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  • 301.
    Hering, Bernhard J.
    et al.
    Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN 55455 USA.;Univ Minnesota, Dept Surg, Box 242 UMHC, Minneapolis, MN 55455 USA..
    Clarke, William R.
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Bridges, Nancy D.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Eggerman, Thomas L.
    NIDDK, NIH, Bethesda, MD 20892 USA..
    Alejandro, Rodolfo
    Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA..
    Bellin, Melena D.
    Univ Minnesota, Schulze Diabet Inst, Minneapolis, MN 55455 USA.;Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA..
    Chaloner, Kathryn
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Czarniecki, Christine W.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Goldstein, Julia S.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Hunsicker, Lawrence G.
    Univ Iowa, Clin Trials Stat & Data Management Ctr, Iowa City, IA USA..
    Kaufman, Dixon B.
    Univ Wisconsin, Dept Surg, Div Transplantat, Madison, WI USA..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsen, Christian P.
    Emory Univ, Emory Transplant Ctr, Atlanta, GA 30322 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, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA..
    Oberholzer, Jose
    Univ Illinois Hosp & Hlth Sci Syst, Div Transplantat, Chicago, IL USA..
    Posselt, Andrew M.
    Univ Calif San Francisco, Dept Surg, San Francisco, CA USA..
    Rickels, Michael R.
    Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Surg, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA..
    Ricordi, Camillo
    Univ Miami, Miller Sch Med, Diabet Res Inst, Miami, FL 33136 USA..
    Robien, Mark A.
    NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA..
    Senior, Peter A.
    Univ Alberta, Clin Islet Transplant Program, Edmonton, AB, Canada.;Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada..
    Shapiro, A. M. James
    Univ Alberta, Clin Islet Transplant Program, Edmonton, AB, Canada.;Univ Alberta, Fac Med & Dent, Edmonton, AB, Canada..
    Stock, Peter G.
    Univ Calif San Francisco, Dept Surg, San Francisco, CA USA..
    Turgeon, Nicole A.
    Emory Univ, Emory Transplant Ctr, Atlanta, GA 30322 USA..
    Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia2016In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 39, no 7, p. 1230-1240Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA(1c) <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. RESULTS The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA(1c) level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

  • 302.
    Herisson, F. M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Waikato, Dept Biol Sci, Fac Sci & Engn, Private Bag 3105, Hamilton, New Zealand..
    Waas, J. R.
    Univ Waikato, Dept Biol Sci, Fac Sci & Engn, Private Bag 3105, Hamilton, New Zealand..
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, A. S.
    Univ Minnesota, Dept Food Sci & Nutr, 1334 Eckles Ave, St Paul, MN USA..
    Olszewski, P. K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Univ Waikato, Dept Biol Sci, Fac Sci & Engn, Private Bag 3105, Hamilton, New Zealand.;Univ Minnesota, Dept Food Sci & Nutr, 1334 Eckles Ave, St Paul, MN USA..
    Oxytocin Acting in the Nucleus Accumbens Core Decreases Food Intake2016In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 28, no 4Article in journal (Refereed)
    Abstract [en]

    Central oxytocin (OT) promotes feeding termination in response to homeostatic challenges, such as excessive stomach distension, salt loading and toxicity. OT has also been proposed to affect feeding reward by decreasing the consumption of palatable carbohydrates and sweet tastants. Because the OT receptor (OTR) is expressed in the nucleus accumbens core (AcbC) and shell (AcbSh), a site regulating diverse aspects of eating behaviour, we investigated whether OT acts there to affect appetite in rats. First, we examined whether direct AcbC and AcbSh OT injections affect hunger- and palatability-driven consumption. We found that only AcbC OT infusions decrease deprivation-induced chow intake and reduce the consumption of palatable sucrose and saccharin solutions in nondeprived animals. These effects were abolished by pretreatment with an OTR antagonist, L-368,899, injected in the same site. AcbC OT at an anorexigenic dose did not induce a conditioned taste aversion, which indicates that AcbC OT-driven anorexia is not caused by sickness/malaise. The appetite-specific effect of AcbC OT is supported by the real-time polymerase chain reaction analysis of OTR mRNA in the AcbC, which revealed that food deprivation elevates OTR mRNA expression, whereas saccharin solution intake decreases OTR transcript levels. We also used c-Fos immunohistochemistry as a marker of neuronal activation and found that AcbC OT injection increases activation of the AcbC itself, as well as of two feeding-related sites: the hypothalamic paraventricular and supraoptic nuclei. Finally, considering the fact that OT plays a significant role in social behaviour, we examined whether offering animals a meal in a social setting would modify their hypophagic response to AcbC OT injections. We found that a social context abolishes the anorexigenic effects of AcbC OT. We conclude that OT acting via the AcbC decreases food intake driven by hunger and reward in rats offered a meal in a nonsocial setting.

  • 303.
    Hero, C.
    et al.
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Stockholm, Sweden..
    Ritsinger, V.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Cardiol Unit, Stockholm, Sweden.;Reg Kronoberg, Dept Res & Dev, Gothenburg, Sweden..
    Svensson, A. -M
    Saleh, N.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Cardiol Unit, Stockholm, Sweden..
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Norhammar, A.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Cardiol Unit, Stockholm, Sweden..
    Eeg-Olofsson, K.
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Med, Stockholm, Sweden..
    Gender aspects in type 1 diabetes patients undergoing angiography: a registry report2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S139-S139Article in journal (Other academic)
  • 304. Herrera, Miguel F.
    et al.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Angelos, Peter
    Grant, Clive S.
    Hoff, Ana O.
    Pantoja, Juan Pablo
    Perez-Johnston, Rocio
    Sahani, Dushyant V.
    Wong, Richard J.
    Randolph, Gregory
    AACE/ACE DISEASE STATE CLINICAL REVIEW: PANCREATIC NEUROENDOCRINE INCIDENTALOMAS2015In: Endocrine Practice, ISSN 1530-891X, E-ISSN 1934-2403, Vol. 21, no 5, p. 546-553Article, review/survey (Refereed)
    Abstract [en]

    Incidental detection of pancreatic neuroendocrine tumors (PNETs) has substantially increased over the last decade due to widespread use of advanced imaging studies. Reliable initial imaging-based characterization is crucial for the differential diagnosis from other exocrine neoplasms and to determine the appropriate management plan. Measurements of chromogranin A, pancreatic polypeptide, and calcitonin are recommended for the biochemical evaluation. A thorough medical history needs to be performed to rule out multiple endocrine neoplasia (MEN) type 1. The European Neuroendocrine Tumor Society (ENETS)/Tumor Node Metastasis (TNM) staging system together with a grading based on the Ki-67 proliferation index and mitotic counts has proven to give more appropriate prognostic information than the World Health Organization (WHO)/American Joint Committee on Cancer (AJCC) TNM staging but may still fail to safely differentiate benign from malignant lesions. Poorly differentiated PNETs generally present with metastases and are rarely amenable for resection. Well-or intermediately differentiated tumors >= 2 cm with imaging evidence of malignancy or with a Ki-67 > 2% should be resected. It has been suggested that non-MEN related, nonfunctioning, and asymptomatic PNETs < 2 cm with a Ki-67 index >= 2% carry a low risk of metastasis and may be observed in the absence of clinical or radiologic criteria of malignancy or progression, especially in older patients. However, because metastases may occur with long delay with smaller PNETS, physicians should consider patient age, lesion location, and the risks of operation, and patients not undergoing surgery need to be closely followed closely.

  • 305. Hesse, Bernhard
    et al.
    Varga, Peter
    Langer, Max
    Pacureanu, Alexandra
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schrof, Susanne
    Maennicke, Nils
    Suhonen, Heikki
    Maurer, Peter
    Cloetens, Peter
    Peyrin, Francoise
    Raum, Kay
    Canalicular Network Morphology is the Major Determinant of the Spatial Distribution of Mass Density in Human Bone Tissue: Evidence by Means of Synchrotron Radiation Phase-Contrast nano-CT2015In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 30, no 2, p. 346-356Article in journal (Refereed)
    Abstract [en]

    In bone remodeling, maturation of the newly formed osteonal tissue is associated with a rapid primary increase followed by a slower secondary increase of mineralization. This requires supply and precipitation of mineral into the bone matrix. Mineral delivery can occur only from the extracellular fluid via interfaces such as the Haversian system and the osteocyte pore network. We hypothesized that in mineralization, mineral exchange is achieved by the diffusion of mineral from the lacunar-canalicular network (LCN) to the bone matrix, resulting in a gradual change in tissue mineralization with respect to the distance from the pore-matrix interface. We expected to observe alterations in the mass density distribution with tissue age. We further hypothesized that mineral exchange occurs not only at the lacunar but also at the canalicular boundaries. The aim of this study was, therefore, to investigate the spatial distribution of mass density in the perilacunar and pericanalicular bone matrix and to explore how these densities are influenced by tissue aging. This is achieved by analyzing human jawbone specimens originating from four healthy donors and four treated with high-dosage bisphosphonate using synchrotron radiation phase-contrast nano-CT with a 50-nm voxel size. Our results provide the first experimental evidence that mass density in the direct vicinity of both lacunae (p<0.001) and canaliculi (p<0.001) is different from the mean matrix mass density, resulting in gradients with respect to the distance from both pore-matrix interfaces, which diminish with increasing tissue age. Though limited by the sample size, these findings support our hypotheses. Moreover, the density gradients are more pronounced around the lacunae than around the canaliculi, which are explained by geometrical considerations in the LCN morphology. In addition, we speculate that mineral exchange occurs at all interfaces of the LCN, not only in mineralization but also in mineral homeostasis.

  • 306.
    Hicks, Rodney J.
    et al.
    Peter MacCallum Canc Ctr, Canc Imaging & Neuroendocrine Serv, 305 Grattan St.
    Kwekkeboom, Dik J.
    Erasmus MC, ENETS Ctr Excellence Rotterdam, Div Nucl Med, Dept Internal Med.
    Krenning, Eric
    Erasmus MC, Cyclotron Rotterdam BV.
    Bodei, Lisa
    Mem Sloan Kettering Canc Ctr.
    Grozinsky-Glasberg, Simona
    Hadassah Hebrew Univ, Med Ctr, Neuroendocrine Tumor Unit, Endocrinol & Metab Serv,Dept Med.
    Arnold, Rudolf
    Munich, Germany.
    Borbath, Ivan
    Clin Univ St Luc, Serv Gastroenterol.
    Cwikla, Jaroslaw
    Univ Warmia & Mazury, Dept Radiol, Fac Med Sci.
    Toumpanakis, Christos
    Royal Free Hosp, Neuroendocrine Tumour Unit.
    Kaltsas, Greg
    Natl Univ Athens, Div Endocrinol, Dept Pathophysiol.
    Davies, Philippa
    Royal Free Hosp, Neuroendocrine Tumour Unit.
    Hoersch, Dieter
    Gastroenterol & Endocrinol Ctr Neuroendocrine Tum.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Ramage, John
    Hampshire Hosp NHS Trust, Gastroenterol Dept, Basingstoke.
    ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Peptide Receptor Radionuclide Therapy with Radiolabelled Somatostatin Analogues2017In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 3, p. 295-309Article in journal (Refereed)
    Abstract [en]

    The purpose of these guidelines is to assist physicians caring for patients with neuroendocrine neoplasia in considering eligibility criteria for peptide receptor radionuclide therapy (PRRT) and in defining the minimum requirements for PRRT. It is not these guidelines' aim to give recommendations on the use of specific radiolabelled somatostatin analogues for PRRT as different analogues are being used, and their availability is governed by varying international regulations. However, a recent randomized controlled trial, NETTER-1, has provided evidence that may establish Lu-177-DOTA-octreotate (LutaThera (R)) as the first widely approved agent. It also makes recommendations on what minimal patient, tumour, and treatment outcome characteristics should be reported for PRRT to facilitate robust comparisons between studies.

