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  • 101.
    Pereira, Maria J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lundkvist, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kamble, Prasad G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lau, Joey
    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, Clinical diabetology and metabolism.
    Martins, Julian G.
    Springer Healthcare, InSci Commun, Paris, France.
    Sjostrom, C. David
    AstraZeneca Gothenburg, Molndal, Sweden.
    Schnecke, Volker
    AstraZeneca Gothenburg, Molndal, Sweden.
    Walentinsson, Anna
    AstraZeneca Gothenburg, Molndal, Sweden.
    Johnsson, Eva
    AstraZeneca Gothenburg, Molndal, Sweden.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss2018In: Diabetes Therapy, ISSN 1869-6953, E-ISSN 1869-6961, Vol. 9, no 4, p. 1511-1532Article in journal (Refereed)
    Abstract [en]

    The sodium-glucose cotransporter 2 inhibitor dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduce bodyweight via differing and complementary mechanisms. This post hoc analysis investigated the metabolic effects and baseline associations with bodyweight loss on coadministration of dapagliflozin and exenatide once weekly (QW) among adults with obesity and without diabetes. In the primary trial, adults with obesity and without diabetes [n = 50; 18-70 years; body mass index (BMI) 30-45 kg/m(2)] were randomized to double-blind oral dapagliflozin 10 mg (DAPA) once daily plus subcutaneous long-acting exenatide 2 mg QW (ExQW) or placebo over 24 weeks, followed by an open-label extension from 24-52 weeks during which all participants received active treatment. Primary results have been published previously. This analysis evaluated: (1) the effects of DAPA + ExQW on changes in substrates [free fatty acids (FFAs), glycerol, beta-OH-butyrate, and glucose], hormones (glucagon and insulin), and insulin secretion [insulinogenic index (IGI)] via an oral glucose tolerance test (OGTT) and (2) associations between bodyweight loss and baseline characteristics (e.g., BMI), single-nucleotide polymorphisms (SNPs) associated with the GLP-1 pathway, and markers of glucose regulation. Compared with placebo at 24 weeks, 2-h FFAs post-OGTT increased (mean difference, +20.4 mu mol/l; P < 0.05), and fasting glucose, 2-h glucose post-OGTT, and glucose area under the concentration-time curve (AUC) decreased with DAPA + ExQW [mean differences, -0.68 mmol/l [P < 0.001], -2.20 mmol/l (P < 0.01), and -306 mmol/l min (P < 0.001), respectively]. Glucagon, glycerol, beta-OH-butyrate, and IGI did not differ by treatment group at 24 weeks. Over 52 weeks, DAPA + ExQW decreased fasting insulin, 2-h post-OGTT insulin, and insulin AUC. Among DAPA + ExQW-treated participants, for each copy of the SNP variant rs10010131 A allele (gene WFS1), bodyweight decreased by 2.4 kg (P < 0.05). Lower BMI and a lower IGI were also associated with greater bodyweight loss with DAPA + ExQW. Metabolic effects with DAPA + ExQW included less FFA suppression versus placebo during the OGTT, suggesting compensatory lipid mobilization for energy production when glucose availability was reduced because of glucosuria. The expected increase in glucagon with DAPA did not occur with DAPA + ExQW coadministration. Bodyweight loss with DAPA + ExQW was associated with the SNP variant rs10010131 A allele, lower baseline adiposity (BMI), and lower baseline insulin secretion (IGI). These findings require further validation. AstraZeneca.

  • 102.
    Pereira, Maria J
    et al.
    The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Palming, Jenny
    Rizell, Magnus
    Aureliano, Manuel
    Carvalho, Eugénia
    Svensson, Maria K
    Eriksson, Jan W
    The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    mTOR inhibition with rapamycin causes impaired insulin signalling and glucose uptake in human subcutaneous and omental adipocytes2012In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 355, no 1, p. 96-105Article in journal (Refereed)
    Abstract [en]

    Rapamycin is an immunosuppressive agent used after organ transplantation, but its molecular effects on glucose metabolism needs further evaluation. We explored rapamycin effects on glucose uptake and insulin signalling proteins in adipocytes obtained via subcutaneous (n=62) and omental (n=10) fat biopsies in human donors. At therapeutic concentration (0.01 μM) rapamycin reduced basal and insulin-stimulated glucose uptake by 20-30%, after short-term (15 min) or long-term (20 h) culture of subcutaneous (n=23 and n=10) and omental adipocytes (n=6 and n=7). Rapamycin reduced PKB Ser473 and AS160 Thr642 phosphorylation, and IRS2 protein levels in subcutaneous adipocytes. Additionally, it reduced mTOR-raptor, mTOR-rictor and mTOR-Sin1 interactions, suggesting decreased mTORC1 and mTORC2 formation. Rapamycin also reduced IR Tyr1146 and IRS1 Ser307/Ser616/Ser636 phosphorylation, whereas no effects were observed on the insulin stimulated IRS1-Tyr and TSC2 Thr1462 phosphorylation. This is the first study to show that rapamycin reduces glucose uptake in human adipocytes through impaired insulin signalling and this may contribute to the development of insulin resistance associated with rapamycin therapy.

