy, Leiden University.
    van Iperen, Liesbeth
    Department of Embryology and Anatomy, Leiden University.
    Wentzel, Parri
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gittenberger-de Groot, Adriana C.
    Department of Embryology and Anatomy, Leiden University.
    Specific Local Cardiovascular Changes of N-epsilon-(Carboxymethyl)lysine, Vascular Endothelial Growth Factor, and Smad2 in the Developing Embryos Coincide With Maternal Diabetes-Induced Congenital Heart Defects2009Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, nr 5, s. 1222-1228Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Embryos exposed to a diabetic environment in utero have an increased risk to develop congenital heart malformations. The mechanism behind the teratogenicity of diabetes still remains enigmatic. Detrimental effects of glycation products in diabetic patients have been well documented. We therefore studied a possible link between glycation products and the development of congenital cardiovascular malformations. Furthermore, we investigated other possible mechanisms involved in this pathogenesis: alterations in the levels of vascular endothelial growth factor (VEGF) or phosphorylated Smad2 (the latter can be induced by both glycation products and VEGF). RESEARCH DESIGN AND METHODS: We examined the temporal spatial patterning of the glycation products Nepsilon(carboxymethyl)lysine (CML) and methylglyoxal (MG) adducts, VEGF expression, and phosphorylated Smad2 during cardiovascular development in embryos from normal and diabetic rats. RESULTS: Maternal diabetes increased the CML accumulation in the areas susceptible to diabetes-induced congenital heart disease, including the outflow tract of the heart and the aortic arch. No MG adducts could be detected, suggesting that CML is more likely to be indicative for increased oxidative stress than for glycation. An increase of CML in the outflow tract of the heart was accompanied by an increase in phosphorylated Smad2, unrelated to VEGF. VEGF showed a time-specific decrease in the outflow tract of embryos from diabetic dams. CONCLUSIONS: From our results, we can conclude that maternal diabetes results in transient and localized alterations in CML, VEGF expression, and Smad2 phosphorylation overlapping with those regions of the developing heart that are most sensitive to diabetes-induced congenital heart disease.

  • 76. Rosdahl, Hans
    et al.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Millgård, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lithell, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Ungerstedt, Urban
    Henriksson, Jan
    Effect of physiological hyperinsulinemia on blood flow and interstitial glucose concentration in human skeletal muscle and adipose tissue studied by microdialysis1998Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 47, nr 8, s. 1296-1301Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effect of an euglycemic-hyperinsulinemic glucose clamp (94 +/- 5 microU/ml) on blood flow and glucose extraction fraction in human skeletal muscle and adipose tissue was investigated. Limb blood flow was measured by venous occlusion pletysmography and tissue blood flow by the microdialysis ethanol technique. Insulin infusion resulted in an increased blood flow in the calf and forearm (64 and 36%, respectively; P < 0.01) but not in the studied muscles of these limbs (ethanol outflow-to-inflow ratio: m. gastrocnemius 0.144 +/- 0.009 to 0.140 +/- 0.011, NS; m. brachioradialis 0.159 +/- 0.025 to 0.168 +/- 0.027, NS). This was accompanied by an increased extraction fraction of glucose, as measured by an increased arteriovenous difference over the forearm (0.16 +/- 0.04 to 0.70 +/- 0.10 mmol/l; P < 0.001) and by an increase in the estimated arterial-interstitial glucose difference in the gastrocnemius (0.82-1.42 mmol/l) and brachioradialis muscle (0.82-1.97 mmol/l). The blood flow in adipose tissue was significantly increased during insulin infusion, as evidenced by a decreased ethanol outflow-to-inflow ratio (0.369 +/- 0.048 to 0.325 +/- 0.046; P < 0.01). This was accompanied by an unchanged concentration of glucose in the dialysate (-2.6%, NS). In summary, during physiological hyperinsulinemia 1) a blood flow increase was detected in the calf and forearm, but not in the studied muscles of these limbs; 2) the blood flow increased in the subcutaneous adipose tissue; and 3) the estimated arterial-interstitial glucose difference increased in both muscles studied and was larger in the forearm muscle than the arteriovenous glucose difference over the forearm. The present study shows that microdialysis is a useful tool to obtain tissue-specific information about the effect of insulin on blood flow and glucose extraction in human skeletal muscle and adipose tissue.

  • 77.
    Rosqvist, Fredrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Iggman, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Cedernaes, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Johansson, Hans-Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Arner, Peter
    Dahlman, Ingrid
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Overfeeding Polyunsaturated and Saturated Fat Causes Distinct Effects on Liver and Visceral Fat Accumulation in Humans2014Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 7, s. 2356-2368Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Excess ectopic fat storage is linked to type 2 diabetes. The importance of dietary fat composition for ectopic fat storage in humans is unknown. We investigated liver fat accumulation and body composition during overfeeding saturated (SFA) or polyunsaturated (PUFA) fat. LIPOGAIN was a double-blind, parallel-group, randomized trial. Thirty-nine young and normal-weight individuals were overfed muffins high in SFA (palm oil) or n-6 PUFA (sunflower oil) for 7 weeks. Liver fat, visceral (VAT), subcutaneous abdominal (SAT), and total adipose tissue (TAT), pancreatic fat, and lean tissue was assessed by MRI. Transcriptomics were performed in SAT. Both groups gained similar weight. SFA however markedly increased liver fat compared with PUFA and caused 2-fold larger increase in VAT than PUFA. Conversely, PUFA caused a nearly 3-fold larger increase in lean tissue than SFA. Increase in liver fat directly correlated with changes in plasma SFA and inversely with PUFA. Genes involved in regulating energy dissipation, insulin resistance, body composition and fat cell differentiation in SAT were differentially regulated between diets, and associated with increased PUFA in SAT. In conclusion, overeating SFA promotes hepatic and visceral fat storage whereas excess energy from PUFA may instead promote lean tissue in healthy humans.

  • 78.
    Salami, Falastin
    et al.
    Lund Univ, Clin Res Ctr, Skåne Univ Hosp, Dept Clin Sci, Malmö, Sweden.
    Lee, Hye-Seung
    Univ S Florida, Hlth Informat Inst, Dept Pediat, Tampa, FL USA.
    Freyhult, Eva
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Larsson, Helena Elding
    Lund Univ, Clin Res Ctr, Skåne Univ Hosp, Dept Clin Sci, Malmö, Sweden.
    Lernmark, Åke
    Lund Univ, Clin Res Ctr, Skåne Univ Hosp, Dept Clin Sci, Malmö, Sweden.
    Törn, Carina
    Lund Univ, Clin Res Ctr, Skåne Univ Hosp, Dept Clin Sci, Malmö, Sweden.
    Reduction in White Blood Cell, Neutrophil and Red Blood Cell counts Related to Gender, HLA and Islet Autoantibodies in Swedish TEDDY Children at Increased Risk for Type 1 Diabetes2018Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, nr 11, s. 2329--2336, artikel-id db180355Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Islet autoantibodies (IAs) precede the clinical onset of type 1 diabetes (T1D); however, the knowledge is limited about whether the prodrome affects complete blood counts (CBCs) in 4- to 12-year-old children with increased genetic risk for T1D. This study tested whether CBCs were altered in 4- to 12-year-old children without (n = 376) or with one or several IAs against insulin, GAD65, or IA-2 (n = 72). CBC was analyzed during longitudinal follow-up in 448 Swedish children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A linear mixed-effects model was used to assess potential association between IA and CBC measurements over time. The white blood cell and neutrophil counts were reduced in children with IAs, primarily in boys. In contrast, girls had lower levels of hemoglobin and hematocrit. Positivity for multiple IAs showed the lowest counts in white blood cells and neutrophils in boys and red blood cells, hemoglobin, and hematocrit in girls. These associations were primarily observed in children with the HLA-DR3-DQ2/DR4-DQ8 genotype. We conclude that the reduction in neutrophils and red blood cells in children with multiple IAs and HLA-DR3-DQ2/DR4-DQ8 genotype may signal a sex-dependent islet autoimmunity detected in longitudinal CBCs.