  • 307. Hightower, C. Makena
    et al.
    Zhang, Kuixing
    Miramontes-Gonzalez, Jose P.
    Rao, Fangwen
    Wei, Zhiyun
    Schork, Andrew J.
    Nievergelt, Caroline M.
    Biswas, Nilima
    Mahata, Manjula
    Elkelis, Nina
    Taupenot, Laurent
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Ziegler, Michael G.
    O'Connor, Daniel T.
    Genetic variation at the delta-sarcoglycan (SGCD) locus elevates heritable sympathetic nerve activity in human twin pairs2013In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 127, no 6, p. 750-761Article in journal (Refereed)
    Abstract [en]

    The Syrian Cardiomyopathic Hamster (BIO-14.6/53.58 strains) model of cardiac failure, resulting from naturally occurring deletion at the SGCD (delta-sarcoglycan) locus, displays widespread disturbances in catecholamine metabolism. Rare Mendelian myopathy disorders of human SGCD occur, although common naturally occurring SGCD genetic variation has not been evaluated for effects on human norepinephrine (NE) secretion. This study investigated the effect of SGCD genetic variation on control of NE secretion in healthy twin pairs. Genetic associations profiled SNPs across the SGCD locus. Trait heritability (h(2)) and genetic covariance (pleiotropy; shared h(2)) were evaluated. Sympathochromaffin exocytosis in vivo was probed in plasma by both catecholamines and Chromogranin B (CHGB). Plasma NE is substantially heritable (p=3.19E-16, at 65.2 +/- 5.0% of trait variance), sharing significant (p<0.05) genetic determination with circulating and urinary catecholamines, CHGB, eGFR, and several cardio-metabolic traits. Participants with higher pNE showed significant (p<0.05) differences in several traits, including increased BP and hypertension risk factors. Peak SGCD variant rs1835919 predicted elevated systemic vascular compliance, without changes in specifically myocardial traits. We used a chimeric-regulated secretory pathway photoprotein (CHGA-EAP) to evaluate the effect of SGCD on the exocytotic pathway in transfected PC12 cells; in transfected cells, expression of SGCD augmented CHGA trafficking into the exocytotic regulated secretory pathway. Thus, our investigation determined human NE secretion to be a highly heritable trait, influenced by common genetic variation within the SGCD locus. Circulating NE aggregates with BP and hypertension risk factors. In addition, coordinate NE and CHGB elevation by rs1835919 implicates exocytosis as the mechanism of release.

  • 308.
    Hilden, K.
    et al.
    Univ Orebro, Sch Hlth & Med Sci, Dept Obstet & Gynaecol, Orebro, Sweden..
    Hanson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Univ Orebro, Sch Hlth & Med Sci, Dept Obstet & Gynaecol, Orebro, Sweden.
    Persson, M.
    Karolinska Inst, Dept Clin Epidemiol, Stockholm, Sweden..
    Fadl, H.
    Univ Orebro, Sch Hlth & Med Sci, Dept Obstet & Gynaecol, Orebro, Sweden..
    Overweight and obesity: a remaining problem in women treated for severe gestational diabetes2016In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 33, no 8, p. 1045-1051Article in journal (Refereed)
    Abstract [en]

    Aim: To analyse the impact of overweight and obesity on the risk of adverse maternal outcomes and fetal macrosomia in pregnancies of women treated for severe gestational diabetes.

    Methods: This was a population-based cohort study including all singleton pregnancies in Sweden without pre-existing diabetes in the period 1998-2012. Only mothers with an early-pregnancy BMI of >= 18.5 kg/m(2) were included. Logistic regression analysis was used to determine odds ratios with 95% CIs for maternal outcomes and fetal growth. Analyses were stratified by maternal gestational diabetes/non-gestational diabetes to investigate the impact of overweight/obesity in each group.

    Results: Of 1 249 908 singleton births, 13 057 were diagnosed with gestational diabetes (1.0%). Overweight/obesity had the same impact on the risks of caesarean section and fetal macrosomia in pregnancies with and without gestational diabetes, but the impact of maternal BMI on the risk of preeclampsia was less pronounced in women with gestational diabetes. Normal-weight women with gestational diabetes had an increased risk of caesarean section [odds ratio 1.26 (95% CI 1.16-1.37)], preeclampsia [odds ratio 2.03 (95% CI 1.71-2.41)] and large-for-gestational-age infants [odds ratio 2.25 (95% CI 2.06-2.46)]. Risks were similar in the overweight group without gestational diabetes, caesarean section [odds ratio 1.34 (1.33-1.36)], preeclampsia odds ratio [1.76 (95% CI 1.72-1.81)], large-for-gestational-age [odds ratio 1.76 (95% CI 1.74-1.79)].

    Conclusions: Maternal overweight and obesity is associated with similar increments in risks of adverse maternal outcomes and delivery of large-for-gestational-age infants in women with and without gestational diabetes. Obese women with gestational diabetes are defined as a high-risk group. Normal-weight women with gestational diabetes have similar risks of adverse outcomes to overweight women without gestational diabetes.

  • 309.
    Hilden, K.
    et al.
    Orebro Univ, Sch Med Sci, Dept Obstet & Gynaecol, Orebro, Sweden.
    Hanson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Orebro Univ, Sch Med Sci, Orebro, Sweden.
    Persson, M.
    Karolinska Univ Sjukhuset, Dept Med, Clin Epidemiol Unit, Solna, Sweden.
    Magnuson, A.
    Orebro Univ, Sch Med Sci, Clin Epidemiol & Biostat, Orebro, Sweden.
    Simmons, D.
    Orebro Univ, Sch Med Sci, Orebro, Sweden;Western Sydney Univ, Sch Med, Campbelltown, NSW, Australia.
    Fadl, H.
    Orebro Univ, Sch Med Sci, Dept Obstet & Gynaecol, Orebro, Sweden.
    Gestational diabetes and adiposity are independent risk factors for perinatal outcomes: a population based cohort study in Sweden2019In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 36, no 2, p. 151-157Article in journal (Refereed)
    Abstract [en]

    Aims To evaluate the interaction effects of gestational diabetes (GDM) with obesity on perinatal outcomes. Methods A population-based cohort study in Sweden excluding women without pre-gestational diabetes with a singleton birth between 1998 and 2012. Logistic regression was performed to evaluate the potential independent associations of GDM and BMI with adverse perinatal outcomes as well as their interactions. Main outcome measures were malformations, stillbirths, perinatal mortality, low Apgar score, fetal distress, prematurity and Erb's palsy. Results Some 1,294,006 women were included, with a GDM prevalence of 1% (n = 14,833). The rate of overweight/obesity was 67.7% in the GDM-group and 36.1% in the non-GDM-group. No significant interaction existed. Offspring of women with GDM had significantly increased risk of malformations, adjusted odds ratio (aOR) 1.16 (95% confidence intervals 1.06-1.26), prematurity, aOR 1.86 (1.76-1. 98), low Apgar score, aOR 1.36 (1.10-1.70), fetal distress, aOR 1.09 (1.02-1.16) and Erb's palsy aOR 2.26 (1.79-2.86). No risk for stillbirth or perinatal mortality was seen. Offspring of overweight (BMI 25-29.9 kg/m(2)), obese (BMI 30-34.9 kg/m(2)) and severely obese women (BMI >= 35.0 kg/m(2)) had significantly increased risks of all outcomes including stillbirth 1.51 (1.40-1.62) to 2.85 (2.52-3.22) and perinatal mortality 1.49 (1.40-1.59) to 2.83 (2.54-3.15). Conclusions There is no interaction effect between GDM and BMI for the studied outcomes. Higher BMI and GDM are major independent risk factors for most serious adverse perinatal outcomes. More effective pre-pregnancy and antenatal interventions are required to prevent serious adverse pregnancy outcomes among women with either GDM or high BMI.

  • 310.
    Hjort, R.
    et al.
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, S-17177 Stockholm, Sweden..
    Alfredsson, L.
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Stockholm, Sweden..
    Andersson, T.
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, S-17177 Stockholm, Sweden.;Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden..
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grill, V.
    Norwegian Univ Sci & Technol, NTNU Inst Canc Res & Mol Med, Trondheim, Norway.;Trondheim Reg & Univ Hosp, Dept Endocrinol, Trondheim, Norway..
    Groop, L.
    Lund Univ, Clin Res Ctr, Dept Clin Sci Malmo, Malmo, Sweden..
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Rasouli, B.
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, S-17177 Stockholm, Sweden..
    Storm, P.
    Lund Univ, Clin Res Ctr, Dept Clin Sci Malmo, Malmo, Sweden..
    Tuomi, T.
    Univ Helsinki, Div Endocrinol, Abdominal Ctr, Finnish Inst Mol Med, Helsinki, Finland.;Univ Helsinki, Res Program Diabet & Obes, Helsinki, Finland.;Helsinki Univ Hosp, Folkhalsan Res Ctr, Helsinki, Finland..
    Carlsson, S.
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, S-17177 Stockholm, Sweden..
    Family history of type 1 and type 2 diabetes and risk of latent autoimmune diabetes in adults (LADA)2017In: Diabetes & Metabolism, ISSN 1262-3636, E-ISSN 1878-1780, Vol. 43, no 6, p. 536-542Article in journal (Refereed)
    Abstract [en]

    Background. - A family history of diabetes (FHD) is a strong predictor of diabetes risk, yet has rarely been investigated in latent autoimmune diabetes in adults (LADA). This study therefore investigated the risk of LADA and type 2 diabetes (T2D) in relation to FHD, taking into account the type of diabetes in relatives. Methods. - Data from a population-based study were used, including incident cases of LADA [glutamic acid decarboxylase antibody (GADA)-positive, n = 378] and T2D (GADA-negative, n = 1199), and their matched controls (n = 1484). First-degree relatives with disease onset at age < 40 years and taking insulin treatment were classified as type 1 diabetes (T1D) or, if otherwise, as T2D. Odds ratios (ORs) were adjusted for age, gender, BMI, education and smoking. Cases were genotyped for high- and low-risk HLA genotypes. Results. - Both FHD-T1D (OR: 5.8; 95% CI: 3.2-10.3) and FHD-T2D (OR: 1.9; 95% CI: 1.5-2.5) were associated with an increased risk of LADA, whereas the risk of T2D was associated with FHD-T2D (OR: 2.7; 95% CI: 2.2-3.3), but not FHD-Tl D. In LADA patients, FHD-T1D vs FHD-T2D was associated with higher GADA but lower C-peptide levels, lower prevalence of low-risk HLA genotypes (5.0% vs 28.6%, respectively; P = 0.038) and a tendency for higher prevalence of high-risk genotypes (90.0% vs 69.1%, respectively; P = 0.0576). Conclusion. - The risk of LADA is substantially increased with FHD-Tl D but also, albeit significantly less so, with FHD-T2D. This supports the idea of LADA as a mix of both T1D and T2D, but suggests that the genes related to T1D have greater impact. LADA patients with FHD-Tl D had more T1D-like features, emphasizing the heterogeneity of LADA. (C) 2017 Elsevier Masson SAS. All rights reserved.