  • 103.
    Pereira, Maria J
    et al.
    he Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
    Palming, Jenny
    Rizell, Magnus
    Aureliano, Manuel
    Carvalho, Eugénia
    Svensson, Maria K
    Eriksson, Jan W
    The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden.
    The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue2013In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 365, no 2, p. 260-269Article in journal (Refereed)
    Abstract [en]

    Cyclosporin A (CsA), tacrolimus and rapamycin are immunosuppressive agents (IAs) associated with insulin resistance and dyslipidemia, although their molecular effects on lipid metabolism in adipose tissue are unknown. We explored IAs effects on lipolysis, lipid storage and expression of genes involved on lipid metabolism in isolated human adipocytes and/or adipose tissue obtained via subcutaneous and omental fat biopsies. CsA, tacrolimus and rapamycin increased isoproterenol-stimulated lipolysis and inhibited lipid storage by 20-35% and enhanced isoproterenol-stimulated hormone-sensitive lipase Ser552 phosphorylation. Rapamycin also increased basal lipolysis (~20%) and impaired insulin's antilipolytic effect. Rapamycin, down-regulated the gene expression of perilipin, sterol regulatory element-binding protein 1 (SREBP1) and lipin 1, while tacrolimus down-regulated CD36 and aP2 gene expression. All three IAs increased IL-6 gene expression and secretion, but not expression and secretion of TNF-α or adiponectin. These findings suggest that CsA, tacrolimus and rapamycin enhance lipolysis, inhibit lipid storage and expression of lipogenic genes in adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.

  • 104.
    Pereira, Maria J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Palming, Jenny
    Svensson, Maria K
    Rizell, Magnus
    Dalenbäck, Jan
    Hammar, Mårten
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sidibeh, Cherno O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Svensson, Per-Arne
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    FKBP5 expression in human adipose tissue increases following dexamethasone exposure and is associated with insulin resistance2014In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 63, no 9, p. 1198-1208Article in journal (Refereed)
    Abstract [en]

    Objective

    To study effects of dexamethasone on gene expression in human adipose tissue aiming to identify potential novel mechanisms for glucocorticoid-induced insulin resistance.

    Materials/methods

    Subcutaneous and omental adipose tissue, obtained from non-diabetic donors (10 M/15 F; age: 28–60 years; BMI: 20.7–30.6 kg/m2), was incubated with or without dexamethasone (0.003–3 μmol/L) for 24 h. Gene expression was assessed by microarray and real time-PCR and protein expression by immunoblotting.

    Results

    FKBP5 (FK506-binding protein 5) and CNR1 (cannabinoid receptor 1) were the most responsive genes to dexamethasone in both subcutaneous and omental adipose tissue (~ 7-fold). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots. The gene product, FKBP51 protein, was 10-fold higher in the omental than in the subcutaneous depot, whereas the mRNA levels were similar. Higher FKBP5 gene expression in omental adipose tissue was associated with reduced insulin effects on glucose uptake in both depots. Furthermore, FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter and negatively with plasma HDL-cholesterol. FKBP5 SNPs were found to be associated with type 2 diabetes and diabetes-related phenotypes in large population-based samples.

    Conclusions

    Dexamethasone exposure promotes expression of FKBP5 in adipose tissue, a gene that may be implicated in glucocorticoid-induced insulin resistance.

  • 105.
    Pereira, Maria J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Skrtic, S.
    AstraZeneca R&D, Molndal, Sweden..
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Nowak, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    CDKN2C expression is low in type 2 diabetes and associated with reduced lipid storage capacity in subcutaneous adipose tissue and elevated free fatty acid levels2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no S1, p. S272-S272, article id 598Article in journal (Other academic)
  • 106.
    Pereira, Maria J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Skrtic, S.
    AstraZeneca R&D, Molndal, Sweden.;Gothenburg Univ, Sahlgrenska Acad, Inst Med, Dept Endocrinol, Gothenburg, Sweden..
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sidibeh, Cherno O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Dahgam, S.
    AstraZeneca R&D, Molndal, Sweden..
    Mansson, M.
    AstraZeneca R&D, Molndal, Sweden..
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Impaired adipose tissue lipid storage, but not altered lipolysis, contributes to elevated levels of free fatty acids in type 2 diabetes2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S323-S323Article in journal (Refereed)
  • 107.
    Pereira, Maria J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Skrtic, Stanko
    AstraZeneca R&D, Molndal, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Endocrinol, Gothenburg, Sweden..
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sidibeh, Cherno O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Dahgam, Santosh
    AstraZeneca R&D, Molndal, Sweden..
    Mansson, Marianne
    AstraZeneca R&D, Molndal, Sweden..
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Impaired adipose tissue lipid storage, but not altered lipolysis, contributes to elevated levels of NEFA in type 2 diabetes. Degree of hyperglycemia and adiposity are important factors2016In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 65, no 12, p. 1768-1780Article in journal (Refereed)
    Abstract [en]

