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  • 101. 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.

  • 102.
    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.

  • 103.
    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.

  • 104.
    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.

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  • 105.
    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.

  • 106. 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.

  • 107.
    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.

  • 108. 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.

  • 109.
    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.

  • 110.
    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.

  • 111.
    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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  • 112.
    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.
    Folic acid supplementation diminishes diabetes- and glucose-induced dysmorphogenesis2005Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, nr 2, s. 546-553Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Maternal administration of folic acid diminishes the risk of neural tube defects (NTDs) in offspring, but whether folic acid exerts a similar effect in diabetic pregnancy is unknown. The aim was to investigate whether maldevelopment in rat embryos caused by exposure to diabetes in vivo or high-glucose concentrations in vitro is affected by subcutaneous administration of folic acid to the pregnant mother or by adding the compound to the culture medium, respectively. Exposure of embryos to maternal diabetes in vivo or 30 mmol/l glucose in vitro yielded an increased malformation rate (71 and 88% NTD, respectively) and lowered somite number and crown-rump length compared with control embryos. When we injected folic acid into the diabetic pregnant rat, or added 2 mmol/l folic acid to the culture medium with high glucose, the embryonic parameters improved (3 and 5% NTD, respectively). The present work shows that administration of folic acid can diminish diabetes-induced maldevelopment. This suggests that folic acid supplementation may have a role in the prevention of malformations in diabetic pregnancy.

  • 113.
    Wentzel, Parri
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Nils
    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.
    Developmental damage, increased lipid peroxidation, diminished cyclooxygenase-2 gene expression, and lowered PGE-2 levels in rat embryos exposed to a diabetic environment1999Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 48, nr 4, s. 813-820Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous experimental studies suggest that diabetic embryopathy is associated with an excess of radical oxygen species (ROS), as well as with a disturbance of prostaglandin (PG) metabolism. We aimed to investigate the relationship between these pathways and used hyperglycemia in vitro (embryo culture for 24-48 h) and maternal diabetes in vivo to affect embryonic development. Subsequently, we assessed lipid peroxidation and gene expression of cyclooxygenase (COX)-1 and -2 and measured the concentration of prostaglandin E2 (PGE2) in embryos and membranes. Both hyperglycemia in vitro and maternal diabetes in vivo caused embryonic dysmorphogenesis and increased embryonic levels of 8-epi-PGF2alpha, an indicator of lipid peroxidation. Addition of N-acetylcysteine (NAC) to the culture medium normalized the morphology and 8-epi-PGF2alpha concentration of the embryos exposed to high glucose. Neither hyperglycemia nor diabetes altered COX-1 expression, but embryonic COX-2 expression was diminished on gestational day 10. The PGE2 concentration of day 10 embryos and membranes was decreased after exposure to high glucose in vitro or diabetes in vivo. In vitro addition of NAC to high glucose cultures largely rectified morphology and restored PGE2 concentration, but without normalizing the COX-2 expression in embryos and membranes. Hyperglycemia/diabetes-induced downregulation of embryonic COX-2 gene expression may be a primary event in diabetic embryopathy, leading to lowered PGE2 levels and dysmorphogenesis. Antioxidant treatment does not prevent the decrease in COX-2 mRNA levels but restores PGE2 concentrations, suggesting that diabetes-induced oxidative stress aggravates the loss of COX-2 activity. This may explain in part the antiteratogenic effect of antioxidant treatment.