  • 311. Hjort, R.
    et al.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Dorkhan, M.
    Groop, L.
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Rasouli, B.
    Toumi, T.
    Carlsson, S.
    Low birth weight is associated with an increased risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes: results from ESTRID a Swedish case-control study2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S80-S80Article in journal (Other academic)
  • 312.
    Hjort, R.
    et al.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Lofvenborg, J. E.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Ahlqvist, E.
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden..
    Alfredsson, L.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Andersson, T.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.;Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden..
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Groop, L.
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Rasouli, B.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Rosengren, A.
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden..
    Tuomi, T.
    Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland.;Univ Helsinki, Helsinki Univ Hosp, Res Program Diabet & Obes, Div Endocrinol,Abdominal Ctr, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Carlsson, S.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Overweight, obesity, genetic susceptibility and the risk of LADA: Latent Autoimmune Diabetes in Adults2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no S1, p. S118-S118, article id 252Article in journal (Other academic)
  • 313.
    Hjort, Rebecka
    et al.
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Box 210, S-17177 Stockholm, Sweden.
    Ahlqvist, Emma
    Lund Univ, Dept Clin Sci Malmo, Clin Res Ctr, Malmo, Sweden.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Grill, Valdemar
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, NTNU, Trondheim, Norway;Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Endocrinol, Trondheim, Norway.
    Groop, Leif
    Lund Univ, Dept Clin Sci Malmo, Clin Res Ctr, Malmo, Sweden;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland.
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Rasouli, Bahareh
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Box 210, S-17177 Stockholm, Sweden.
    Rosengren, Anders
    Lund Univ, Dept Clin Sci Malmo, Clin Res Ctr, Malmo, Sweden.
    Tuomi, Tiinamaija
    Univ Helsinki, Helsinki Univ Hosp, Div Endocrinol, Abdominal Ctr,Res Program Diabet & Obes, Helsinki, Finland;Folkhalsan Res Ctr, Helsinki, Finland.
    Asvold, Bjorn Olav
    Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Endocrinol, Trondheim, Norway;Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, KG Jebsen Ctr Genet Epidemiol, NTNU, Trondheim, Norway.
    Carlsson, Sofia
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Box 210, S-17177 Stockholm, Sweden.
    Overweight, obesity and the risk of LADA: results from a Swedish case-control study and the Norwegian HUNT Study2018In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, no 6, p. 1333-1343Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Excessive weight is a risk factor for type 2 diabetes, but its role in the promotion of autoimmune diabetes is not clear. We investigated the risk of latent autoimmune diabetes in adults (LADA) in relation to overweight/obesity in two large population-based studies. Methods Analyses were based on incident cases of LADA (n = 425) and type 2 diabetes (n = 1420), and 1704 randomly selected control participants from a Swedish case-control study and prospective data from the Norwegian HUNT Study including 147 people with LADA and 1,012,957 person-years of follow-up (1984-2008). We present adjusted ORs and HRs with 95% CI. Results In the Swedish data, obesity was associated with an increased risk of LADA (OR 2.93, 95% CI 2.17, 3.97), which was even stronger for type 2 diabetes (OR 18.88, 95% CI 14.29, 24.94). The association was stronger in LADA with low GAD antibody (GADA; <median) (OR 4.25; 95% CI 2.76, 6.52) but present also in LADA with high GADA (OR 2.14; 95% CI 1.42, 3.24). In the Swedish data, obese vs normal weight LADA patients had lower GADA levels, better beta cell function, and were more likely to have low-risk HLA-genotypes. The combination of overweight and family history of diabetes (FHD) conferred an OR of 4.57 (95% CI 3.27, 6.39) for LADA and 24.51 (95% CI 17.82, 33.71) for type 2 diabetes. Prospective data from HUNT indicated even stronger associations; HR for LADA was 6.07 (95% CI 3.76, 9.78) for obesity and 7.45 (95% CI 4.02, 13.82) for overweight and FHD. Conclusions/interpretation Overweight/obesity is associated with increased risk of LADA, particularly when in combination with FHD. These findings support the hypothesis that, even in the presence of autoimmunity, factors linked to insulin resistance, such as excessive weight, could promote onset of diabetes.

  • 314.
    Hjort, Rebecka
    et al.
    Karolinska Inst, Inst Environm Med, Epidemiol Unit, S-17177 Stockholm, Sweden..
    Alfredsson, Lars
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, S-17177 Stockholm, Sweden..
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Groop, Leif
    Lund Univ, Clin Res Ctr, Dept Clin Sci Malmo, Malmo, Sweden..
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Storm, Petter
    Lund Univ, Clin Res Ctr, Dept Clin Sci Malmo, Malmo, Sweden..
    Tuomi, Tiinamaija
    Helsinki Univ Hosp, Div Endocrinol, Abdominal Ctr, Helsinki, Finland.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland.;Univ Helsinki, Res Program Diabet & Obes, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Carlsson, Sofia
    Karolinska Inst, Inst Environm Med, Epidemiol Unit, S-17177 Stockholm, Sweden..
    Low birthweight is associated with an increased risk of LADA and type 2 diabetes: results from a Swedish case-control study2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 11, p. 2525-2532Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Our aim was to investigate the association between birthweight and latent autoimmune diabetes in adults (LADA), a common diabetes form with features of both type 1 and type 2 diabetes. Methods We used data from the Epidemiological Study of Risk Factors for LADA and Type 2 Diabetes (ESTRID), a Swedish population-based study. Eligible for the analysis were 134 incident LADA cases (glutamic acid decarboxylase antibody [GADA] positive), 350 incident type 2 diabetes cases (GADA negative) and 603 randomly selected controls. We present ORs and 95% CIs for LADA and type 2 diabetes in relation to birthweight, adjusted for sex, age, BMI and family history of diabetes. Results Low birthweight increased the risk of LADA as well as the risk of type 2 diabetes; OR per kg reduction was estimated as 1.52 (95% CI 1.12, 2.08) and 1.58 (1.23, 2.04), respectively. The OR for participants weighing < 3 kg compared with >= 4 kg at birth was estimated as 2.38 (1.23, 4.60) for LADA and 2.37 (1.37, 4.10) for type 2 diabetes. A combination of low birthweight (< 3 kg) and current overweight (BMI >= 25) further augmented the risk: LADA, OR 3.26 (1.69, 6.29); and type 2 diabetes, OR 39.93 (19.27, 82.71). Family history of diabetes had little impact on these estimates. Conclusions/interpretation Our results suggest that low birthweight may be a risk factor for LADA of the same strength as for type 2 diabetes. These findings support LADA, despite its autoimmune component, having an aetiology that includes factors related to type 2 diabetes.

  • 315.
    Hodik, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isaza-Correa, J. M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands..
    Kuipers, J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands..
    Giepmans, B. N. G.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands..
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Enterovirus infection of human islets of Langerhans affects beta-cell function resulting in disintegrated islets, decreased glucose stimulated insulin secretion and loss of Golgi structure2016In: BMJ OPEN DIABETES RESEARCH & CARE, ISSN 2052-4897, Vol. 4, no 1, article id e000179Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: In type 1 diabetes (T1D), most insulin-producing beta cells are destroyed, but the trigger is unknown. One of the possible triggers is a virus infection and the aim of this study was to test if enterovirus infection affects glucose stimulated insulin secretion and the effect of virus replication on cellular macromolecules and organelles involved in insulin secretion. Methods: Isolated human islets were infected with different strains of coxsackievirus B (CVB) virus and the glucose-stimulated insulin release (GSIS) was measured in a dynamic perifusion system. Classical morphological electron microscopy, large-scale electron microscopy, so-called nanotomy, and immunohistochemistry were used to study to what extent virus-infected beta cells contained insulin, and real-time PCR was used to analyze virus induced changes of islet specific genes. Results: In islets infected with CVB, GSIS was reduced in correlation with the degree of virus-induced islet disintegration. The expression of the gene encoding insulin was decreased in infected islets, whereas the expression of glucagon was not affected. Also, in islets that were somewhat disintegrated, there were uninfected beta cells. Ultrastructural analysis revealed that virus particles and virus replication complexes were only present in beta cells. There was a significant number of insulin granules remaining in the virus-infected beta cells, despite decreased expression of insulin mRNA. In addition, no typical Golgi apparatus was detected in these cells. Exposure of islets to synthetic dsRNA potentiated glucose-stimulated insulin secretion. Conclusions/interpretation: Glucose-stimulated insulin secretion; organelles involved in insulin secretion and gene expression were all affected by CVB replication in beta cells.

  • 316.
    Hogenkamp, Pleunie S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zhou, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Dahlberg, Linda Solstrand
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Stark, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Larsen, A. L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wiemerslage, Lyle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Higher resting-state activity in reward-related brain circuits in obese versus normal-weight females independent of food intake2016In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, no 11, p. 1687-1692Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In response to food cues, obese vs normal-weight individuals show greater activation in brain regions involved in the regulation of food intake under both fasted and sated conditions. Putative effects of obesity on task-independent low-frequency blood-oxygenation-level-dependent signals-that is, resting-state brain activity-in the context of food intake are, however, less well studied.

    OBJECTIVE: To compare eyes closed, whole-brain low-frequency BOLD signals between severely obese and normal-weight females, as assessed by functional magnetic resonance imaging (fMRI).

    METHODS: Fractional amplitude of low-frequency fluctuations were measured in the morning following an overnight fast in 17 obese (age: 39±11 years, body mass index (BMI): 42.3±4.8 kg m(-)(2)) and 12 normal-weight females (age: 36±12 years, BMI: 22.7±1.8 kg m(-)(2)), both before and 30 min after consumption of a standardized meal (~260 kcal).

    RESULTS: Compared with normal-weight controls, obese females had increased low-frequency activity in clusters located in the putamen, claustrum and insula (P<0.05). This group difference was not altered by food intake. Self-reported hunger dropped and plasma glucose concentrations increased after food intake (P<0.05); however, these changes did not differ between the BMI groups.