  • 79.
    Salehi, Albert
    et al.
    Institutionen för klinisk vetenskap, Malmö universitetssjukhus, Lunds universitet.
    Vieira, Elaine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gylfe, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Paradoxical stimulation of glucagon secretion by high glucose concentrations2006Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, nr 8, s. 2318-2323Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hypersecretion of glucagon contributes to the dysregulation of glucose homeostasis in diabetes. To clarify the underlying mechanism, glucose-regulated glucagon secretion was studied in mouse pancreatic islets and clonal hamster In-R1-G9 glucagon-releasing cells. Apart from the well-known inhibition of secretion with maximal effect around 7 mmol/l glucose, we discovered that mouse islets showed paradoxical stimulation of glucagon release at 25-30 mmol/l and In-R1-G9 cells at 12-20 mmol/l sugar. Whereas glucagon secretion in the absence of glucose was inhibited by hyperpolarization with diazoxide, this agent tended to further enhance secretion stimulated by high concentrations of the sugar. Because U-shaped dose-response relationships for glucose-regulated glucagon secretion were observed in normal islets and in clonal glucagon-releasing cells, both the inhibitory and stimulatory components probably reflect direct effects on the a-cells. Studies of isolated mouse a-cells indicated that glucose inhibited glucagon secretion by lowering the cytoplasmic Ca2+ concentration. However, stimulation of glucagon release by high glucose concentrations did not require elevation of Ca2+, indicating involvement of novel mechanisms in glucose regulation of glucagon secretion. A U-shaped dose-response relationship for glucose-regulated glucagon secretion may explain why diabetic patients with pronounced hyperglycemia display paradoxical hyperglucagonemia.

  • 80. Sandqvist, M M
    et al.
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Jansson, P A
    Increased lactate release per fat cell in normoglycemic first-degree relatives of individuals with type 2 diabetes.2001Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 50, nr 10, s. 2344-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to examine subcutaneous lactate production in the relatives of individuals with type 2 diabetes. Therefore, we recruited seven healthy first-degree relatives of type 2 diabetic patients and seven pairwise, matched, healthy control subjects without any heredity for diabetes. All subjects were studied with a euglycemic insulin clamp at approximately 600 pmol/l, abdominal subcutaneous microdialysis, and (133)Xe clearance. Furthermore, a subcutaneous needle biopsy was performed to determine fat cell size. In the fasting state, interstitial lactate was 40% higher in relatives than in control subjects (P = 0.043), but net lactate production was similar in both groups. However, during the insulin clamp, interstitial lactate (2.50 +/- 0.29 vs. 1.98 +/- 0.26 mmol/l, P = 0.018), interstitial-arterial lactate concentration difference (1.08 +/- 0.30 vs. 0.53 +/- 0.24 mmol/l, P = 0.028), and net lactate release per fat cell (10.9 +/- 3.7 vs. 2.8 +/- 1.3 fmol. cell(-1). min(-1), P = 0.018) were increased in the relatives. We conclude that first-degree relatives of type 2 diabetic patients may have an enhanced net lactate release per fat cell in abdominal subcutaneous tissue. This could suggest a pathological regulation in adipose tissue that is of importance for the metabolic defects known in type 2 diabetic relatives.

  • 81.
    Satin, Leslie S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA.;Univ Michigan, Sch Med, Brehm Ctr Diabet Res, Ann Arbor, MI 48109 USA..
    Ha, Joon
    NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA..
    Sherman, Arthur S.
    NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA..
    Islets Transplanted Into the Eye: Do They Improve Our Insight Into Islet Adaptation to Insulin Resistance?2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 9, s. 2470-2472Artikel i tidskrift (Övrigt vetenskapligt)
  • 82.
    Schmidt, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för klinisk immunologi.
    Krook, Henrik
    Maeda, Akira
    Korsgren, Olle
    Benda, Birgitta
    A new murine model of islet xenograft rejection: Graft destruction is dependent on a major histocompatibility-specific interaction between T-cells and macrophages2003Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, nr 5, s. 1111-1118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new murine model of porcine islet-like cell cluster (ICC) xenograft rejection, avoiding interference of unspecific inflammation, was introduced and used to investigate rejection mechanisms. Athymic (nu/nu) mice were transplanted with syngeneic, allogeneic, or xenogeneic islets under the kidney capsule. After the original transplantation, immune cells in porcine ICC xenografts undergoing rejection in native immunocompetent mice were transferred to the peritoneal cavity of the athymic mice. At defined time points after transfer, the primary grafts were evaluated by immunohistochemistry and real-time quantitative RT-PCR to estimate cytokine and chemokine mRNA expression. Transfer of immunocompetent cells enabled athymic (nu/nu) mice to reject a previously tolerated ICC xenograft only when donor and recipient were matched for major histocompatibility complex (MHC). In contrast, allogeneic and syngeneic islets were not rejected. The ICC xenograft rejection was mediated by transferred T-cells. The main effector cells, macrophages, were shown to be part of a specific immune response. By day 4 after transplantation, there was an upreglation of both Th1- and Th2-associated cytokine transcripts. The transferred T-cells were xenospecific and required MHC compatibility to induce rejection. Interaction between the TCR of transferred T-cells and MHC on host endothelial cells and/or macrophages seems necessary for inducing ICC xenograft rejection.

  • 83. Scott, Robert A
    et al.
    Chu, Audrey Y
    Grarup, Niels
    Manning, Alisa K
    Hivert, Marie-France
    Shungin, Dmitry
    Tönjes, Anke
    Yesupriya, Ajay
    Barnes, Daniel
    Bouatia-Naji, Nabila
    Glazer, Nicole L
    Jackson, Anne U
    Kutalik, Zoltán
    Lagou, Vasiliki
    Marek, Diana
    Rasmussen-Torvik, Laura J
    Stringham, Heather M
    Tanaka, Toshiko
    Aadahl, Mette
    Arking, Dan E
    Bergmann, Sven
    Boerwinkle, Eric
    Bonnycastle, Lori L
    Bornstein, Stefan R
    Brunner, Eric
    Bumpstead, Suzannah J
    Brage, Soren
    Carlson, Olga D
    Chen, Han
    Chen, Yii-Der Ida
    Chines, Peter S
    Collins, Francis S
    Couper, David J
    Dennison, Elaine M
    Dowling, Nicole F
    Egan, Josephine S
    Ekelund, Ulf
    Erdos, Michael R
    Forouhi, Nita G
    Fox, Caroline S
    Goodarzi, Mark O
    Grässler, Jürgen
    Gustafsson, Stefan
    Hallmans, Göran
    Hansen, Torben
    Hingorani, Aroon
    Holloway, John W
    Hu, Frank B
    Isomaa, Bo
    Jameson, Karen A
    Johansson, Ingegerd
    Jonsson, Anna
    Jørgensen, Torben
    Kivimaki, Mika
    Kovacs, Peter
    Kumari, Meena
    Kuusisto, Johanna
    Laakso, Markku
    Lecoeur, Cécile
    Lévy-Marchal, Claire
    Li, Guo
    Loos, Ruth J F
    Lyssenko, Valeri
    Marmot, Michael
    Marques-Vidal, Pedro
    Morken, Mario A
    Müller, Gabriele
    North, Kari E
    Pankow, James S
    Payne, Felicity
    Prokopenko, Inga
    Psaty, Bruce M
    Renström, Frida
    Rice, Ken
    Rotter, Jerome I
    Rybin, Denis
    Sandholt, Camilla H
    Sayer, Avan A
    Shrader, Peter
    Schwarz, Peter E H
    Siscovick, David S
    Stancáková, Alena
    Stumvoll, Michael
    Teslovich, Tanya M
    Waeber, Gérard
    Williams, Gordon H
    Witte, Daniel R
    Wood, Andrew R
    Xie, Weijia
    Boehnke, Michael
    Cooper, Cyrus
    Ferrucci, Luigi
    Froguel, Philippe
    Groop, Leif
    Kao, W H Linda
    Vollenweider, Peter
    Walker, Mark
    Watanabe, Richard M
    Pedersen, Oluf
    Meigs, James B
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Barroso, Inês
    Florez, Jose C
    Franks, Paul W
    Dupuis, Josée
    Wareham, Nicholas J
    Langenberg, Claudia
    No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels2012Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, nr 5, s. 1291-1296Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