  • 114.
    WOOD, ANDREW R.
    et al.
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    JONES, SAMUEL E.
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    RICHMOND, REBECCA
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    AHMAD, SHAFQAT
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    YAGHOOTKAR, HANIEH
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    BEAUMONT, ROBERT
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    RUTH, KATHERINE S.
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    TUKE, MARCUS
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    MURRAY, ANNA
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    FREATHY, RACHEL M.
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    SMITH, GEORGE DAVEY
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    LEE, I-MIN
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    TIMPSON, NIC
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    CHASMAN, DANIEL
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    KUTALIK, ZOLTAN
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    WEEDON, MICHAEL N.
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    TYRRELL, JESSICA
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    FRAYLING, TIMOTHY M.
    Exeter, United Kingdom, Bristol, United Kingdom, Boston, MA, Lausanne, Switzerland.
    Physical Inactivity and Sleep Inefficiency Accentuate the Genetic Risk of Obesity2018Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, nr Supplement_1Artikel i tidskrift (Övrigt vetenskapligt)
  • 115. Yaghootkar, Hanieh
    et al.
    Lamina, Claudia
    Scott, Robert A.
    Dastani, Zari
    Hivert, Marie-France
    Warren, Liling L.
    Stancakova, Alena
    Buxbaum, Sarah G.
    Lyytikaeinen, Leo-Pekka
    Henneman, Peter
    Wu, Ying
    Cheung, Chloe Y. Y.
    Pankow, James S.
    Jackson, Anne U.
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zhao, Jing Hua
    Ballantyne, Christie M.
    Xie, Weijia
    Bergman, Richard N.
    Boehnke, Michael
    el Bouazzaoui, Fatiha
    Collins, Francis S.
    Dunn, Sandra H.
    Dupuis, Josee
    Forouhi, Nita G.
    Gillson, Christopher
    Hattersley, Andrew T.
    Hong, Jaeyoung
    Kaehoenen, Mika
    Kuusisto, Johanna
    Kedenko, Lyudmyla
    Kronenberg, Florian
    Doria, Alessandro
    Assimes, Themistocles L.
    Ferrannini, Ele
    Hansen, Torben
    Hao, Ke
    Haering, Hans
    Knowles, Joshua W.
    Lindgren, Cecilia M.
    Nolan, John J.
    Paananen, Jussi
    Pedersen, Oluf
    Quertermous, Thomas
    Smith, Ulf
    Lehtimaeki, Terho
    Liu, Ching-Ti
    Loos, Ruth J. F.
    McCarthy, Mark I.
    Morris, Andrew D.
    Vasan, Ramachandran S.
    Spector, Tim D.
    Teslovich, Tanya M.
    Tuomilehto, Jaakko
    van Dijk, Ko Willems
    Viikari, Jorma S.
    Zhu, Na
    Langenberg, Claudia
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Semple, Robert K.
    Sinaiko, Alan R.
    Palmer, Colin N. A.
    Walker, Mark
    Lam, Karen S. L.
    Paulweber, Bernhard
    Mohlke, Karen L.
    van Duijn, Cornelia
    Raitakari, Olli T.
    Bidulescu, Aurelian
    Wareham, Nick J.
    Laakso, Markku
    Waterworth, Dawn M.
    Lawlor, Debbie A.
    Meigs, James B.
    Richards, J. Brent
    Frayling, Timothy M.
    Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes2013Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, nr 10, s. 3589-3598Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.