    CONCLUSION: Reward-related brain regions are more active under resting-state conditions in obese than in normal-weight females. This difference was independent of food intake under the experimental settings applied in the current study. Future studies involving males and females, as well as utilizing repeated post-prandial resting-state fMRI scans and various types of meals are needed to further investigate how food intake alters resting-state brain activity in obese humans.International Journal of Obesity advance online publication, 28 June 2016; doi:10.1038/ijo.2016.105.

  • 317.
    Holmlund-Suila, Elisa
    et al.
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Viljakainen, Heli
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Hytinantti, Timo
    Helsinki Matern Hosp, Helsinki, Finland..
    Andersson, Sture
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Makitie, Outi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Fibroblast Growth Factor 23 Concentrations Reflect Sex Differences in Mineral Metabolism and Growth in Early Infancy2016In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 85, no 4, p. 232-241Article in journal (Refereed)
    Abstract [en]

    Background: The role of fibroblast growth factor 23 (FGF23) in the regulation of mineral homeostasis in early life is inadequately understood. We aimed to explore the effects of vitamin D supplementation on serum FGF23 and to elucidate longitudinal changes in FGF23, in addition to studying its association with mineral metabolism in early infancy. Methods: Altogether 113 healthy infants received vitamin D 3 10, 30 or 40 mu g/day from age 0.5 to 3.0 months. Cord blood at birth and capillary blood samples at 3 months were analyzed for serum 25-hydroxyvitamin D, parathyroid hormone, phosphate, calcium and intact and C-terminal FGF23. Results: In repeated-measures ANCOVA, intact FGF23 concentration increased with time (p < 0.001) and C-terminal FGF23 decreased (p < 0.001). At 3 months, girls had a higher concentration of intact FGF23 (51 vs. 26 pg/ml, p < 0.001) and a greater increase over time (Delta FGF23 intact 45 vs. 16 pg/ml, p = 0.001) than boys. Vitamin D did not affect serum intact or C-terminal FGF23 concentrations. Girls showed a positive correlation between phosphate and intact FGF23 (p = 0.004), whereas in boys phosphate and C-terminal FGF23 correlated inversely (p = 0.006). Conclusions: A substantial sex-related difference in intact FGF23 concentration exists during early infancy, possibly related to differences in skeletal growth between boys and girls. (C) 2016 S. Karger AG, Basel

  • 318. Hong, N-S
    et al.
    Kim, K-S
    Lee, I-K
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jacobs, D R
    Lee, D-H
    The association between obesity and mortality in the elderly differs by serum concentrations of persistent organic pollutants: a possible explanation for the obesity paradox2011In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 36, no 9, p. 1170-1175Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Numerous studies have documented an obesity paradox in which the overweight and obese elderly have a better prognosis than those with ideal body weight. Good prognosis among the overweight or obese elderly may reflect the relative safety of storing the harmful lipophilic chemicals, known as persistent organic pollutants (POPs), in adipose tissue rather than in other critical organs. Therefore, we hypothesized lower mortality among the obese elderly with a higher body burden of POPs, but this pattern may not exist among the obese elderly with a lower body burden of POPs.

    PARTICIPANTS: Using the National Health and Nutrition Examination Survey (NHANES) 1999-2004 study with a mean 4.2-year follow-up, we tested whether the association between fat mass and total mortality in 635 (652 for organochlorine pesticides) elderly participants aged >= 70 years differed depending on serum concentrations of 23 POPs.

    RESULTS: There were statistically significant interactions between fat mass and POPs in predicting total mortality. In those with low POP concentrations, there was no obesity paradox; mortality increased with fat mass (hazard ratios about 2-3 in the highest vs lowest quintile of fat mass). However, consistent with an obesity paradox, these patterns completely disappeared in those with high POP concentrations. Compared with the lowest quintile of fat mass, statistically significantly lower mortality was observed in the elderly in the third to fifth quintiles of fat mass. In the case of polychlorinated biphenyls, the mortality in the highest quintile of fat mass was only one-fifth of that in the lowest quintile.

    CONCLUSION: These findings are consistent with our hypothesis that adipose tissue provides relatively safe storage of toxic lipophilic chemicals, a phenomenon that could explain the obesity paradox. Although weight loss may be beneficial among the obese elderly with low POP concentrations, weight loss in the obese elderly with higher serum concentrations of POPs may carry some risk.

  • 319.
    Hopfgarten, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Stenwall, Per-Anton
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wiberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Anagandula, Mahesh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rosenling, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gene expression analysis of human islets in a subject at onset of type 1 diabetes2014In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 51, no 2, p. 199-204Article in journal (Refereed)
    Abstract [en]

    Swollen islet cells have been repeatedly described at onset of type 1 diabetes, but the underlying mechanism of this observation, termed hydropic degeneration, awaits characterization. In this study, laser capture microdissection was applied to extract the islets from an organ donor that died at onset of type 1 diabetes and from an organ donor without pancreatic disease. Morphologic analysis revealed extensive hydropic degeneration in 73 % of the islets from the donor with type 1 diabetes. Expression levels of genes involved in apoptosis, ER stress, beta cell function, and inflammation were analyzed in isolated and laser-captured islets by qPCR. The chemokine MCP-1 was expressed in islets from the donor with type 1 diabetes while undetectable in the control donor. No other signs of inflammation were detected. There were no signs of apoptosis on the gene expression level, which was also confirmed by negative immunostaining for cleaved caspase-8. There was an increased expression of the transcription factor ATF4, involved in transcription of ER stress genes, in the diabetic islets, but no further signs of ER stress were identified. In summary, on the transcription level, islets at onset of type 1 diabetes in which many beta cells display hydropic degeneration show no obvious signs of apoptosis, ER stress, or inflammation, supporting the notion that these cells are responding normally to high glucose and eventually succumbing to beta cell exhaustion. Also, this study validates the feasibility of performing qPCR analysis of RNA extracted from islets from subjects with recent onset of T1D and healthy controls by laser capture microdissection.

  • 320.
    Hrsch, D.
    et al.
    Zent Klin Bad Berka, Bad Berka, Germany..
    Kulke, M.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Caplin, M.
    Royal Free Hosp, London, England..
    Anthony, L.
    Univ Kentucky, Lexington, KY 40506 USA..
    Bergsland, E.
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Warner, R.
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA..
    Lombard-Bohas, C.
    Hosp Civils Lyon, Hop Edouard Herriot, Lyon, France..
    Kunz, P.
    Stanford Univ, Palo Alto, CA 94304 USA..
    Valle, J.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England..
    Fleming, D.
    Ipsen BioSci, Cambridge, MA USA..
    Lapuerta, P.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Banks, P.
    Lexicon Pharmaceut Inc, The Woodlands, TX USA..
    Pavel, M.
    Charite, Berlin, Germany..
    Efficacy and Safety of Telotristat Etiprate in Patients with Carcinoid Syndrome Not Adequately Controlled by Somatostatin Analog Therapy: Analysis of the Ongoing TELESTAR Extension Period2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, p. 88-88Article in journal (Refereed)
  • 321. Huang, Xiaoyan
    et al.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Lindholm, Bengt
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Carrero, Juan Jesús
    Serum and adipose tissue fatty acid composition as biomarkers of habitual dietary fat intake in elderly men with chronic kidney disease2014In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, no 1, p. 128-136Article in journal (Refereed)
    Abstract [en]

    Background

    Fatty acid (FA) composition in serum cholesterol esters (CE) and adipose tissue (AT) reflect the long-term FA intake in the general population. Because both dietary intake and FA biomarkers associate with renal function, our aim was to identify which CE and AT FAs are useful biomarkers of habitual FA intake in individuals with chronic kidney disease (CKD).

    Methods

    Cross-sectional analysis was performed in 506 men (aged 70 years) with a glomerular filtration rate (GFR) of <60 mL/min per 1.73 m(2) from the Uppsala Longitudinal Study of Adult Men cohort. Dietary habits were evaluated with a 7-day dietary record. FA compositions in CE and AT were analyzed by gas-liquid chromatography in two random subsamples of 248 and 318 individuals, respectively.

    Results

    Both CE and AT linoleic acid and docosahexaenoic acid (DHA) were strongly associated with their corresponding intake, after adjustments for non-dietary factors. The proportions of eicosapentaenoic acid (EPA) and palmitic acid in CE and AT moderately correlated with dietary intake, whereas correlations of other FAs were weaker or absent. Proportions of EPA and DHA in CE and AT were positively associated with the total energy-adjusted fish intake. Results were confirmed in adequate reporters as identified by the Goldberg cutoff method. These relationships held constant, regardless of a GFR above or below 45 mL/min per 1.73 m(2) or the prevalence of microalbuminuria.

    Conclusions

    Proportions of EPA, DHA, palmitic and linoleic acid in serum CE and AT are good indicators of their dietary intake in men with CKD. They can be considered valid biomarkers for epidemiological studies and assessment of compliance.

  • 322.
    Husdal, Rebecka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Karlsson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Leksell, Janeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eliasson, Björn
    Jansson, Stefan
    Jerden, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Stålhammar, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Steen, Lars
    Wallman, Thorne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Svensson, Ann-Marie
    Thors Adolfsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Resources and organisation in primary health care are associated with HbA1c level: A nationwide study of 230958 people with Type 2 diabetes mellitus.2018In: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 12, no 1, p. 23-33Article in journal (Refereed)
    Abstract [en]

    AIMS: To examine the association between personnel resources and organisational features of primary health care centres (PHCCs) and individual HbA1c level in people with Type 2 diabetes mellitus (T2DM).

    METHODS: People with T2DM attending 846 PHCCs (n=230958) were included in this cross-sectional study based on PHCC-level data from a questionnaire sent to PHCCs in 2013 and individual-level clinical data from 2013 for people with T2DM reported in the Swedish National Diabetes Register, linked to individual-level data on socio-economic status and comorbidities. Data were analysed using a generalized estimating equations linear regression models.

    RESULTS: After adjusting for PHCC- and individual-level confounding factors, personnel resources associated with lower individual HbA1c level were mean credits of diabetes-specific education among registered nurses (RNs) (-0.02mmol/mol for each additional credit; P<0.001) and length of regular visits to RNs (-0.19mmol/mol for each additional 15min; P<0.001). Organisational features associated with HbA1c level were having a diabetes team (-0.18mmol/mol; P<0.01) and providing group education (-0.20mmol/mol; P<0.01).

    CONCLUSIONS: In this large sample, PHCC personnel resources and organisational features were associated with lower HbA1c level in people with T2DM.

  • 323.
    Husdal, Rebecka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Rosenblad, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Leksell, Janeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eliasson, Björn
    Jansson, Stefan
    Jerdén, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Stålhammar, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Steen, Lars
    Wallman, Thorne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Adolfsson, Eva Thors
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Resource allocation and organisational features in Swedish primary diabetes care: Changes from 2006 to 20132017In: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 11, no 1, p. 20-28Article in journal (Refereed)
    Abstract [en]

    AIMS: To compare the resource allocation and organisational features in Swedish primary diabetes care for patients with type 2 diabetes mellitus (T2DM) between 2006 and 2013.