  • 84. Scott, Robert A
    et al.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pasko, Dorota
    Barker, Adam
    Sharp, Stephen J
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Barroso, Inês
    Boeing, Heiner
    Clavel-Chapelon, Françoise
    Crowe, Francesca L
    Dekker, Jacqueline M
    Fagherazzi, Guy
    Ferrannini, Ele
    Forouhi, Nita G
    Franks, Paul W
    Gavrila, Diana
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Grioni, Sara
    Groop, Leif C
    Kaaks, Rudolf
    Key, Timothy J
    Kühn, Tilman
    Lotta, Luca A
    Nilsson, Peter M
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quirós, J Ramón
    Rolandsson, Olov
    Roswall, Nina
    Sacerdote, Carlotta
    Sala, Núria
    Sánchez, María-José
    Schulze, Matthias B
    Siddiq, Afshan
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke Mw
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L
    Yaghootkar, Hanieh
    McCarthy, Mark I
    Semple, Robert K
    Riboli, Elio
    Walker, Mark
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Frayling, Tim M
    Savage, David B
    Langenberg, Claudia
    Wareham, Nicholas J
    Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity2014Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 12, s. 4378-4387Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-based measures of insulin resistance and secretion, and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs-per-allele [95%CI]:-0.03[-0.04,-0.01];p=0.004). This score was associated with lower BMI (-0.01[-0.01,-0.0;p=0.02) and gluteofemoral fat-mass (-0.03[-0.05,-0.02;p=1.4x10-6), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (0.02[0.01,0.03];p=0.001). While the secretion score had a stronger association with T2D in leaner individuals (pinteraction=0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI- or waist-strata(pinteraction>0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