  • 116.
    Yaghootkar, Hanieh
    et al.
    Univ Exeter, Royal Devon & Exeter Hosp, Genet Complex Traits, Med Sch, Exeter, Devon, England.;Luleå Univ Technol, Div Med Sci, Dept Hlth Sci, Luleå, Sweden.;Univ Westminster, Sch Life Sci, Res Ctr Optimal Hlth, London, England..
    Zhang, Yiying
    Columbia Univ, Dept Pediat, Div Mol Genet, New York, NY 10027 USA..
    Spracklen, Cassandra N.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA.;Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA..
    Karaderi, Tugce
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Eastern Mediterranean Univ, Fac Arts & Sci, Dept Biol Sci, Gazimagusa, Cyprus.;Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Prot Res, Copenhagen, Denmark.;Tech Univ Denmark, DTU Hlth Technol, Lyngby, Denmark..
    Huang, Lam Opal
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Bradfield, Jonathan
    Childrens Hosp Philadelphia, Div Human Genet, Ctr Appl Gen, Philadelphia, PA 19104 USA.;Quantinuum Res LLC, San Diego, CA USA..
    Schurmann, Claudia
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Fine, Rebecca S.
    Harvard Med Sch, Dept Genet, Boston, MA 02115 USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA..
    Preuss, Michael H.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Kutalik, Zoltan
    Univ Exeter, Royal Devon & Exeter Hosp, Genet Complex Traits, Med Sch, Exeter, Devon, England.;Univ Lausanne, Ctr Primary Care & Publ Hlth, Lausanne, Switzerland.;Swiss Inst Bioinformat, Lausanne, Switzerland..
    Wittemans, Laura B. L.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Vanderbilt Univ, Sch Med, Dept Med, Div Epidemiol,Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA.;Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA..
    Metz, Sophia
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Willems, Sara M.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Li-Gao, Ruifang
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Wang, Shuai
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Molnos, Sophie
    German Ctr Diabet Res, Munich, Germany.;Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen Res, Inst Epidemiol, Munich, Germany..
    Sandoval-Zarate, America A.
    Inst Mol Med Finland, Helsinki, Finland..
    Nalls, Mike A.
    NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA.;Data Tecn Int, Glen Echo, MD USA..
    Lange, Leslie A.
    Univ Colorado, Dept Med, Div Biomed Informat & Personalized Med, Denver, CO USA..
    Haesser, Jeffrey
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Guo, Xiuqing
    Harbor UCLA Med Ctr, Dept Pediat, Lundquist Inst Biomed Innovat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr Tampere, Dept Clin Chem, Tampere, Finland..
    Feitosa, Mary F.
    Washington Univ, Sch Med, Dept Genet, Div Stat Gen, St Louis, MO 63110 USA..
    Sitlani, Colleen M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA..
    Venturini, Cristina
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Kacprowski, Tim
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany..
    Wang, Carol A.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA..
    Amin, Najaf
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands..
    Broer, Linda
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Internal Med, Rotterdam, Netherlands..
    Robertson, Neil
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Young, Kristin L.
    Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27515 USA..
    Allison, Matthew
    Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA..
    Auer, Paul L.
    Univ Wisconsin, Joseph J Zilber Sch Publ Hlth, Milwaukee, WI 53201 USA..
    Bluher, Matthias
    Univ Leipzig, Med Dept Endocrinol 3, Nephrol, Med Ctr,Rheumatol, Leipzig, Germany..
    Borja, Judith B.
    Off Populat Studies Fdn Inc, Cebu, Philippines.;Univ San Carlos, Dept Nutr & Dietet, Cebu, Philippines..
    Bork-Jensen, Jette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Carrasquilla, German D.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Christofidou, Paraskevi
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Demirkan, Ayse
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands..
    Doege, Claudia A.
    Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA..
    Garcia, Melissa E.
    NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA..
    Graff, Mariaelisa
    Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27515 USA.;Carolina Ctr Genome Sci, Chapel Hill, NC USA..
    Guo, Kaiying
    Columbia Univ, Dept Pediat, Div Mol Genet, New York, NY 10027 USA..
    Hakonarson, Hakon
    Childrens Hosp Philadelphia, Div Human Genet, Ctr Appl Gen, Philadelphia, PA 19104 USA.;Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Hong, Jaeyoung
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Ida Chen, Yii-Der
    Harbor UCLA Med Ctr, Dept Pediat, Lundquist Inst Biomed Innovat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Jackson, Rebecca
    Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA..
    Jakupovic, Hermina
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Jousilahti, Pekka
    Finnish Inst Hlth & Welf, Dept Publ Hlth Solut, Helsinki, Finland..
    Justice, Anne E.
    Ctr Biomed & Translat Informat, Danville, PA USA..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.;Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr Tampere, Dept Clin Physiol, Tampere, Finland..
    Kizer, Jorge R.
    Univ Calif San Francisco, San Francisco Vet Affairs Hlth Care Syst, Cardiol Sect, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA..
    Kriebel, Jennifer
    German Ctr Diabet Res, Munich, Germany.;Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen Res, Inst Epidemiol, Munich, Germany..
    LeDuc, Charles A.
    Columbia Univ, Dept Pediat, Div Mol Genet, New York, NY 10027 USA..
    Li, Jin
    Stanford Univ, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94304 USA..
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk epidemiologi.
    Luan, Jian'an
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Mackey, David A.
    Univ Western Australia, Lions Eye Inst, Ctr Ophthalmol & Visual Sci, Perth, WA, Australia..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London, England..
    Mannisto, Satu
    Finnish Inst Hlth & Welf, Dept Publ Hlth Solut, Helsinki, Finland..
    Martin Carli, Jayne F.
    Columbia Univ, Dept Pediat, Div Mol Genet, New York, NY 10027 USA..
    Medina-Gomez, Carolina
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Univ Med Ctr Rotterdam, Dept Internal Med, Rotterdam, Netherlands..
    Mook-Kanamori, Dennis O.
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands.;Leiden Univ, Dept Publ Hlth & Primary Care, Med Ctr, Leiden, Netherlands..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England.;Univ Manchester, Div Musculoskeletal & Dermatol Sci, Manchester, Lancs, England..
    de Mutsert, Renee
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands..
    Nauck, Matthias
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.;Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany..
    Prokic, Ivana
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands..
    Pennell, Craig E.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Pradhan, Arund D.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.;Univ Washington, Dept Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.;Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA..
    Raitakari, Olli T.
    Univ Turku, Ctr Populat Hlth Res, Turku, Finland.;Turku Univ Hosp, Turku, Finland.;Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.;Turku Univ Hosp, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    Scott, Robert A.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Skaaby, Tea
    Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Dis Prevent, Copenhagen, Denmark..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Ludwig Maximilian Univ Munich, Fac Med, Inst Med Informat Proc Biometry & Epidemiol IBE, Chair Genet Epidemiol, Munich, Germany..
    Taylor, Kent D.
    Harbor UCLA Med Ctr, Dept Pediat, Lundquist Inst Biomed Innovat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Teumer, Alexander
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, Greifswald, Germany.;Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Uitterlinden, Andre G.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Univ Med Ctr Rotterdam, Dept Internal Med, Rotterdam, Netherlands..
    Wu, Ying
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA..
    Yao, Jie
    Harbor UCLA Med Ctr, Dept Pediat, Lundquist Inst Biomed Innovat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Walker, Mark
    Newcastle Univ, Inst Cellular Med Diabet, Newcastle Upon Tyne, Tyne & Wear, England..
    North, Kari E.
    Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27515 USA..
    Kovacs, Peter
    Univ Leipzig, Med Dept Endocrinol 3, Nephrol, Med Ctr,Rheumatol, Leipzig, Germany..
    Ikram, M. Arfan
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Univ Med Ctr Rotterdam, Dept Internal Med, Rotterdam, Netherlands..
    van Duijn, Cornelia M.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA 02115 USA..
    Lye, Stephen
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada..
    Homuth, Georg
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany..
    Ingelsson, Erik
    Stanford Univ, Dept Med, Div Cardiovasc Med, Palo Alto, CA 94304 USA.;Stanford Univ, Sch Med, Stanford Cardiovasc Inst, Palo Alto, CA 94304 USA.;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA.;Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    McKnight, Barbara
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Province, Michael A.
    Washington Univ, Sch Med, Dept Genet, Div Stat Gen, St Louis, MO 63110 USA..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Tampere Univ, Fac Med & Hlth Technol, Finnish Cardiovasc Res Ctr Tampere, Dept Clin Chem, Tampere, Finland..
    Adair, Linda S.
    Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC 27515 USA..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Dept Pediat, Lundquist Inst Biomed Innovat, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA..
    Reiner, Alexander P.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Phys & Biophys, Jackson, MS 39216 USA..
    Harris, Tamara B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA..
    Ripatti, Samuli
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.;Inst Mol Med Finland, Helsinki, Finland.;Univ Helsinki, Publ Hlth, Helsinki, Finland..
    Grallert, Harald
    German Ctr Diabet Res, Munich, Germany.;Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen Res, Inst Epidemiol, Munich, Germany..
    Meigs, James B.
    Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Program Populat & Med Genet, Cambridge, MA 02142 USA..
    Salomaa, Veikko
    Finnish Inst Hlth & Welf, Dept Publ Hlth Solut, Helsinki, Finland..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark..
    Willems van Dijk, Ko
    Leiden Univ, Med Ctr, Dept Internal Med, Div Endocrinol, Leiden, Netherlands.;Einthoven Lab Expt Vasc Med, Leiden, Netherlands.;Leiden Univ, Dept Human Genet, Med Ctr, Leiden, Netherlands..
    Wareham, Nicholas J.
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Grant, Struan F. A.
    Childrens Hosp Philadelphia, Div Human Genet, Ctr Appl Gen, Philadelphia, PA 19104 USA.;Univ Penn, Dept Pediat, Perelman Sch Med, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Div Human Genet, Ctr Spatial & Funct Genom, Philadelphia, PA 19104 USA.;Childrens Hosp Philadelphia, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA.;Univ Penn, Inst Diabet Obes & Metab, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Langenberg, Claudia
    Univ Cambridge, MRC Epidemiol Unit, Cambridge, England..
    Frayling, Timothy M.
    Univ Exeter, Royal Devon & Exeter Hosp, Genet Complex Traits, Med Sch, Exeter, Devon, England..
    Lindgren, Cecilia M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.;Univ Oxford, Big Data Inst, Nuffield Dept Med, Oxford, England..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA..
    Leibel, Rudolph L.
    Columbia Univ, Dept Pediat, Div Mol Genet, New York, NY 10027 USA..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA..
    Kilpelainen, Tuomas O.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn, Ctr Basic Metab Res, Copenhagen, Denmark.;Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, New York, NY 10029 USA..
    Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity2020Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 69, nr 12, s. 2806-2818Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 x 10(-16), n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