    METHODS: Using a repeated cross-sectional study design, questionnaires covering personnel resources and organisational features for patients with T2DM in 2006 and 2013 were sent to all Swedish primary health care centres (PHCCs) during the following year. In total, 684 (74.3%) PHCCs responded in 2006 and 880 (76.4%) in 2013.

    RESULTS: Compared with 2006, the median list size had decreased in 2013 (p<0.001), whereas the median number of listed patients with T2DM had increased (p<0.001). Time devoted to patients with T2DM and diabetes-specific education levels for registered nurses (RNs) had increased, and more PHCCs had in-house psychologists (all p<0.001). The use of follow-up systems and medical check-ups had increased (all p<0.05). Individual counselling was more often based on patients' needs, while arrangement of group-based education remained low. Patient participation in setting treatment targets mainly remained low.

    CONCLUSIONS: Even though the diabetes-specific educational level among RNs increased, the arrangement of group-based education and patient participation in setting treatment targets remained low. These results are of concern and should be prioritised as key features in the care of patients with T2DM.

  • 324.
    Husdal, Rebecka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Rosenblad, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Leksell, Janeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden..
    Thors Adolfsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Hosp Vastmanland, Dept Primary Hlth Care, Reg Vastmanland, Vasteras, Sweden..
    Organisation of diabetes care is associated with systolic blood pressure level: a cross-sectional study of 230,958 people with type 2 diabetes2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no S1, p. S298-S299, article id 657Article in journal (Other academic)
  • 325.
    Husdal, Rebecka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Thors Adolfsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Leksell, Janeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Eliasson, Björn
    Sahlgrens Univ Hosp, Dept Med, Gothenburg, Sweden.
    Jansson, Stefan
    Örebro Univ, Univ Hlth Care Res Ctr, Sch Med Sci, Örebro, Sweden.
    Jerdén, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Stålhammar, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Steen, Lars
    Sörmland Cty Council, Drug & Therapeut Comm, Eskilstuna, Sweden.
    Wallman, Thorne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Svensson, Ann-Marie
    Natl Diabet Register, Ctr Registers, Gothenburg, Sweden.
    Rosenblad, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Associations between quality of work features in primary health care and glycaemic control in people with Type 2 diabetes mellitus: A nationwide survey.2019In: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 13, no 2, p. 176-186, article id S1751-9918(18)30277-8Article in journal (Refereed)
    Abstract [en]

    Aims: To describe and analyse the associations between primary health care centres’ (PHCCs’) quality of work (QOW) and individual HbA1c levels in people with Type 2 diabetes mellitus (T2DM).

    Methods: This cross-sectional study invited all 1152 Swedish PHCCs to answer a questionnaire addressing QOW conditions. Clinical, socio-economic and comorbidity data for 230,958 people with T2DM were linked to data on QOW conditions for 846 (73.4%) PHCCs.

    Results: Of the participants, 56% had controlled (≤52 mmol/mol), 31.9% intermediate (53–69 mmol/mol), and 12.1% uncontrolled (≥70 mmol/mol) HbA1c. An explanatory factor analysis identified seven QOW features. The features having a call-recall system, having individualized treatment plans, PHCCs’ results always on the agenda, and having a follow-up strategy combined with taking responsibility of outcomes/results were associated with lower HbA1c levels in the controlled group (all < 0.05). For people with intermediate or uncontrolled HbA1c, having individualized treatment plans was the only QOW feature that was significantly associated with a lower HbA1c level (< 0.05).

    Conclusions: This nationwide study adds important knowledge regarding associations between QOW in real life clinical practice and HbA1c levels. PHCCs’ QOW may mainly only benefit people with controlled HbA1c and more effective QOW strategies are needed to support people with uncontrolled HbA1c.

  • 326.
    Hänni, Arvo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Treatment with a beta-blocker with beta-2-agonism improves glucose and lipid metabolism in essential hypertension1994In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 43, p. 455-461Article in journal (Refereed)
  • 327.
    Hänni, Arvo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Falun Cent Hosp, Dept Surg, Bariatr Clin, Falun, Sweden.
    Nilsen, Inger
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Food, Nutrition and Dietetics. Mora Hosp, Dept Surg, Mora, Sweden.
    Johansson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Falun Cent Hosp, Dept Surg, Bariatr Clin, Falun, Sweden.
    Increased circulating magnesium concentrations after Roux-en-Y gastric bypass surgery in patients with type 2 diabetes2018In: Surgery for Obesity and Related Diseases, ISSN 1550-7289, E-ISSN 1878-7533, Vol. 14, no 5, p. 576-582Article in journal (Refereed)
    Abstract [en]

    Background: Low circulating magnesium concentrations predict cardiovascular and all-cause mortality in patients with type 2 diabetes (T2D). Epidemiologic and clinical studies have indicated lower extra- and intracellular magnesium concentrations in patients with diabetes.

    Objective: We aimed to describe alterations, if any, in circulating magnesium concentrations after laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) in patients with obesity and T2D.

    Setting: Outpatient clinic of obesity and central hospital.

    Methods: Retrospective analysis of 1-year outcome of plasma magnesium (p-Mg) and glucometabolic status in all consecutive patients who underwent primary LRYGBP and who completed the follow-up visits, including biochemical test panels 6 and 12 months after surgery.

    Results: LRYGBP and complete follow-up visits were performed in 51 patients with T2D and 86 patients without T2D. All patients were given similar dietary advice and multivitamin and mineral supplementation after surgery. Before RYGB, the patients with T2D showed lower p-Mg compared with patients without T2D (.79 ± .06 mM and .82 ± .05 mM, respectively, P<.01). P-Mg was inversely correlated to fasting blood glucose and glycosylated hemoglobin levels. After surgery, mean p-Mg increased by 5.2% in the group with T2D compared with 1.4% in the patients without T2D (P<.01), ending at an equal level of .83 mM. The alterations in p-Mg were inversely related to the changes in fasting glucose and glycosylated hemoglobin concentrations.

    Conclusion: The lowered p-Mg associated with impaired glucometabolic status in patients with T2D was increased after LRYGBP, reaching similar concentrations as in patients without T2D.

  • 328.
    Höglund, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mattsson, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tyrberg, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Andersson, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Growth Hormone Increases Beta-Cell Proliferation in Transplanted Human and Fetal Rat Islets2009In: Journal of the Pancreas, ISSN 1590-8577, E-ISSN 1590-8577, Vol. 10, no 3, p. 242-248Article in journal (Refereed)
    Abstract [en]

    Objective The aim of the study was to increase the number of human islet beta-cells after transplantation with injections of human growth hormone (hGH).

     

    Interventions Human islets and fetal rat islets were transplanted under the left kidney capsule and under the right kidney capsule, respectively in nude normoglycemic mice which were then given a daily injection of 200 µg hGH for 1-4 weeks.

     

    Main outcome measure Beta-cell proliferation was determined using thymidine incorporation and the beta-cell area was assessed using light microscopy.

     

    Results Mice given hGH increased their body weight one week after transplantation and had a more efficient removal of glucose after 3 and 4 weeks. Treatment with hGH resulted in increased beta-cell proliferation in human and fetal rat beta-cells, and the beta-cell area tended to increase. However, serum insulin concentrations and pancreas insulin content remained unchanged.

     

    Conclusions hGH increased the proliferation of transplanted human beta-cells as well as improving the glucose tolerance of the transplanted mice.

  • 329.
    Iliadis, Stavros
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sylvén, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Jocelien, Olivier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Hannefors, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Elfström, Dick
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Corticotropin-releasing hormone and postpartum depression: A longitudinal study2015In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 61, p. 61-61Article in journal (Other academic)
  • 330.
    Ingelsson, Erik
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
    Kilpeläinen, Tuomas O.
    The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Genome-wide association studies (GWAS) of adiposity2016In: The Genetics of Type 2 Diabetes and Related Traits: Biology, Physiology and Translation / [ed] Jose C. Florez, Cham: Springer Publishing Company, 2016, p. 91-109Chapter in book (Refereed)
    Abstract [en]

    Adiposity is strongly heritable and one of the leading risk factors for type 2 diabetes, cardiovascular disease, cancer, and premature death. In the past 8 years, genome-wide association studies (GWAS) have greatly increased our understanding of the genes and biological pathways that regulate adiposity by identifying more than 100 novel susceptibility loci for overall adiposity and more than 70 loci for body fat distribution. The results for overall adiposity highlight a significant neuronal component, whereas loci regulating body fat distribution demonstrate a central role for adipocyte biology and insulin resistance in the pathophysiology. The effect sizes of all identified loci are small, and even in aggregate, they explain <3 % of the variance in each adiposity trait. This and other evidence suggest that numerous new loci will be identified in extended meta-analyses in the future. The translation of the new discoveries into clinical care remains a major challenge. As the first step, further studies are required to establish the causal genes and variants and to disentangle the exact physiological mechanisms underlying each genotype-phenotype association.

  • 331.
    Isaksson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Nilsson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Lindblad, Frank
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Early psychosocial adversity and cortisol levels in children with attention-deficit/hyperactivity disorder2013In: European Child and Adolescent Psychiatry, ISSN 1018-8827, E-ISSN 1435-165X, Vol. 22, no 7, p. 425-432Article in journal (Refereed)
    Abstract [en]

    Previous studies suggest a different regulation of the hypothalamus-pituitary-adrenal axis (HPA-axis) with lower diurnal cortisol levels, especially in the morning, in children with attention-deficit/hyperactivity disorder (ADHD) compared with controls. Since exposure to foetal and childhood psychosocial adversity has been associated with both ADHD and HPA-axis functioning, such exposures may explain these low cortisol levels in ADHD via early programming of the HPA-axis. Thus, our main aim was to retrospectively study foetal and early childhood exposures to psychosocial adversity in children with ADHD and to relate these exposures to cortisol levels. Saliva samples were collected during a regular weekday in children, 6-17 years old, with clinically confirmed ADHD (n = 197) and non-affected comparisons (n = 221) for radioimmunoassay analysis of cortisol. Parental rating scales were used for categorising subtypes of ADHD and degree of exposure to adversity. Children with ADHD had more reports of at least one rated foetal adversity (p = 0.041) and childhood adversity (p < 0.001) than comparisons. The association between low morning cortisol levels and ADHD-symptoms remained when analyses were adjusted for adversities, age, sex, sampling time and symptoms of oppositional defiant disorder. No relation was found between exposures to foetal/childhood adversity and cortisol levels except for a positive relation between childhood adversity and cortisol morning increase in children with ADHD. The hypothesis that early adversity may influence the HPA-axis, leading to lower cortisol levels in children with ADHD, was not supported by our findings.