  • 85.
    Scott, Robert A.
    et al.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Scott, Laura J.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Maegi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Marullo, Letizia
    Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy..
    Gaulton, Kyle J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Stanford Univ, Dept Genet, Stanford, CA USA..
    Kaakinen, Marika
    Imperial Coll London, Dept Genom Common Dis, London, England..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Pers, Tune H.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Boston Childrens Hosp, Div Endocrinol, Ctr Basic & Translat Obes Res, Boston, MA USA.;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark..
    Johnson, Andrew D.
    Natl Heart Lung & Blood Inst, Div Intramural Res, Framingham Heart Study Populat Sci Branch, Framingham, MA USA..
    Eicher, John D.
    Natl Heart Lung & Blood Inst, Div Intramural Res, Framingham Heart Study Populat Sci Branch, Framingham, MA USA..
    Jackson, Anne U.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Lee, Yeji
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Ma, Clement
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Steinthorsdottir, Valgerdur
    Amgen Inc, DECODE genet, Reykjavik, Iceland..
    Thorleifsson, Gudmar
    Amgen Inc, DECODE genet, Reykjavik, Iceland..
    Qi, Lu
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA..
    Van Zuydam, Natalie R.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Chen, Han
    Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Human Genet Ctr & Dept Epidemiol, Human Genet Environm Sci, Houston, TX USA.;Univ Texas Hlth Sci Ctr, Sch Biomed Informat, Sch Biomed Informat, Ctr Precis Hlth, Houston, TX USA..
    Almgren, Peter
    Lund Univ, Univ Hosp Scania, Dept Clin Sci Malmo, Lund Univ Diabet Ctr, Lund, Sweden..
    Voight, Ben F.
    Univ Penn sylvania, Perelman Sch Med, Dept Pharm, Philadelphia, PA USA.;Univ Pennsylvania, Perelman Sch Med, Dept Genet, Philadelphia, PA USA.;Univ Pennsylvania, Perelman Sch Medi cine, Inst Translat Med & Therapeut, Philadelphia, PA USA..
    Grallert, Harald
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Univ Hosp Grosshadern, Ludwig Maximilians Univ, Dep Med I, Munich, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat, Genet Epidemiol, Biometry & Epidemiol, Munich, Germany.;Munich Heart Alliance, German Ctr Cardiovascular Dis, Munich, Germany..
    Ried, Janina S.
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Rayner, Nigel W.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Hinxton, England..
    Robertson, Neil
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England..
    Karssen, Lennart C.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Polyomica S Hertogenbosch, Amsterdam, Netherlands..
    Van Leeuwen, Elisabeth M.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Willems, Sara M.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England.;Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Fuchsberger, Christian
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Kwan, Phoenix
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Teslovich, Tanya M.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Chanda, Pritam
    Johns Hopkins Univ Sch Med, High Throughput Biol Ctr, Baltimore, MD USA..
    Li, Man
    Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA..
    Lu, Yingchang
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA.;Icahn Sch Med, Genet Obes & Related Metab Traits Program, Mt Sinai, New York, NY USA..
    Dina, Christian
    Univ Nantes, CNRS, Inst Thorax, Ctr Hosp Univ Nantes, Nantes, France..
    Thuillier, Dorothee
    Lille Inst Biol, European Genom Inst Diabet, Lille, France.;Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Yengo, Loic
    Lille Inst Biol, European Genom Inst Diabet, Lille, France.;Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Jiang, Longda
    Imperial Coll London, Dept Genom Common Dis, London, England..
    Sparso, Thomas
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Kestler, Hans A.
    Fritz Lipmann Inst, Leibniz Inst Aging, Jena, Germany.;Univ Ulm, Inst Med Syst Biol, Ulm, Germany..
    Chheda, Himanshu
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Eisele, Lewin
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Franberg, Mattias
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Numer Anal & Comp Sci, Stockholm, Sweden..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden..
    Benediktsson, Rafn
    Univ Iceland, Fac Med, Reykjavik, Iceland.;Landspitali Univ Hosp, Reykjavik, Iceland..
    Hreidarsson, Astradur B.
    Landspitali Univ Hosp, Reykjavik, Iceland..
    Kong, Augustine
    Amgen Inc, DECODE genet, Reykjavik, Iceland..
    Sigurdsson, Gunnar
    Landspitali Univ Hosp, Reykjavik, Iceland.;Iceland Heart Assoc, Kopavogur, Iceland..
    Kerrison, Nicola D.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Luan, Jian'an
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Liang, Liming
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Biostatist, Boston, MA USA..
    Meitinger, Thomas
    Munich Heart Alliance, German Ctr Cardiovascular Dis, Munich, Germany.;Fritz Lipmann Inst, Leibniz Inst Aging, Jena, Germany.;Inst Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany. Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Roden, Michael
    German Ctr Diabet Res, Neuherberg, Germany.;Heinrich Heine Univ, Fac Med, Dept Endocrinol & Diabet, Dusseldorf, Germany.;Heinrich Heine Univ Dusseldorf, Leibniz Inst Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany..
    Thorand, Barbara
    German Ctr Diabet Res, Neuherberg, Germany..
    Esko, Tonu
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Boston Childrens Hosp, Divis Genet & Endocrinol, Boston, MA USA.;Natl Heart Lung & Blood Inst, Framingham Heart Study, Framingham, MA USA..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Fox, Caroline
    Harvard Med Sch, Divis Endocrinol, Diabet & Hypertens, Brigham & Womens Hosp, Boston, MA USA..
    Liu, Ching-Ti
    Boston Univ Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Rybin, Denis
    Boston Univ Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA..
    Isomaa, Bo
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Social Serv & Hlth Care, Pietarsaari, Finland..
    Lyssenko, Valeriya
    Lund Univ, Univ Hosp Scania, Dept Clin Sci Malmo, Lund Univ Diabet Ctr, Lund, Sweden..
    Tuomi, Tiinamaija
    Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland..
    Couper, David J.
    Univ N Carolina, Dept Biostatist, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA..
    Pankow, James S.
    Univ Minnesota, Divis Epidemiol Community Hlth, Minneapolis, MN USA..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Have, Christian T.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Jorgensen, Torben
    Capital Region Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark..
    Linneberg, Allan
    Capital Region Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshospitalet, Copenhagen, Denmark. Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, DK-1168 Copenhagen, Denmark..
    Cornelis, Marilyn C.
    NW Univ Feinberg Sch Med, Dept Prevent Med, Chicago, IL USA..
    Van Dam, Rob M.
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Hunter, David J.
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA..
    Kraft, Peter
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Biostatist, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA..
    Sun, Qi
    Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA..
    Edkins, Sarah
    Wellcome Trust Sanger Inst, Hinxton, England..
    Owen, Katharine R.
    Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England.;Natl Inst Hlth Res Oxford Biomed Res Ctr, Churchill Hosp, Oxford, England..
    Perry, John R. B.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Wood, Andrew R.
    Univ Exeter Med Sch, Univ Exeter, Genet Complex Traits, Exeter, Devon, England..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Hinxton, England..
    Tajes-Fernandes, Juan
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Abecasis, Goncalo R.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Bonnycastle, Lori L.
    Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD USA..
    Chines, Peter S.
    Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD USA..
    Stringham, Heather M.
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Helsinki Univ Cent Hosp, Dept Med & Abdominal Ctr, Endocrinol, Helsinki, Finland.;Biomedicum Helsinki 2U, Minerva Fdn Inst Med Res, Helsinki, Finland..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Helsinki Univ Cent Hosp, Dept Med & Abdominal Ctr, Endocrinol, Helsinki, Finland.;Biomedicum Helsinki 2U, Minerva Fdn Inst Med Res, Helsinki, Finland..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden..
    Muehleisen, Thomas W.
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Dept Genom, Life Brain Ctr, Bonn, Germany..
    Noethen, Markus M.
    Univ Bonn, Inst Human Genet, Bonn, Germany.;Univ Bonn, Dept Genom, Life Brain Ctr, Bonn, Germany..
    Pechlivanis, Sonali
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    Baldassarre, Damiano
    Ist Ricovero Cura Carattere Sci, Ctr Cardiologico Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol Biomol, Milan, Italy..
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden..
    Humphries, Steve E.
    UCL, Inst Cardiovascular Sci, BHF Labs, Cardiovascular Genet, London, England..
    Tremoli, Elena
    Ist Ricovero Cura Carattere Sci, Ctr Cardiologico Monzino, Milan, Italy.;Univ Milan, Dipartimento Sci Farmacol Biomol, Milan, Italy..
    Klopp, Norman
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany..
    Meyer, Julia
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Steinbach, Gerald
    Univ Ulm, Dept Clin Chem & Cent Lab, Ulm, Germany..
    Wennauer, Roman
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Eriksson, Johan G.
    Folkhalsan Res Ctr, Helsinki, Finland.;Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Helsinki Univ Cent Hosp, Unit Gen Practice, Helsinki, Finland..
    Mannisto, Satu
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Peltonen, Leena
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Broad Inst & Harvard, Cambridge, MA USA..
    Tikkanen, Emmi
    Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland..
    Charpentier, Guillaume
    Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France..
    Eury, Elodie
    Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Lobbens, Stephane
    Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Gigante, Bruna
    Inst Environm Medi cine, Karolinska Inst, Divis Cardiovascular Epidemiol, Stockholm, Sweden..
    Leander, Karin
    Inst Environm Medi cine, Karolinska Inst, Divis Cardiovascular Epidemiol, Stockholm, Sweden..
    McLeod, Olga
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden..
    Bottinger, Erwin P.
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Gottesman, Omri
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Ruderfer, Douglas
    Icahn Sch Med, Dept Psychiat, Divis Psychiat Genom, Mt Sinai, New York, NY USA..
    Blueher, Matthias
    Univ Leipzig, IFB Adiposity Dis, Leipzig, Germany.;Univ Leipzig, Dept Med, Leipzig, Germany..
    Kovacs, Peter
    Univ Leipzig, IFB Adiposity Dis, Leipzig, Germany.;Univ Leipzig, Dept Med, Leipzig, Germany..
    Tonjes, Anke
    Univ Leipzig, IFB Adiposity Dis, Leipzig, Germany.;Univ Leipzig, Dept Med, Leipzig, Germany..
    Maruthur, Nisa M.
    Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA.;Johns Hopkins Bloomberg Sch Med, Dept Med, Divis Gen Internal Med, Baltimore, MD USA.;Johns Hopkins Univ, Welch Ctr Prevent, Epidemiol & Clin Res, Baltimore, MD USA..
    Scapoli, Chiara
    Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy..
    Erbel, Raimund
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    Joeckel, Karl-Heinz
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    Moebus, Susanne
    Univ Hosp Essen, Inst Med Informat, Biometry & Epidemiol, Essen, Germany..
    De Faire, Ulf
    Inst Environm Medi cine, Karolinska Inst, Divis Cardiovascular Epidemiol, Stockholm, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovascular Med Unit, Stockholm, Sweden..
    Stumvoll, Michael
    Univ Leipzig, IFB Adiposity Dis, Leipzig, Germany.;Univ Leipzig, Dept Med, Leipzig, Germany..
    Deloukas, Panagiotis
    Wellcome Trust Sanger Inst, Hinxton, England.;Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England..
    Donnelly, Peter J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Frayling, Timothy M.
    Univ Exeter Med Sch, Univ Exeter, Genet Complex Traits, Exeter, Devon, England..
    Hattersley, Andrew T.
    Univ Exeter Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England..
    Ripatti, Samuli
    Wellcome Trust Sanger Inst, Hinxton, England.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland.;Univ Helsinki, Hjelt Inst, Dept Publ Hlth, Helsinki, Finland.;Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Pedersen, Nancy L.
    Karolinska Inst tutet, Dept Med Epidemiol & Biostatist, Stockholm, Sweden..
    Boehm, Bernhard O.
    Univ Med Ctr Ulm, Dept Internal Med, Divis Endocrinol & Diabet, Ulm, Germany.;Nanyang Technol Univ, Imperial Coll London, Lee Kong Chian Sch Med, Singapore, Singapore..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabetes & Obes Res Inst, Los Angeles, CA USA..
    Collins, Francis S.
    Natl Human Genome Res Inst, Natl Inst Hlth, Bethesda, MD USA..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland.;Dasman Diabet Inst, Dasman, Kuwait.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabetes Res Grp, Jeddah, Saudi Arabia..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Univ So Denmark, Fac Hlth Sci, Odense, Denmark..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Hinxton, England.;Addenbrookes Hosp Cambridge, Wellcome Trust MRC Inst Metab Sci, Hlth Res Cambridge Biomed Res Ctr, Cambridge, England.;Univ Cambridge Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Hlth Res Cambridge Biomed Res Ctr, Cambridge, England..
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Broad Inst & Harvard, Cambridge, MA USA..
    Cauchi, Stephane
    Lille Inst Biol, European Genom Inst Diabet, Lille, France..
    Froguel, Philippe
    Imperial Coll London, Dept Genom Common Dis, London, England.;Lille Inst Biol, European Genom Inst Diabet, Lille, France.;Univ Lille, CNRS UMR 8199, European Genom Inst Diabet EGID, Inst Pasteur Lille, Lille, France..
    Loos, Ruth J. F.
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA.;Icahn Sch Med, Genet Obes & Related Metab Traits Program, Mt Sinai, New York, NY USA.;Mindich Child Hlth & Dev Inst, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Balkau, Beverley
    INSERM, CESP, UMR 1018, Villejuif, France.;Univ Paris Sud, UMR 1018, Villejuif, France..
    Boeing, Heiner
    German Inst Human Nutr Potsdam Rehbrucke, Nuthetal, Germany..
    Franks, Paul W.
    Lund Univ, Malmo, Sweden.;Umea Univ, Umea, Sweden..
    Gurrea, Aurelio Barricarte
    Navarra Publ Hlth Inst, Pamplona, Spain.;Navarra Inst Hlth Res, Pamplona, Spain.;CIBER Epidemiol & Publ Hlth, Madrid, Spain..
    Palli, Domenico
    Canc Res & Prevent Inst, Florence, Italy..
    Van der Schouw, Yvonne T.
    Univ Med Ctr Utrecht, Utrecht, Netherlands..
    Altshuler, David
    Broad Inst & Harvard, Cambridge, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Harvard Med Sch, Dept Mol Biol, Boston, MA USA.;Massachusetts Gen Hosp, Diabet Unit, Boston, MA USA..
    Groop, Leif C.
    Lund Univ, Univ Hosp Scania, Dept Clin Sci Malmo, Lund Univ Diabet Ctr, Lund, Sweden.;Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland..
    Langenberg, Claudia
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Wareham, Nicholas J.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Sijbrands, Eric
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Healthy Ageing & Ctr Med Syst Biol, Netherlands Consortium, Netherlands Genom Initiat, Rotterdam, Netherlands..
    Florez, Jose C.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Diabet Unit, Boston, MA USA..
    Meigs, James B.
    Broad Inst & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Amgen Inc, DECODE genet, Reykjavik, Iceland.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Gen Med Divis, Boston, MA USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr, Human Genet Ctr, Houston, TX USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX USA..
    Gieger, Christian
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;German Res Ctr Environm Hlth, Inst Epidemiol II, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat, Genet Epidemiol, Biometry & Epidemiol, Munich, Germany..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Tartu, Estonia..
    Morris, Andrew D.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Palmer, Colin N. A.
    Univ Dundee, Biomed Res Inst, Ninewells Hosp, Cardiovascular & Diabet Med, Dundee, Scotland..
    Hu, Frank B.
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard T H Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA.;Harvard Med Sch, Boston, MA USA..
    Thorsteinsdottir, Unnur
    Amgen Inc, DECODE genet, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Stefansson, Kari
    Amgen Inc, DECODE genet, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Dupuis, Josee
    Boston Univ Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Morris, Andrew P.
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.;Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England..
    Boehnke, Michael
    Univ Michigan, Dept Biostatist & Ctr Stat Genet, Ann Arbor, MI USA..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England.;Natl Inst Hlth Res Oxford Biomed Res Ctr, Churchill Hosp, Oxford, England..
    Prokopenko, Inga
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Imperial Coll London, Dept Genom Common Dis, London, England.;Univ Oxford, Oxford Ctr Diabet, Endocrinol & Metab, Oxford, England..
    An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans2017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 11, s. 2888-2902Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