  • 117.
    Yin, Hong
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Berg, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Tuvemo, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Frisk, Gun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Enterovirus RNA is found in peripheral blood mononuclear cells in a majority of type 1 diabetic children at onset2002Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 51, nr 6, s. 1964-1971Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have studied the occurrence of enterovirus (EV)-RNA at the onset of childhood type 1 diabetes in all 24 new cases of childhood type 1 diabetes during 1 year in Uppsala county, Sweden. We also studied 24 matched control subjects and 20 siblings of the patients. RNA was isolated from peripheral blood mononuclear cells and EV-RNA detected by RT-PCR. Primers (groups A and B) corresponding to conserved regions in the 5' noncoding region (NCR) of EV were used in the PCRs, and the amplicons were sequenced. By the use of group A primers, EV-RNA was found in 12 (50%) of the 24 type 1 diabetic children, 5 (26%) of 19 siblings, and none of the control subjects. Both patients and siblings showed a higher frequency of EV-RNA compared with the control subjects. The group B primers detected EV-RNA in all three groups but did not show statistically significant differences between the groups. The EV-RNA positivity with the group B primers was 11 (46%) of 24 in the type 1 diabetic children, 11 (58%) of 19 in the siblings, and 7 (29%) of 24 in the control subjects. The significant difference between groups seen with the group A primers but not with the group B primers might indicate the existence of diabetogenic EV strains. The phylogenetic analysis of the PCR products revealed clustering of the sequences from patients and siblings into five major branches when the group A PCR primers were used. With the group B primers, the sequences from patients, siblings, and control subjects formed three major branches in the phylogenetic tree, where 6 of the 7 control subjects clustered together in a sub-branch of CBV-4/VD2921. Seven of the type 1 diabetic children clustered together in another sub-branch of CBV-4/VD2921. Five of the type 1 diabetic children formed a branch together with the CBV-4/E2 strain, four clustered together with CBV-5, and one formed a branch with echovirus serotype. The presence of EV-RNA in the blood cells of most newly diagnosed type 1 diabetic children supports the hypothesis that a viral infection acts as an exogenous factor. In addition, sequencing of the PCR amplicons from the type 1 diabetic children, their siblings, and matched control subjects might reveal differences related to diabetogenic properties of such a virus.