  • 332. Ishikawa, T.
    et al.
    Takemoto, M.
    Akimoto, Y.
    Yan, K.
    Kenichi, S.
    He, P.
    Ishibashi, R.
    Maezawa, Y.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tryggvason, K.
    Yokote, K.
    A novel podocyte gene, R3h domain containing-like inhibits non-canonical TGF-beta signalling2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S44-S44Article in journal (Other academic)
  • 333.
    Iversen, Marjolein M.
    et al.
    Bergen Univ Coll, Fac Hlth & Social Sci, Ctr Evidence Based Practice, Bergen, Norway.;Stavanger Univ Hosp, Endocrinol Sect, Dept Med, Stavanger, Norway..
    Graue, Marit
    Bergen Univ Coll, Fac Hlth & Social Sci, Ctr Evidence Based Practice, Bergen, Norway.;Haukeland Hosp, Dept Pediat, Bergen, Norway..
    Leksell, Janeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden..
    Smide, Bibbi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Zoffmann, Vibeke
    Rigshosp, Univ Copenhagen Hosp, Juliane Marie Ctr, Res Womens & Childrens Hlth, Copenhagen, Denmark..
    Sigurdardottir, Arun K.
    Univ Akureyri, Sch Hlth Sci, Akureyri, Iceland..
    Characteristics of nursing studies in diabetes research published over three decades in Sweden, Norway, Denmark and Iceland: a narrative review of the literature2016In: Scandinavian Journal of Caring Sciences, ISSN 0283-9318, E-ISSN 1471-6712, Vol. 30, no 2, p. 241-249Article, review/survey (Refereed)
    Abstract [en]

    Similarities and differences across borders of Nordic countries constitute a suitable context for investigating and discussing factors related to the development of diabetes nursing research over the last three decades. The present study reviewed the entire body of contemporary diabetes nursing research literature originating in four Nordic countries: Norway, Sweden, Denmark and Iceland. Our aims were (i) to catalogue and characterise trends in research designs and research areas of these studies published over time and (ii) to describe how research involving nurses in Nordic countries has contributed to diabetes research overall. The larger goal of our analyses was to produce a comprehensive picture of this research in order to guide future studies in the field. We conducted a narrative literature review by systematically searching Medline, Medline in process, EMBASE, CINAHL, PsycINFO and Cochrane databases. These searches were limited to studies published between 1979 and 2009 that had an abstract available in English or a Nordic language. Two researchers independently selected studies for analysis, leading to the inclusion of 164 relevant publications for analysis. In summary, Nordic nurse researchers have contributed to the development of new knowledge in self-management of diabetes in childhood, adolescence and adulthood, and to some extent also in the treatment and care of diabetes foot ulcers. Future research may benefit from (i) larger nurse-led research programmes organised in networks in order to share knowledge and expertise across national groups and borders, (ii) more multidisciplinary collaborations in order to promote patient-centred care and (iii) further research directed towards improving the dissemination and implementation of research findings. Using complex intervention designs and a mix of research methods will enrich the research.

  • 334. Jahan, Mahabuba
    et al.
    Johnström, Peter
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svedberg, Marie
    Winzell, Maria Sörhede
    Bernström, Jenny
    Kingston, Lee
    Schou, Magnus
    Jia, Zhisheng
    Skrtic, Stanko
    Johansson, Lars
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Farde, Lars
    Halldin, Christer
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass.2018In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 8, article id 113Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand.

    METHODS: The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments.

    RESULTS: The radiochemical purity of the resulting radioligand [11C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [3H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was > 10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy.

    CONCLUSION: We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM.

  • 335.
    Jansson, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Andersson, Dan KG
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Effects of fasting blood glucose, diabetes treatment, blood pressure, and anti-hypertension treatment on cardiovascular disease incidence: a 30-year follow-up study of 740 incident patients with type 2 diabetes2013In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491Article in journal (Refereed)
    Abstract [en]

    Aims To analyse the effects of hyperglycaemia and blood pressure, diabetes and anti-hypertension treatment on total and various types of cardiovascular disease incidence in patients with Type 2 diabetes followed for 30years. Methods A total of 740 incident patients with Type 2 diabetes were registered at the Laxa Primary Health Care Centre, Sweden between 1972 and 2001. Information on systolic, diastolic, and mean arterial blood pressure, mean fasting blood glucose, type of diabetes and anti-hypertension treatment was obtained from the patient records, and information on cardiovascular disease, myocardial infarction and stroke events from National Registers. Results During the follow-up period the cumulative incidence of cardiovascular disease increased significantly with male sex (HR 1.52, 95% CI 1.251.85), age (HR 1.05, 95% CI 1.041.07), year of diabetes onset (HR 1.03, 95% CI 1.011.05), BMI, (HR 1.04, 95% CI 1.021.07), mean arterial blood pressure (HR 1.04, 95% CI 1.021.05) and number of previous cardiovascular disease events (HR 1.15, 95% CI 1.101.21), and decreased significantly with sulfonylurea treatment (HR 0.64, 95% CI 0.490.84), insulin (HR 0.57, 95% CI 0.330.98) and calcium channel blocker treatment (HR, 0.69, 95% CI 0.480.99). Cumulative incidence of myocardial infarction increased significantly with male sex, age, BMI, mean arterial blood pressure, number of previous myocardial infarction events and diuretic treatment, and decreased with metformin treatment. Cumulative incidence of stroke increased with age, year of diabetes onset, mean arterial blood pressure, and previous number of stroke events. Conclusions Cumulative cardiovascular disease, myocardial infarction and incidence of stroke increased with number of previous events and presence of hypertension and decreased with pharmacological anti-diabetic treatment and, to a lesser extent, with anti-hypertension treatment.

  • 336.
    Jansson, Stefan P O
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Andersson, D K G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Mortality and cardiovascular disease outcomes among 740 patients with new-onset Type 2 diabetes detected by screening or clinically diagnosed in general practice.2016In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 33, no 3, p. 324-331Article in journal (Refereed)
    Abstract [en]

    AIM: Screening for Type 2 diabetes among people at high risk is recommended by many organizations. The aim of this study was to analyse all-cause mortality and cardiovascular disease (CVD) outcomes in patients with Type 2 diabetes detected by screening or diagnosed clinically.

    METHODS: A diabetes register was established at the primary healthcare centre in Laxå, Sweden beginning in 1972. The register was based on data from clinical records with information on medical treatment and laboratory data, as well as all-cause mortality, CVD, myocardial infarction and stroke events from national registers until 31 December 2013. A total of 740 patients with new-onset Type 2 diabetes were registered between 1972 and 2001. In addition, an opportunistic diabetes-screening programme involving people aged 35-79 years started in 1983 and was repeated onwards in 5-year cycles.

    RESULTS: Baseline characteristics showed a significantly higher CVD risk, mainly depending on more prevalent CVD events in the screened compared with the clinically detected group (propensity score 0.59 vs. 0.46, P < 0.0001). After mean follow-up periods of 12.9 and 13.6 years for screening detected vs. clinically detected patients, respectively, hazard ratios were as follows: all-cause mortality, 0.99 (P = 0.89); CVD, 1.17 (P = 0.10); myocardial infarction, 1.08 (P = 0.49); and stroke, 1.03 (P = 0.83).

    CONCLUSIONS: No reduction in total mortality or CVD outcomes was found in patients with Type 2 diabetes that was detected by screening compared with those diagnosed clinically.

  • 337.
    Jastroch, Martin
    et al.
    German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Diabet & Obes, D-85748 Garching, Germany..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    When pigs fly, UCP1 makes heat2015In: MOLECULAR METABOLISM, ISSN 2212-8778, Vol. 4, no 5, p. 359-362Article in journal (Other academic)
    Abstract [en]

    Brown and beige adipose tissue may represent important therapeutic targets for the treatment of diabetes and obesity as these organs dissipate nutrient energy as heat through the thermogenic uncoupling protein 1 (UCP1). While mice are commonly used to mimic the potential effects of brown/beige adipose tissue that may act in human metabolism, new animal models are edging into the market for translational medicine. Pigs reflect human metabolism better than mice in multiple parameters such as obesity-induced hyperglycemia, cholesterol profiles and energy metabolism. Recently, it was reported that energy expenditure and body temperature in pigs is induced by the hormone leptin, and that leptin's action is mediated by UCP1 in adipose tissue. Given the tremendous importance of identifying molecular mechanisms for targeting therapeutics, we critically examine the evidence supporting the presence of UCP1 in pigs and conclude that methodological shortcomings prevent an unequivocal claim for the presence of UCP1 in pigs. Despite this, we believe that leptin's effects on energy expenditure in pigs are potentially more transformative to human medicine in the absence of UCP1, as adult and obese humans possess only minor amounts of UCP1. In general, we propose that the biology of new animal models requires attention to comparative studies with humans given the increasing amount of genomic information for various animal species.

  • 338.
    Jensen, Robert T.
    et al.
    NIDDK, Cell Biol Sect, NIH, Bethesda, MD USA.
    Bodei, Lisa
    Mem Sloan Kettering Canc Ctr, New York, NY USA.
    Capdevila, J.
    Univ Autonoma Barcelona, Vall dHebron Univ Hosp, Vall Hebron Inst Oncol, Dept Med Oncol, Barcelona, Spain.
    Couvelard, Anne
    Hop Bichat Claude Bernard, Serv Pathol, Paris, France.
    Falconi, Massimo
    Univ Vita & Salute, San Raffaele Hosp, IRCCS, Chirurg Pancreas, Milan, Italy.
    Grozinsky-Glasberg, Simona
    Hadassah Hebrew Univ, Med Ctr, Endocrinol & Metab Serv, Neuroendocrine Unit, Jerusalem, Israel.
    Klöppel, Günter
    Tech Univ Munich, Inst Pathol, Munich, Germany.
    Lamberts, Steven W.J.
    Erasmus MC, Div Endocrinol, Dept Internal Med, Rotterdam, Netherlands.
    Peeters, Marc
    Antwerp Univ Hosp, Dept Oncol, Edegem, Belgium.
    Rindi, Guido
    Univ Cattolica Sacro Cuore, Policlin A Gemelli, Inst Anat Pathol, Rome, Italy.
    Rinke, Anja
    UKGM Marburg, Dept Gastroenterol, Marburg, Germany; Philipps Univ, Marburg, Germany.
    Rothmund, M.
    Philipps Univ, Dept Surg, Marburg, Germany.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Fazio, Nicola
    European Inst Oncol IEO, Gastrointestinal & Neuroendocrine Oncol Unit, Milan, Italy.
    Sundin, Anders (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. European Neuroendocrine Tumor Society (ENETS), Berlin, Germany.
    Tiensuu Janson, Eva (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology. European Neuroendocrine Tumor Society (ENETS), Berlin, Germany.
    Welin, Staffan (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology. European Neuroendocrine Tumor Society (ENETS), Berlin, Germany.
    Unmet Needs in Functional and Nonfunctional pancreatic neuroendocrine neoplasms2019In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, no 1, p. 26-36Article in journal (Refereed)
    Abstract [en]

    Recently, the European Neuroendocrine Tumor Society (ENETS) held working sessions composed of members of the advisory board and other neuroendocrine neoplasm (NEN) experts to attempt to identify unmet needs in NENs in different locations or with advanced/poorly differentiated NENs. This report briefly summarizes the main proposed areas of unmet needs in patients with functional and nonfunctional pancreatic NENs.