  • 86.
    Sivaskandarajah, Gavasker A
    et al.
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Maezawa, Yoshiro
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Eremina, Vera
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Baelde, Hans J
    Quaggin, Susan E
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Vegfa protects the glomerular microvasculature in diabetes2012Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, nr 11, s. 2958-2966Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vascular endothelial growth factor A (VEGFA) expression is increased in glomeruli in the context of diabetes. Here, we tested the hypothesis that this upregulation of VEGFA protects the glomerular microvasculature in diabetes and that therefore inhibition of VEGFA will accelerate nephropathy. To determine the role of glomerular Vegfa in the development and progression of diabetic nephropathy, we used an inducible Cre-loxP gene-targeting system that enabled genetic deletion of Vegfa selectively from glomerular podocytes of wild-type or diabetic mice. Type 1 diabetes was induced in mice using streptozotocin (STZ). We then assessed the extent of glomerular dysfunction by measuring proteinuria, glomerular pathology, and glomerular cell apoptosis. Vegfa expression increased in podocytes in the STZ model of diabetes. After 7 weeks of diabetes, diabetic mice lacking Vegfa in podocytes exhibited significantly greater proteinuria with profound glomerular scarring and increased apoptosis compared with control mice with diabetes or Vegfa deletion without diabetes. Reduced local production of glomerular Vegfa in a mouse model of type 1 diabetes promotes endothelial injury accelerating the progression of glomerular injury. These results suggest that upregulation of VEGFA in diabetic kidneys protects the microvasculature from injury and that reduction of VEGFA in diabetes may be harmful.

  • 87.
    Skog, Oskar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Comment on Rodriguez-Calvo et al. Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset. Diabetes 2017;66:1334-13452017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 9, s. e8-e9Artikel i tidskrift (Övrigt vetenskapligt)
  • 88. Strawbridge, Rona J.
    et al.
    Dupuis, Josee
    Prokopenko, Inga
    Barker, Adam
    Ahlqvist, Emma
    Rybin, Denis
    Petrie, John R.
    Travers, Mary E.
    Bouatia-Naji, Nabila
    Dimas, Antigone S.
    Nica, Alexandra
    Wheeler, Eleanor
    Chen, Han
    Voight, Benjamin F.
    Taneera, Jalal
    Kanoni, Stavroula
    Peden, John F.
    Turrini, Fabiola
    Gustafsson, Stefan
    Zabena, Carina
    Almgren, Peter
    Barker, David J. P.
    Barnes, Daniel
    Dennison, Elaine M.
    Eriksson, Johan G.
    Eriksson, Per
    Eury, Elodie
    Folkersen, Lasse
    Fox, Caroline S.
    Frayling, Timothy M.
    Goel, Anuj
    Gu, Harvest F.
    Horikoshi, Momoko
    Isomaa, Bo
    Jackson, Anne U.
    Jameson, Karen A.
    Kajantie, Eero
    Kerr-Conte, Julie
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Loos, Ruth J. F.
    Luan, Jian'an
    Makrilakis, Konstantinos
    Manning, Alisa K.
    Teresa Martinez-Larrad, Maria
    Narisu, Narisu
    Mannila, Maria Nastase
    Ohrvik, John
    Osmond, Clive
    Pascoe, Laura
    Payne, Felicity
    Sayer, Avan A.
    Sennblad, Bengt
    Silveira, Angela
    Stancakova, Alena
    Stirrups, Kathy
    Swift, Amy J.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tuomi, Tiinamaija
    van 't Hooft, Ferdinand M.
    Walker, Mark
    Weedon, Michael N.
    Xie, Weijia
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ongen, Halit
    Malarstig, Anders
    Hopewell, Jemma C.
    Saleheen, Danish
    Chambers, John
    Parish, Sarah
    Danesh, John
    Kooner, Jaspal
    Ostenson, Claes-Goran
    Lind, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Cooper, Cyrus C.
    Serrano-Rios, Manuel
    Ferrannini, Ele
    Forsen, Tom J.
    Clarke, Robert
    Franzosi, Maria Grazia
    Seedorf, Udo
    Watkins, Hugh
    Froguel, Philippe
    Johnson, Paul
    Deloukas, Panos
    Collins, Francis S.
    Laakso, Markku
    Dermitzakis, Emmanouil T.
    Boehnke, Michael
    McCarthy, Mark I.
    Wareham, Nicholas J.
    Groop, Leif
    Pattou, Francois
    Gloyn, Anna L.
    Dedoussis, George V.
    Lyssenko, Valeriya
    Meigs, James B.
    Barroso, Ines
    Watanabe, Richard M.
    Ingelsson, Erik
    Langenberg, Claudia
    Hamsten, Anders
    Florez, Jose C.
    Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes2011Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 10, s. 2624-2634Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE-Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS-We have conducted a meta-analysis of genome-wide association tests of similar to 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS-Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC3OA8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS-We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. 

  • 89.
    Strawbridge, Rona J.
    et al.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Hilding, Agneta
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Silveira, Angela
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Österholm, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Nova Southeastern Univ, Cell Therapy Inst, Ft Lauderdale, FL USA..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Stockholm, Sweden..
    McLeod, Olga
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Tsikrika, Panagiota
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Foroogh, Fariba
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Tremoli, Elena
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy.;Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy..
    Baldassarre, Damiano
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy.;Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy..
    Veglia, Fabrizio
    Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy..
    Rauramaa, Rainer
    Fdn Res Hlth Exercise & Nutr, Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Smit, Andries J.
    Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands..
    Giral, Phillipe
    Grp Hosp Pitie Salpetriere, Assistance Publ Hop Paris, Serv Endocrinol Metab, Unites Prevent Cardiovasc, Paris, France..
    Kurl, Sudhir
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, Kuopio, Finland..
    Mannarino, Elmo
    Univ Perugia, Dept Clin & Expt Med, Internal Med Angiol & Arteriosclerosis Dis, Perugia, Italy..
    Grossi, Enzo
    Bracco Med Dept, Milan, Italy..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Humphries, Steve E.
    UCL, Ctr Cardiovasc Genet, London, England..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Östenson, Claes-Goran
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Maegdefessel, Lars
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Backlund, Alexandra
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 10, s. 2888-2899Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean 6 SD 156.6 +/- 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 +/- 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe(-/-) cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.

  • 90. Thanabalasingham, Gaya
    et al.
    Huffman, Jennifer E.
    Kattla, Jayesh J.
    Novokmet, Mislav
    Rudan, Igor
    Gloyn, Anna L.
    Hayward, Caroline
    Adamczyk, Barbara
    Reynolds, Rebecca M.
    Muzinic, Ana
    Hassanali, Neelam
    Pucic, Maja
    Bennett, Amanda J.
    Essafi, Abdelkader
    Polasek, Ozren
    Mughal, Saima A.
    Redzic, Irma
    Primorac, Dragan
    Zgaga, Lina
    Kokic, Ivana
    Hansen, Torben
    Gasperikova, Daniela
    Tjora, Erling
    Strachan, Mark W. J.
    Nielsen, Trine
    Stanik, Juraj
    Klimes, Iwar
    Pedersen, Oluf B.
    Njolstad, Pal R.
    Wild, Sarah H.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Gornik, Olga
    Wilson, James F.
    Hastie, Nicholas D.
    Campbell, Harry
    McCarthy, Mark I.
    Rudd, Pauline M.
    Owen, Katharine R.
    Lauc, Gordan
    Wright, Alan F.
    Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile2013Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, nr 4, s. 1329-1337Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A recent genome-wide association study identified hepatocyte nuclear factor 1-alpha (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MOD?) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCE)-MODY (n = 118), hepatocyte nuclear factor 4-alpha (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic >= 0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction.