  • 118.
    Yuan, Shuai
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden..
    Kar, Siddhartha
    Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Bristol, Avon, England..
    Carter, Paul
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Vithayathil, Mathew
    Univ Cambridge, MRC Canc Unit, Cambridge, England..
    Mason, Amy M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England.;Univ Cambridge, Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England.;Cambridge Univ Hosp, Cambridge, England..
    Burgess, Stephen
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, MRC Biostat Unit, Cambridge, England..
    Larsson, Susanna C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi. Karolinska Inst, Inst Environm Med, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden..
    Is Type 2 Diabetes Causally Associated With Cancer Risk?: Evidence From a Two-Sample Mendelian Randomization Study2020Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 69, nr 7, s. 1588-1596Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We conducted a two-sample Mendelian randomization study to investigate the causal associations of type 2 diabetes mellitus (T2DM) with risk of overall cancer and 22 site-specific cancers. Summary-level data for cancer were extracted from the Breast Cancer Association Consortium and UK Biobank. Genetic predisposition to T2DM was associated with higher odds of pancreatic, kidney, uterine, and cervical cancer and lower odds of esophageal cancer and melanoma but not associated with 16 other site-specific cancers or overall cancer. The odds ratios (ORs) were 1.13 (95% CI 1.04, 1.22), 1.08 (1.00, 1.17), 1.08 (1.01, 1.15), 1.07 (1.01, 1.15), 0.89 (0.81, 0.98), and 0.93 (0.89, 0.97) for pancreatic, kidney, uterine, cervical, and esophageal cancer and melanoma, respectively. The association between T2DM and pancreatic cancer was also observed in a meta-analysis of this and a previous Mendelian randomization study (OR 1.08; 95% CI 1.02, 1.14;P= 0.009). There was limited evidence supporting causal associations between fasting glucose and cancer. Genetically predicted fasting insulin levels were positively associated with cancers of the uterus, kidney, pancreas, and lung. The current study found causal detrimental effects of T2DM on several cancers. We suggest reinforcing the cancer screening in T2DM patients to enable the early detection of cancer.