  • 339. Jia, Ting
    et al.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Xu, Hong
    Lindholm, Bengt
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Larsson, Tobias E.
    Ikizler, Talat Alp
    Carrero, Juan J.
    Kidney Function, beta-Cell Function and Glucose Tolerance in Older Men2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 2, p. 587-593Article in journal (Refereed)
    Abstract [en]

    Context: Kidney dysfunction induces insulin resistance, but it is unknown if beta cell function is affected. Objective: To investigate insulin release (beta cell function) and glucose tolerance following a standardized oral glucose tolerance test (OGTT) across kidney function strata. Setting and Design: Community-based cohort study from the Uppsala Longitudinal Study of Adult Men (ULSAM). Participants and Main Outcome Measure: Included were 1015 nondiabetic Swedish men aged 70-71 years. All participants underwent OGTT and euglycaemic hyperinsulinaemic clamp (HEGC) tests, allowing determination of insulin sensitivity, beta cell function, and glucose tolerance. Kidney function was estimated by cystatin C-algorithms. Mixed models were used to identify determinants of insulin secretion after the hyperglycemic load. Results: Asmanyas 466 (46%) of participants presented moderate-advanced kidney disease. Insulin sensitivity (by HEGC) decreased across decreasing kidney function quartiles. After the OGTT challenge, however, beta cell function indices (area under the curve for insulin release, the estimated first phase insulin release, and the insulinogenic index) were incrementally higher. Neither the oral disposition index nor the 2-h postload glucose tolerance differed across the kidney function strata. Mixed models showed that dynamic insulin release during the OGTT was inversely associated with kidney function, despite the correction for each individual's insulin sensitivity or its risk factors. Conclusions: In older men, beta cell function after a hyperglycemic load appropriately compensated the loss in insulin sensitivity that accompanies kidney dysfunction. As a result, the net balance between insulin sensitivity and beta cell function was preserved.

  • 340.
    Jobs, Elisabeth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Jobs, Magnus
    University of Dalarna.
    Nerpin, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Iggman, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lars, Lind
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Serum cathepsin S is associated with decreased insulin sensitivity and the development of diabetes type 2 in a community-based cohort of elderly men2013In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, no 1, p. 163-165Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.

    RESEARCH DESIGN AND METHODS:

    Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.

    RESULTS:

    After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase -0.09 [95% CI -0.14 to -0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08-2.01], P = 0.01).

    CONCLUSIONS:

    Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.

  • 341. Johannsson, Gudmundur
    et al.
    Falorni, Alberto
    Skrtic, Stanko
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Quinkler, Marcus
    Monson, John P.
    Stewart, Paul M.
    Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 82, no 1, p. 2-11Article, review/survey (Refereed)
    Abstract [en]

    Glucocorticoid replacement therapy in patients with adrenal insufficiency (AI), whether primary (Addison's disease) or secondary (due to hypopituitarism), has been established for some 50years. The current standard treatment regimen involves twice- or thrice-daily dosing with a glucocorticoid, most commonly oral hydrocortisone. Based on previous small-scale studies and clinical perception, life expectancy with conventional glucocorticoid replacement therapy has been considered normal, with a low incidence of adverse events. Data from the past 10-15years, however, have shown that morbidity remains high and life expectancy is reduced. The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress-related events. This is thought to reflect a failure of treatment to replicate the natural circadian rhythm of cortisol release, together with a failure to identify and deliver individualized cortisol exposure and to manage patients adequately when increased doses are required. The resulting over- or under-treatment may result in Cushing-like symptoms or adrenal crisis, respectively. This review summarizes the morbidity and mortality seen in patients receiving the current standard of care for AI and suggests areas for improvement in glucocorticoid replacement therapy.

  • 342.
    Johannsson, Gudmundur
    et al.
    Univ Gothenburg, Dept Endocrinol, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Marelli, Claudio
    Shire Int GmbH, Zug, Switzerland..
    Rockich, Kevin
    Shire PLC, Wayne, PA USA..
    Skrtic, Stanko
    Univ Gothenburg, Dept Endocrinol, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden.;AstraZeneca R&D, Molndal, Sweden..
    Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study2016In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 175, no 1, p. 85-93Article in journal (Refereed)
    Abstract [en]

    Objective: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure-time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5-20 mg and assess intrasubject variability. Methods: Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20-55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3 x 5), and 20 mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24 h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography-tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration-time profiles. Results: DR-HC 20 mg provided higher than endogenous cortisol plasma concentrations 0-4 h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (C-max) was 82.0 and 178.1 ng/mL, while mean area under the concentration-time curve (AUC)(0-infinity) was 562.8 and 1180.8 h x ng/mL with DR-HC 5 and 20 mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20 mg. All exposure PK parameters were less than dose proportional (slope < 1). PK differences between ethnicities were explained by body weight differences. Conclusions: DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional - an important consideration when managing intercurrent illness in patients with adrenal insufficiency.

  • 343.
    Johansson, H.
    et al.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Harvey, N. C.
    Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    Oden, A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Karlsson, M. K.
    Lund Univ, Skane Univ Hosp, Dept Orthoped & Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Rosengren, B.
    Lund Univ, Skane Univ Hosp, Dept Orthoped & Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    McCloskey, E. V.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Kanis, J. A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Waning Long-Term Predictive Value Of Falls History For Incident Fracture: MROS Sweden2015In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 26, p. S42-S42Article in journal (Other academic)
  • 344.
    Johansson, H.
    et al.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Oden, A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Karlsson, M.
    Lund Univ, Skane Univ Hosp, Dept Orthopaed & Clin Sci, Malmo, Sweden..
    Lorentzon, M.
    Sahlgrens Acad, Inst Med, Dept Internal Med & Clin Nutr, Geriatr Med, Molndal, Sweden..
    Kanis, J. A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Rosengren, B.
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Mellström, D.
    Sahlgrens Acad, Inst Med, Dept Internal Med & Clin Nutr, Geriatr Med, Molndal, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    OhIsson, C.
    Univ Gothenburg, Gothenburg, Sweden..
    Harvey, N. C.
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    McCloskey, E.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Femoral Neck BMD Is Still The Preferred Site In The Assessment Of Hip Fracture In Elderly Men (10-Year Follow-Up Of MROS Sweden)2016In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 27, p. S58-S59Article in journal (Other academic)
  • 345.
    Johansson, Hans-Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hänni, Arvo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Karlsson, F. Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Edén-Engström, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öhrvall, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bileopancreatic Diversion with Duodenal Switch lowers both Early and Late Phases of Glucose, Insulin and Proinsulin responses after Meal2010In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 20, no 5, p. 549-558Article in journal (Refereed)
    Abstract [en]

    Hyperproinsulinemia is associated with obesity and type 2 diabetes. We explored the after-meal dynamics of proinsulin and insulin and postprandial effects on glucose and lipids in patients treated with bileopancreatic diversion with duodenal switch (BPD-DS) surgery compared with normal-weight controls [body mass index (BMI)+/- SD, 23.2 +/- 2.4 kg/m(2)].

    Ten previously morbidly obese (BMI +/- SD, 53.5 +/- 3.8 kg/m(2)) patients free from diabetes who had undergone BPD-DS (BMI +/- SD, 29.0 +/- 5.2 kg/m(2)) 2 years earlier were recruited. A standardised meal (2400 kJ) was ingested, and glucose, proinsulin, insulin, free fatty acids and triglycerides (TGs) were determined during 180 min. Follow-up characteristics yearly on glucose, lipids, creatinine and uric acid over 3 years after BPD-DS are presented.

    Fasting glucose and insulin were lower, 0.4 mmol/L and 4.6 pmol/L, respectively, in the BPD-DS group despite higher BMI. Fasting proinsulin was similar in both groups. Postprandial area under the curve (AUC) for glucose, proinsulin and insulin did not differ between the two groups (p = 0.106-734). Postprandial changes in glucose, proinsulin and insulin were essentially similar but absolute concentrations of proinsulin and insulin were lower in the later phases in the BPD-DS group (p = 0.052-0.001). Postprandial AUC for TGs was lower in the BPD-DS group (p = 0.005). Postprandial changes in TGs were lowered in the intermediate phase (p = 0.07-0.08) and in the late phase (0.002). Follow-up data showed markedly lowered creatinine and uric acid after BPD-DS.

    BPD-DS surgery induces a large weight loss and lowers, close to normal, postprandial responses of glucose, proinsulin and insulin but with marked lowering of TGs.

  • 346.
    Johansson, Karin
    et al.
    Linnaeus Univ, Fac Hlth & Life Sci, Dept Hlth & Care Sci, Vaxjo, Sweden.;Kronoberg Cty Council, Dept Adm, Vaxjo, Sweden.;Reg Kronoberg Cty Council, Primary Care, Vaxjo, Sweden..
    Osterberg, Sofia Almerud
    Linnaeus Univ, Fac Hlth & Life Sci, Dept Hlth & Care Sci, Vaxjo, Sweden..
    Leksell, Janeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Univ Dalarna, Sch Hlth & Social Sci, Falun, Sweden..
    Berglund, Mia
    Univ Skovde, Sch Hlth & Educ, Skovde, Sweden..
    Patients' experiences of support for learning to live with diabetes to promote health and well-being: A lifeworld phenomenological study2016In: International Journal of Qualitative Studies on Health and Well-being, ISSN 1748-2623, E-ISSN 1748-2631, Vol. 11, article id 31330Article in journal (Refereed)
    Abstract [en]

    Learning to live with diabetes in such a way that the new conditions will be a normal and natural part of life imposes requirements on the person living with diabetes. Previous studies have shown that there is no clear picture of what and how the learning that would allow persons to incorporate the illness into their everyday life will be supported. The aim of this study is to describe the phenomenon of support for learning to live with diabetes to promote health and well-being, from the patient's perspective. Data were collected by interviews with patients living with type 1 or type 2 diabetes. The interviews were analysed using a reflective lifeworld approach. The results show that reflection plays a central role for patients with diabetes in achieving a new understanding of the health process, and awareness of their own responsibility was found to be the key factor for such a reflection. The constituents are responsibility creating curiosity and willpower, openness enabling support, technology verifying bodily feelings, a permissive climate providing for participation and exchanging experiences with others. The study concludes that the challenge for caregivers is to create interactions in an open learning climate that initiates and supports reflection to promote health and well-being.

  • 347.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Properties of Endothelium and its Importance in Endogenous and Transplanted Islets of Langerhans2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Transplantation of insulin producing cells is currently the only cure for type 1 diabetes. However, even though the Edmonton protocol markedly increased the success rate of pancreatic islet transplantation, the long term insulin independence is still very poor. An adequate engraftment is critical for islet graft survival and function.

    In the present thesis, isolated islet endothelial cells were found to have a low proliferatory and migratory capacity towards vascular endothelial growth factor (VEGF), but this could be reversed by using neutralizing antibodies to the angiostatic factors thrombospondin-1, endostatin or alpha1-antitrypsin.