  • 91.
    Thore, Sophia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Wuttke, Anne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Rapid turnover of phosphatidylinositol-4,5-bisphosphate in insulin-secreting cells mediated by Ca2+ and the ATP-to-ADP ratio2007Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, nr 3, s. 818-826Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Phosphatidylinositol-4,5-bisphosphate (PIP2) is important for a variety of cellular processes as a precursor for second messengers and by regulating ion channels, the cytoskeleton, and vesicle traffic in many types of cells, including insulin-secreting β-cells. Here, we applied evanescent wave microscopy and the PIP2-binding pleckstrin homology domain from phospholipase C (PLC)-δ fused to the green fluorescent protein to characterize the regulation of plasma membrane PIP2 in individual insulin-secreting MIN6 β-cells. Elevation of the glucose concentration from 3 to 11 mmol/l evoked antisynchronous oscillations of [PIP2] and cytoplasmic Ca2+concentration, consistent with PLC being periodically activated by the voltage-dependent Ca2+ influx. The effect of adenine nucleotides on [PIP2] was studied in cells permeabilized with α-toxin. ATP dose- dependently stimulated PIP2 synthesis with half-maximal effect at 300 μmol/l. Omission of the nucleotide resulted in rapid loss of PIP2 with t1/2 < 40 s. ADP also stimulated PIP2 formation, but this effect reflected local ATP formation and was prevented by the adenylate kinase inhibitor diadenosine-pentaphosphate. The ATP-induced PIP2 synthesis was counteracted by the ADP analog adenosine-5′-O-2-thiodiphosphate. We conclude that plasma membrane PIP2 is dynamically regulated by intracellular Ca2+ and the ATP-to-ADP ratio in insulin-secreting cells. The rapid turnover allows maintenance of PIP2 levels while generating second messengers of critical importance for insulin secretion.

  • 92.
    Tian, Geng
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, Stellan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gylfe, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Glucose- and Hormone-Induced cAMP Oscillations in α- and β-Cells Within Intact Pancreatic Islets2011Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 5, s. 1535-1543Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE

    cAMP is a critical messenger for insulin and glucagon secretion from pancreatic beta- and alpha-cells, respectively. Dispersed beta-cells show cAMP oscillations, but the signaling kinetics in cells within intact islets of Langerhans is unknown.

    RESEARCH DESIGN AND METHODS

    The subplasma-membrane cAMP concentration ([cAMP](pm)) was recorded in alpha-and beta-cells in the mantle of intact mouse pancreatic islets using total internal reflection microscopy and a fluorescent translocation biosensor. Cell identification was based on the opposite effects of adrenaline on cAMP in alpha- and beta-cells.

    RESULTS

    In islets exposed to 3 mmol/L glucose, [cAMP](pm) was low and stable. Glucagon and glucagon-like peptide-1(7-36)-amide (GLP-1) induced dose-dependent elevation of [cAMP](pm), often with oscillations synchronized among beta-cells. Whereas glucagon also induced [cAMP](pm) oscillations in most alpha-cells, < 20% of the alpha-cells responded to GLP-1. Elevation of the glucose concentration to 11-30 mmol/L in the absence of hormones induced slow [cAMP](pm) oscillations in both alpha- and beta-cells. These cAMP oscillations were coordinated with those of the cytoplasmic Ca2+ concentration ([Ca2+](i)) in the beta-cells but not caused by the changes in [Ca2+](i) . The transmembrane adenylyl cyclase (AC) inhibitor 2'5'-dideoxyadenosine suppressed the glucose- and hormone-induced [cAMP](pm) elevations, whereas the preferential inhibitors of soluble AC, KH7, and 1,3,5(10)-estratrien-2,3,17-beta-triol perturbed cell metabolism and lacked effect, respectively.

    CONCLUSIONS

    Oscillatory [cAMP](pm) signaling in secretagogue-stimulated beta-cells is maintained within intact islets and depends on transmembrane AC activity. The discovery of glucose- and glucagon-induced [cAMP](pm) oscillations in alpha-cells indicates the involvement of cAMP in the regulation of pulsatile glucagon secretion.

  • 93.
    Tian, Geng
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sol, Eri Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Xu, Yunjian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Shuai, Hongyan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Impaired cAMP generation contributes to defective glucose-stimulated insulin secretion after long-term exposure to palmitate2015Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 3, s. 904-915Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chronic palmitate exposure impairs glucose-stimulated insulin secretion and other aspects of β-cell function but the underlying mechanisms are not known. Using various live-cell fluorescence imaging approaches we show here that long-term palmitate treatment influences cAMP signaling in pancreatic β-cells. Glucose stimulation of mouse and human β-cells induced oscillations of the sub-plasma-membrane cAMP concentration but after 48 h exposure to palmitate, most β-cells failed to increase cAMP in response to glucose. In contrast, GLP-1-triggered cAMP formation and glucose- and depolarization-induced increases in cytoplasmic Ca2+ concentration were unaffected by the fatty acid treatment. Insulin secretion from control β-cells was pulsatile but the response deteriorated after long-term palmitate exposure. Palmitate-treated mouse islets showed reduced expression of adenylyl cyclase 9 and knockdown of this protein in insulinoma cells reduced the glucose-stimulated cAMP response and insulin secretion. We conclude that impaired glucose-induced generation of cAMP is an important determinant of defective insulin secretion after chronic palmitate exposure.

  • 94.
    Treebak, Jonas T
    et al.
    Department of Human Physiology, Institute of Exercise and Sport Sciences, Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark.
    Glund, Stephan
    Department of Molecular Medicine and Surgery, Section Integrative Physiology, Karolinska Institute, Stockholm, Sweden.
    Deshmukh, Atul
    Department of Molecular Medicine and Surgery, Section Integrative Physiology, Karolinska Institute, Stockholm, Sweden.
    Klein, Ditte K
    Department of Human Physiology, Institute of Exercise and Sport Sciences, Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark.
    Long, Yun Chau
    Department of Molecular Medicine and Surgery, Section Integrative Physiology, Karolinska Institute, Stockholm, Sweden.
    Jensen, Thomas E
    Department of Human Physiology, Institute of Exercise and Sport Sciences, Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark.
    Jörgensen, Sebastian B
    Department of Human Physiology, Institute of Exercise and Sport Sciences, Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark.
    Viollet, Benoit
    René Descartes University, Institute Cochin, Paris, France.
    Andersson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Neumann, Dietbert
    Swiss Federal Institute of Technology, Zurich, Switzerland.
    Wallimann, Theo
    Swiss Federal Institute of Technology, Zurich, Switzerland.
    Richter, Erik A
    Department of Human Physiology, Institute of Exercise and Sport Sciences, Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark.
    Chibalin, Alexander V
    Department of Molecular Medicine and Surgery, Section Integrative Physiology, Karolinska Institute, Stockholm, Sweden.
    Zierath, Juleen R
    Department of Molecular Medicine and Surgery, Section Integrative Physiology, Karolinska Institute, Stockholm, Sweden.
    Wojtaszewski, Jörgen F P
    Department of Human Physiology, Institute of Exercise and Sport Sciences, Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark.
    AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits.2006Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, nr 7, s. 2051-2058Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AMP-activated protein kinase (AMPK) is a heterotrimeric protein that regulates glucose transport mediated by cellular stress or pharmacological agonists such as 5-aminoimidazole-4-carboxamide 1 beta-D-ribonucleoside (AICAR). AS160, a Rab GTPase-activating protein, provides a mechanism linking AMPK signaling to glucose uptake. We show that AICAR increases AMPK, acetyl-CoA carboxylase, and AS160 phosphorylation by insulin-independent mechanisms in isolated skeletal muscle. Recombinant AMPK heterotrimeric complexes (alpha 1 beta 1 gamma l and alpha 2 beta 2 gamma 1) phosphorylate AS160 in a cell-free assay. In mice deficient in AMPK signaling (alpha 2 AMPK knockout [KO], alpha 2 AMPK kinase dead [KD], and gamma 3 AMPK KO), AICAR effects on AS160 phosphorylation were severely blunted, highlighting that complexes containing alpha 2 and gamma 3 are necessary for AICAR-stimulated AS160 phosphorylation in intact skeletal muscle. Contraction-mediated AS160 phosphorylation was also impaired in alpha 2 AMPK KO and KD but not gamma 3 AMPK KO mice. Our results implicate AS160 as a downstream target of AMPK.