  • 119. Yuan, Shuai
    et al.
    Mason, Amy M
    Burgess, Stephen
    Larsson, Susanna C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Medicinsk epidemiologi. Karolinska Inst, Karolinska Inst, Unit Cardiovasc & Nutr Epidemiol, Stockholm, Sweden.
    Differentiating Associations of Glycemic Traits With Atherosclerotic and Thrombotic Outcomes: Mendelian Randomization Investigation2022Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 71, nr 10, s. 2222-2232Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We conducted a Mendelian randomization analysis to differentiate associations of four glycemic indicators with a broad range of atherosclerotic and thrombotic diseases. Independent genetic variants associated with fasting glucose (FG), 2 h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) at the genome-wide significance threshold were used as instrumental variables. Summary-level data for 12 atherosclerotic and 4 thrombotic outcomes were obtained from large genetic consortia and the FinnGen and UK Biobank studies. Higher levels of genetically predicted glycemic traits were consistently associated with increased risk of coronary atherosclerosis-related diseases and symptoms. Genetically predicted glycemic traits except HbA1c showed positive associations with peripheral artery disease risk. Genetically predicted FI levels were positively associated with risk of ischemic stroke and chronic kidney disease. Genetically predicted FG and 2hGlu were positively associated with risk of large artery stroke. Genetically predicted 2hGlu levels showed positive associations with risk of small vessel stroke. Higher levels of genetically predicted glycemic traits were not associated with increased risk of thrombotic outcomes. Most associations for genetically predicted levels of 2hGlu and FI remained after adjustment for other glycemic traits. Increase in glycemic status appears to increase risks of coronary and peripheral artery atherosclerosis but not thrombosis.

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