    In the adult islet endothelial cell, VEGF may act as a permeability inducer more than an inducer of angiogenesis. p38 MAP kinase activity has been shown to serve as a switch between these properties of VEGF. Inhibition of p38 MAP kinase by daily injections of SB203580 in the early posttransplantation phase lead to a redistribution of the islet graft blood vessels from the stroma into the endocrine tissue and this was accompanied by a higher oxygen tension.

    Besides transports of oxygen and nutrients, beta-cells may require signals from the endothelial cells for their growth and differentiation. It was demonstrated that islet endothelial cells secrete factors, including laminin, that have positive effects on beta-cell insulin release and insulin content.

    Our results suggest that improved revascularization of transplanted islets may be achieved by either inhibition of angiostatic factors, or by blocking p38 MAPkinase activity, in the implanted tissue. Islet endothelial cells have a supportive paracrine role for beta-cells that might be hampered by the normally poor revascularization.

    List of papers
    1. Inhibition of p38 MAP kinase in the early posttransplantation phase redistributes blood vessels from the surrounding stroma into the transplanted endocrine tissue
    Open this publication in new window or tab >>Inhibition of p38 MAP kinase in the early posttransplantation phase redistributes blood vessels from the surrounding stroma into the transplanted endocrine tissue
    2006 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 15, no 6, p. 483-488Article in journal (Refereed) Published
    Abstract [en]

    Transplanted pancreatic islets attain a chronically decreased vascular density following transplantation, despite the increased concentrations of vascular endothelial growth factor (VEGF) secreted from beta-cells in response to hypoxia during culture and in the immediate posttransplantation phase. VEGF, however, exerts dual effects on endothelial cells, and in islet endothelial cells of the adult, the vascular permeability-inducing effects of VEGF seem normally more pronounced than those to induce angiogenesis. p38 MAP kinase activity has recently been shown to serve as a switch to separate these properties of VEGF; inhibition of p38 MAP kinase activity enhances VEGF-induced angiogenesis and, at the same time, abrogates VEGF-induced vascular permeability. We hypothesized that the revascularization of transplanted islets may be hampered by a predisposition of adult islet endothelial cells to react to VEGF by forming fenestrae rather than migrating and proliferating. We therefore administered the p38 MAP kinase inhibitor SB203580 by daily IP injections for the first 14 days following transplantation, and then studied the influence of this treatment on the oxygen tension, blood perfusion, and vascular density of the islet grafts I month posttransplantation. SB203580 treatment redistributed islet graft blood vessels from the stroma into the endocrine tissue, and this redistribution of blood vessels into the endocrine tissue was accompanied by an increased oxygenation of the islet cells. However, the total number of blood vessels in the tissue was not affected. The blood perfusion of the islet grafts was also similar in control and SB203580-treated animals. Our results suggest that effects of VEGF to preferentially induce vascular permeability may partially contribute to, but is not the main cause of, low revascularization of transplanted islets.

    Keywords
    engraftment, Bandeiraea simplicifolia, blood flow, oxygen tension
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-24727 (URN)10.3727/000000006783981729 (DOI)000241571900005 ()17121159 (PubMedID)
    Available from: 2007-02-07 Created: 2007-02-07 Last updated: 2017-12-07Bibliographically approved
    2. Endothelial cell signalling supports pancreatic beta cellfunction in the rat
    Open this publication in new window or tab >>Endothelial cell signalling supports pancreatic beta cellfunction in the rat
    Show others...
    2009 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 11, p. 2385-2394Article in journal (Refereed) Published
    Abstract [en]

    Aims/hypothesis The proximity of endothelial cells andbeta cells in islets by necessity means that they are exposedto each other’s products. Whereas islet endothelial cellsrequire signals from beta cells to function properly,endothelin-1, thrombospondin-1 and laminins, amongothers, have been identified as endothelial-derived molecules,although their full effects on beta cells have not beenexplored. We tested the hypothesis that islet endothelialderivedproducts affect beta cell function.Methods Endothelial cells from rat islets were proliferatedand purified. Endothelium-conditioned culture medium(ECCM) was obtained by maintaining the endothelial cellsin culture medium. Islet function was evaluated followingexposure of cultured islets to standard culture medium orECCM. Changes in mRNA levels for key beta cellmetabolic enzymes were also measured in islets afterECCM exposure.Results Glucose-stimulated insulin release and islet insulincontent were markedly enhanced by exposure to ECCM.This was at least partly explained by improved mitochondrialfunction, as assessed by glucose oxidation and anupregulation of the mitochondrial gene for glycerol-3-phosphate dehydrogenase (mGpdh [also known as Gpd2]),combined with upregulation of the rate-limiting enzyme inthe glycolysis, glucokinase, in the islets. The intracellulardegradation of insulin was also decreased in the islets. Isletendothelial cells produced laminins, and the positive effectsof islet endothelial cells were prevented by addition of aneutralising antibody to the β1-chain of laminin. Additionof exogenous laminin stimulated islet function.Conclusions/interpretation This study provides proof ofprinciple that endothelial cells can affect the function of betacells in their vicinity and that this is at least partially mediatedby laminins.

    Keywords
    Endothelial cells, Beta cells, Laminin
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-109712 (URN)10.1007/s00125-009-1485-6 (DOI)000270650600018 ()19669728 (PubMedID)
    Available from: 2009-10-22 Created: 2009-10-22 Last updated: 2018-05-18Bibliographically approved
    3. Angiostatic factors normally restrict islet endothelial cell proliferation and migration: implications for islet transplantation
    Open this publication in new window or tab >>Angiostatic factors normally restrict islet endothelial cell proliferation and migration: implications for islet transplantation
    2009 (English)In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 22, no 12, p. 1182-1188Article in journal (Refereed) Published
    Abstract [en]

    New blood vessel formation in transplanted islets occurs within 7-14 days posttransplantation through both the expansion of donor islet endothelium and ingrowth of blood vessels from the implantation organ. However, several studies indicate that although the islets attract recipient blood vessels, the formed intra-islet vascular network is insufficient, which affects islet posttransplant function. This study aimed to develop an in vitro model to investigate the migration and proliferation properties of isolated liver and islet endothelium. Rat islet or liver endothelium was purified using Bandeiraea simplicifolia (BS-1)-coated Dynabeads. The liver endothelium displayed an increased migration towards islet-conditioned medium, and this chemo-attractant effect was fully prevented by adding a neutralizing vascular endothelial growth factor (VEGF)-antibody. In contrast, islet-produced VEGF failed to induce islet endothelial cell migration and only had marginal effects on islet endothelial cell proliferation. These properties could, however, be activated through blocking the effects of either endostatin, thrombospondin-1 or α1-antitrypsin. In conclusion, VEGF may attract recipient blood vessels towards intrahepatically transplanted islets, but intra-islet vascular expansion is hampered by angiostatic factors present within the islets and the islet endothelium. Inhibition of these early after transplantation may provide a strategy to restore the islet vascular network and improve islet graft function.

    Keywords
    endostatin, islet endothelial cells, islet transplantation, thrombospondin-1, alpha(1)-antitrypsin
    National Category
    Medical and Health Sciences
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-98725 (URN)10.1111/j.1432-2277.2009.00939.x (DOI)000271251800008 ()
    Available from: 2009-03-10 Created: 2009-03-02 Last updated: 2017-12-13Bibliographically approved
  • 348.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp..
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Wilking, H.
    Uppsala Univ Hosp..
    De Grauw, Haro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Takahashi, K.
    RIKEN Ctr Life Sci Technol..
    Antoni, G.
    Uppsala Univ Hosp..
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp..
    Tracer kinetic analysis of [C-11] Cetrozole as a PET tracer for aromatase in the human brain2017In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 37, p. 71-72Article in journal (Other academic)
  • 349. Jonsdottír, Ingibjörg H.
    et al.
    Halford, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Eek, Frida
    Mental health and salivary cortisol2012In: The role of saliva cortisol measurement in health and disease / [ed] Kristenson M, Garvin P, Lundberg U, Bentham eBooks, 2012, p. 132-166Chapter in book (Refereed)
    Abstract [en]

    The aim of this chapter was to analyze associations between measures of cortisol in saliva and mental health and to see if divergent results were functions of the methods used. Measures of mental health outcome included Major Depressive Disorder (MDD), symptoms of depression, and symptoms of anxiety, Burnout (BO), and Vital Exhaustion (VE). Only studies on otherwise healthy individuals were included. Cortisol measures were grouped into single time point measures, measures of deviations, laboratory test responses, Area Under the Curve (AUC), and response to dexamethasone. Some consistency is seen for MDD, mainly higher mean levels. The results regarding single measures and depressive mood are less consistent, but the overall picture for depression shows poorer diurnal deviation and response to stress. Inconsistency among papers studying depression seems to be related mainly to the study population. Very few significant findings were found for anxiety, therefore cortisol does not seem to be strongly related to anxiety. Most of the statistical analysis does not show a significant relationship between BO and cortisol, and when these are present, the results are inconsistent. One explanation seems to be the measures of BO used, probably due to the different conceptual basis for BO. VE measured using the Maastricht Questionnaire seems to be related to a poorer cortisol response to stress and poorer diurnal deviation. The coexistence of BO and VE in many studies does make it difficult to conclude how the different concepts are related to cortisol. However, an interesting difference appeared between MDD and VE in response to dexamethasone administration, showing lower suppression in MDD patients and higher suppression in VE patients. A general conclusion for all mental health measures is that a large proportion of non-significant findings are due to low power and few sampling days combined with low contrasts between study groups and within study populations. Generally, deviation measures such as diurnal deviation seem to be more valid measures compared with single measures to capture possible changes in the hypothalamus-pituitaryadrenal axis, measured using salivary cortisol.

  • 350.
    Jonsson, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yngve, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Gothenburg, Inst Biomed, Gothenburg, Sweden.
    Protein Kinase R Is Constitutively Expressed in the Human Pancreas2019In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 67, no 2, p. 99-105Article in journal (Refereed)
    Abstract [en]

    Viral infection of the insulin-producing cells in the pancreas has been proposed in the etiology of type 1 diabetes. Protein kinase R (PKR) is a cytoplasmic protein activated through phosphorylation in response to cellular stress and particularly viral infection. As PKR expression in pancreatic beta-cells has been interpreted as a viral footprint, this cross-sectional study aimed at characterizing the PKR expression in non-diabetic human pancreases. PKR expression was evaluated in pancreas tissue from 16 non-diabetic organ donors, using immunohistochemistry, qPCR, and western blot. Immunohistochemistry and western blot showed readily detectable PKR expression in the pancreatic parenchyma. The qPCR detected PKR mRNA in both endocrine and exocrine samples, with a slightly higher expression in the islets. In conclusion, PKR is constitutively expressed in both endocrine and exocrine parts of the pancreas and its expression should not be interpreted as a viral footprint in pancreatic beta cells.

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