  • 95. Vessby, B
    et al.
    Aro, A
    Skarfors, E
    Berglund, L
    Salminen, I
    Lithell, H
    The risk to develop NIDDM is related to the fatty acid composition of the serum cholesterol esters.1994Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 43, nr 11, s. 1353-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This investigation was undertaken to study whether the risk to develop non-insulin-dependent diabetes mellitus (NIDDM) among 50-year-old men during a 10-year follow-up period was related to the fatty acid composition of their serum cholesterol esters. There were highly significant differences in the initial health survey between the fatty acid composition in serum in subjects who remained normoglycemic (n = 1,753) and in those who later developed NIDDM (n = 75). The main differences were that the latter had higher proportions of saturated fatty acids and palmitoleic acid (16:1 omega-7), a low proportion of linoleic acid (18:2 omega-6), and a relatively high content of gamma-linolenic (18:3 omega-6) and dihomo-gamma-linolenic (20:3 omega-6) acids in the serum cholesterol esters. The picture was similar also after adjusting for differences in body mass index. In a logistic model, a high proportion of dihomo-gamma-linolenic acid remained a significant contributor to the development of diabetes, along with the height of the insulin index, the blood glucose concentration at 60 min, and the fasting insulin concentration. The increased risk to develop NIDDM related to the serum cholesterol ester fatty acid composition may be mediated by diet and/or genetic factors.

  • 96.
    Walford, Geoffrey A.
    et al.
    Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA 02115 USA..
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rybin, Denis
    Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA..
    Stancakova, Alena
    Univ Eastern Finland, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Chen, Han
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Liu, Ching-Ti
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Hong, Jaeyoung
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Jensen, Richard A.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA USA..
    Rice, Ken
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Morris, Andrew P.
    Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Toenjes, Anke
    Univ Leipzig, Dept Med, Leipzig, Germany..
    Prokopenko, Inga
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Imperial Coll London, Dept Genom Common Dis, London, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany..
    Delgado, Graciela
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany..
    Silbernagel, Guenther
    Med Univ Graz, Dept Internal Med, Div Angiol, Graz, Austria..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Appel, Emil V.
    Univ Copenhagen, Fac Hlth & Med Sci, Ctr Basic Metab Res, Novo Nordisk Fdn, Copenhagen, Denmark..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Ctr Basic Metab Res, Novo Nordisk Fdn, Copenhagen, Denmark..
    Lewis, Joshua P.
    Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA.;Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA..
    Montasser, May E.
    Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA.;Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA..
    Ladenvall, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden.
    Staiger, Harald
    Univ Tubingen Hosp, Div Endocrinol & Diabetol Angiol Nephrol & Clin C, Dept Internal Med, Tubingen, Germany.;German Ctr Diabet Res DZD, Tubingen, Germany.;Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England..
    Frayling, Timothy M.
    Univ Exeter, Sch Med, Exeter, Devon, England..
    Weedon, Michael N.
    Univ Exeter, Sch Med, Exeter, Devon, England..
    Xie, Weijia
    Univ Exeter, Sch Med, Exeter, Devon, England..
    Morcillo, Sonsoles
    CIBER Pathophysiol Obes & Nutr, Madrid, Spain.;Hosp Reg Univ Malaga, Dept Endocrinol & Nutr, Malaga, Spain..
    Teresa Martinez-Larrad, Maria
    Hosp Clin San Carlos IdISSC, Spanish Biomed Res Ctr Diabet & Associated Metab, Inst Invest Sanitaria, Madrid, Spain..
    Biggs, Mary L.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Chen, Yii-Der Ida
    Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Med, LABioMed, Torrance, CA 90509 USA..
    Corbaton-Anchuelo, Arturo
    Hosp Clin San Carlos IdISSC, Spanish Biomed Res Ctr Diabet & Associated Metab, Inst Invest Sanitaria, Madrid, Spain..
    Faerch, Kristine
    Steno Diabet Ctr, Gentofte, Denmark..
    Miguel Gomez-Zumaquero, Juan
    Inst Invest Biomed Malaga IBIMA, Malaga, Spain.;Hosp Carlos Haya Malaga, Sequencing & Genotyping Platform, Malaga, Spain..
    Goodarzi, Mark O.
    Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA..
    Kizer, Jorge R.
    Albert Einstein Coll Med, Dept Med, Bronx, NY 10467 USA.;Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA.;Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Minerva Fdn, Inst Med Res, Biomedicum 2U, Helsinki, Finland.;Univ Helsinki, Dept Med, Helsinki, Finland.;Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Leong, Aaron
    Harvard Med Sch, Dept Med, Boston, MA 02115 USA.;Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindgren, Cecilia
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA USA..
    Machicao, Fausto
    German Ctr Diabet Res DZD, Tubingen, Germany.;Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany..
    Manning, Alisa K.
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA 02115 USA.;Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA USA..
    Maria Martin-Nunez, Gracia
    Hosp Reg Univ & Virgen de la Victoria Malaga, Dept Endocrinol & Nutr, Malaga, Spain..
    Rojo-Martinez, Gemma
    Hosp Reg Univ Malaga, Dept Endocrinol & Nutr, Malaga, Spain.;Inst Invest Biomed Malaga IBIMA, Malaga, Spain.;CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Med, LABioMed, Torrance, CA 90509 USA..
    Siscovick, David S.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;New York Acad Med, New York, NY USA..
    Zmuda, Joseph M.
    Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA..
    Zhang, Zhongyang
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA..
    Serrano-Rios, Manuel
    Hosp Clin San Carlos IdISSC, Spanish Biomed Res Ctr Diabet & Associated Metab, Inst Invest Sanitaria, Madrid, Spain..
    Smith, Ulf
    Univ Gothenburg, Sahlgrenska Acad, Dept Mol & Clin Med, Lundberg Lab Diabet Res, Gothenburg, Sweden..
    Soriguer, Federico
    Hosp Reg Univ Malaga, Dept Endocrinol & Nutr, Malaga, Spain.;Inst Invest Biomed Malaga IBIMA, Malaga, Spain.;CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Ctr Basic Metab Res, Novo Nordisk Fdn, Copenhagen, Denmark..
    Jorgensen, Torben J.
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, Copenhagen, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark.;Res Ctr Prevent & Hlth, Copenhagen, Denmark..
    Linnenberg, Allan
    Res Ctr Prevent & Hlth, Copenhagen, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Ctr Basic Metab Res, Novo Nordisk Fdn, Copenhagen, Denmark..
    Walker, Mark
    Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England..
    Scott, Robert A.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England..
    Fritsche, Andreas
    Univ Tubingen Hosp, Div Endocrinol & Diabetol Angiol Nephrol & Clin C, Dept Internal Med, Tubingen, Germany.;German Ctr Diabet Res DZD, Tubingen, Germany.;Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany..
    Haering, Hans-Ulrich
    Univ Tubingen Hosp, Div Endocrinol & Diabetol Angiol Nephrol & Clin C, Dept Internal Med, Tubingen, Germany.;German Ctr Diabet Res DZD, Tubingen, Germany.;Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany..
    Stefan, Norbert
    Univ Tubingen Hosp, Div Endocrinol & Diabetol Angiol Nephrol & Clin C, Dept Internal Med, Tubingen, Germany.;German Ctr Diabet Res DZD, Tubingen, Germany.;Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany..
    Groop, Leif
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    O'Connell, Jeff R.
    Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA.;Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Bergman, Richard N.
    Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA USA..
    Collins, Francis S.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.;Dasman Diabet Inst, Dasman, Kuwait..
    Maerz, Winfried
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Heidelberg, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria.;Synlab Serv GmbH, Synlab Acad, Mannheim, Germany.;Synlab Serv GmbH, Synlab Acad, Augsburg, Germany..
    Kovacs, Peter
    Univ Leipzig, Integrated Res & Treatment IFB Ctr AdiposityDis, Leipzig, Germany..
    Stumvoll, Michael
    Univ Leipzig, Dept Med, Leipzig, Germany..
    Psaty, Bruce M.
    Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Seattle, WA USA.;Univ Washington, Epidemiol & Hlth Serv, Seattle, WA 98195 USA.;Grp Hlth Res Inst, Seattle, WA USA.;Grp Hlth Cooperat Puget Sound, Seattle, WA USA..
    Kuusisto, Johanna
    Kuopio Univ Hosp, Kuopio, Finland.;Univ Eastern Finland, Dept Med, Kuopio, Finland..
    Laakso, Markku
    Kuopio Univ Hosp, Kuopio, Finland.;Univ Eastern Finland, Dept Med, Kuopio, Finland..
    Meigs, James B.
    Harvard Med Sch, Dept Med, Boston, MA 02115 USA.;Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA.;Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA USA..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Med, Sch Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Florez, Jose C.
    Massachusetts Gen Hosp, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA 02115 USA..
    Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 10, s. 3200-3211Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 x 10(-11)), rs12454712 (BCL2; P = 2.7 x 10(-8)), and rs10506418 (FAM19A2; P = 1.9 x 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

  • 97. Wendt, Anna
    et al.
    Birnir, Bryndis
    Department of Physiological Sciences, Lund University.
    Buschard, Karsten
    Gromada, Jesper
    Salehi, Albert
    Sewing, Sabine
    Rorsman, Patrik
    Braun, Matthias
    Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells.2004Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 53, nr 4, s. 1038-45Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    gamma-Aminobutyric acid (GABA) has been proposed to function as a paracrine signaling molecule in islets of Langerhans. We have shown that rat beta-cells release GABA by Ca(2+)-dependent exocytosis of synaptic-like microvesicles. Here we demonstrate that GABA thus released can diffuse over sufficient distances within the islet interstitium to activate GABA(A) receptors in neighboring cells. Confocal immunocytochemistry revealed the presence of GABA(A) receptors in glucagon-secreting alpha-cells but not in beta- and delta-cells. RT-PCR analysis detected transcripts of alpha(1) and alpha(4) as well as beta(1-3) GABA(A) receptor subunits in purified alpha-cells but not in beta-cells. In whole-cell voltage-clamp recordings, exogenous application of GABA activated Cl(-) currents in alpha-cells. The GABA(A) receptor antagonist SR95531 was used to investigate the effects of endogenous GABA (released from beta-cells) on pancreatic islet hormone secretion. The antagonist increased glucagon secretion at 1 mmol/l glucose twofold and completely abolished the inhibitory action of 20 mmol/l glucose on glucagon release. Basal and glucose-stimulated secretion of insulin and somatostatin were unaffected by SR95531. The L-type Ca(2+) channel blocker isradipine evoked a paradoxical stimulation of glucagon secretion. This effect was not observed in the presence of SR95531, and we therefore conclude that isradipine stimulates glucagon secretion by inhibition of GABA release.

  • 98.
    Wentzel, Parri
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ejdesjö, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Maternal Diabetes In Vivo and High Glucose In Vitro Diminish GAPDHActivity in Rat Embryos2003Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, nr 5, s. 1222-1228Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of the present study was to investigate whether diabetic embryopathy may be associated with the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) resulting from an excess of reactive oxygen species (ROS) in the embryo. Recent demonstrations of enhanced ROS production in mitochondria of bovine aortic endothelial cells exposed to high glucose have supported the idea that the pathogenesis of diabetic complications may involve ROS-induced GAPDH inhibition. We investigated whether a teratogenic diabetic environment also inhibits embryonic GAPDH activity and alters GAPDH gene expression and whether antioxidants diminish such GAPDH inhibition. In addition, we determined whether the inhibition of GAPDH with iodoacetate induces dysmorphogenesis, analogous to that caused by high glucose concentration, and whether antioxidants modulated the putative teratogenic effect of such direct GAPDH inhibition. We found that embryos from diabetic rats and embryos cultured in high glucose concentrations showed decreased activity of GAPDH (by 40-60%) and severe dysmorphogenesis on gestational days 10.5 and 11.5. GAPDH mRNA was decreased in embryos of diabetic rats compared to control embryos. Supplementing the high-glucose culture with the antioxidant N-acetylcysteine (NAC) increased GAPDH activity and diminished embryonic dysmorphogenesis. Embryos cultured with iodoacetate showed both decreased GAPDH activity and dysmorphogenesis; supplementing the culture with NAC increased both parameters toward normal values. In conclusion, dysmorphogenesis caused by maternal diabetes is correlated with ROS-induced inhibition of GAPDH in embryos, which could indicate that inhibition of GAPDH plays a causal role in diabetic embryopathy.

  • 99.
    Wentzel, Parri
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Antioxidants diminish developmental damage induced by high glucose and cyclooxygenase inhibitors in rat embryos in vitro1998Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 47, nr 4, s. 677-684Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous studies have suggested that the metabolism of arachidonic acid and radical oxygen species (ROS) are altered in diabetes and that these disturbances may induce severe embryonic dysmorphogenesis in diabetic pregnancy. We tested this hypothesis by studying whether an inhibition of the rate-limiting enzyme of prostaglandin biosynthesis, cyclooxygenase (COX), caused developmental disturbances analogous to those seen in embryos exposed to high glucose concentration. Whether antioxidants could prevent such developmental alterations was also investigated. Whole embryo culture was used in which day-9 embryos were exposed to high concentrations of glucose, arachidonic acid, prostaglandin (PG)E2, COX inhibitors, and antioxidants for 48 h. Increased glucose concentration (from 10 to 30 mmol/l) caused embryonic dysmorphogenesis, and addition of either 60 pmol/l arachidonic acid or 280 nmol/l PGE2 largely protected the embryo from this maldevelopment. Furthermore, exposure to the COX inhibitors indomethacin (200 micromol/l) or acetylsalicylic acid (700 micromol/l) in 10 mmol/l glucose concentration yielded embryonic dysmorphogenesis similar to that caused by 30 mmol/l glucose. Supplementation of either arachidonic acid or PGE2 to the culture medium with COX inhibitors in low glucose rectified the embryonic development, and PGE2 supplementation also normalized the development of embryos cultured with COX inhibitors in high glucose concentration. Interestingly, the antioxidants superoxide dismutase (SOD) and N-acetylcysteine (NAC) were each able to diminish the dysmorphogenesis induced by the COX inhibitors, at doses previously shown to diminish glucose-induced embryonic damage in the same in vitro culture system. In conclusion, the present study shows that a high glucose concentration disturbs embryonic development and that this disturbance may be partly mediated via altered metabolism of arachidonic acid and ROS in the embryo.

  • 100.
    Wentzel, Parri
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gäreskog, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Decreased cardiac glutathione peroxidase levels and enhanced mandibular apoptosis in malformed embryos of diabetic rats2008Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 57, nr 12, s. 3344-3352Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To characterize normal and malformed embryos within the same litters from control and diabetic rats for expression of genes related to metabolism of reactive oxygen species (ROS) or glucose as well as developmental genes. RESEARCH DESIGN AND METHODS: Embryos from nondiabetic and streptozotocin-induced diabetic rats were collected on gestational day 11 and evaluated for gene expression (PCR) and distribution of activated caspase-3 and glutathione peroxidase (Gpx)-1 by immunohistochemistry. RESULTS: Maternal diabetes (MD group) caused growth retardation and an increased malformation rate in the embryos of MD group rats compared with those of controls (N group). We found decreased gene expression of Gpx-1 and increased expression of vascular endothelial growth factor-A (Vegf-A) in malformed embryos of diabetic rats (MDm group) compared with nonmalformed littermates (MDn group). Alterations of messenger RNA levels of other genes were similar in MDm and MDn embryos. Thus, expression of copper zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), and sonic hedgehog homolog (Shh) were decreased, and bone morphogenetic protein-4 (Bmp-4) was increased, in the MD embryos compared with the N embryos. In MDm embryos, we detected increased activated caspase-3 immunostaining in the first visceral arch and cardiac area and decreased Gpx-1 immunostaining in the cardiac tissue; both findings differed from the caspase/Gpx-1 immunostaining of the MDn and N embryos. CONCLUSIONS: Maternal diabetes causes growth retardation, congenital malformations, and decreased general antioxidative gene expression in the embryo. In particular, enhanced apoptosis of the first visceral arch and heart, together with decreased cardiac Gpx-1 levels, may compromise the mandible and heart and thus cause an increased risk of developing congenital malformation.

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