    Background. Elevated levels of circulating non-esterified fatty acids (NEFA) mediate many adverse metabolic effects. In this work we aim to determine the impact of type 2 diabetes (T2D), glycemic control and obesity on lipolysis regulation. Design and Participants. 20 control and 20 metformin-treated T2D subjects were matched for sex (10 M/10 F), age (58 +/- 11 vs 58 +/- 9 y) and BMI (30.8 +/- 4.6 vs 30.7 +/- 4.9 kg/m(2)). In vivo lipolysis was assessed during a 3 h-OGTT with plasma glycerol and NEFA levels. Subcutaneous adipose tissue (SAT) biopsies were obtained to measure mRNA and metabolite levels of factors related to lipolysis and lipid storage and to assess in vitro lipolysis in isolated subcutaneous adipocytes. Results. Plasma NEFA AUC during the OGTT where higher 30% (P = 0.005) in T2D than in control subjects, but plasma glycerol AUC and subcutaneous adipocyte lipolysis in vitro were similar, suggesting that adipose tissue lipolysis is not altered. Expression in SAT of genes involved in lipid storage (FABP4, DGAT1, FASN) were reduced in T2D subjects compared with controls, but no differences were seen for genes involved in lipolysis. T2D subjects had elevated markers of beta-oxidation, alpha-hydroxybutyrate (1.4-fold, P < 0.01) and p-hydroxybutyrate (1.7-fold, P < 0.05) in plasma. In multivariate analysis, HbA1c, visceral adipose tissue volume and sex (male) were significantly associated with NEFA AUC in T2D subjects. Conclusions. In T2D subjects, NEFA turnover is impaired, but not due to defects in lipolysis or lipid beta-oxidation. Impaired adipose NEFA re-esterification or de novo lipogenesis is likely to contribute to higher NEFA plasma levels in T2D. The data suggest that hyperglycemia and adiposity are important contributing factors for the regulation of plasma NEFA concentrations.

  • 108.
    Pereira, Maria João
    et al.
    The Lundberg Laboratory for Diabetes Research, Institute of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Carvalho, Eugénia
    Eriksson, Jan W
    The Lundberg Laboratory for Diabetes Research, Institute of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Crans, Debbie C
    Aureliano, Manuel
    Effects of decavanadate and insulin enhancing vanadium compounds on glucose uptake in isolated rat adipocytes2009In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 103, no 12, p. 1687-1692Article in journal (Refereed)
    Abstract [en]

    The effects of different vanadium compounds namely pyridine-2,6-dicarboxylatedioxovanadium(V) (V5-dipic), bis(maltolato) oxovanadium(IV) (BMOV) and amavadine, and oligovanadates namely metavanadate and decavanadate were analysed on basal and insulin stimulated glucose uptake in rat adipocytes. Decavanadate (50 microM), manifest a higher increases (6-fold) on glucose uptake compared with basal, followed by BMOV (1 mM) and metavanadate (1 mM) solutions (3-fold) whereas V5 dipic and amavadine had no effect. Decavanadate (100 microM) also shows the highest insulin like activity when compared with the others compounds studied. In the presence of insulin (10 nM), only decavanadate increases (50%) the glucose uptake when compared with insulin stimulated glucose uptake whereas BMOV and metavanadate, had no effect and V5 dipic and amavadine prevent the stimulation to about half of the basal value. Decavanadate is also able to reduce or eradicate the suppressor effect caused by dexamethasone on glucose uptake at the level of the adipocytes. Altogether, vanadium compounds and oligovanadates with several structures and coordination spheres reveal different effects on glucose uptake in rat primary adipocytes.

  • 109.
    Pereira, Maria João
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Palming, J.
    Rizell, M.
    Aureliano, M.
    Carvalho, E.
    Svensson, M. K.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Cyclosporin A and tacrolimus impair dynamics of GLUT4 traffic in insulin-responsive cells2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, p. S330-S330Article in journal (Other academic)
  • 110.
    Pereira, Maria João
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Palming, J.
    Svensson, M. K.
    Rizell, M.
    Dalenback, J.
    Hammar, M.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Sidibeh, Cherno O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Svensson, P. -A
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    FKBP5 gene polymorphisms and expression in human adipose tissue are associated with insulin resistance and type 2 diabetes2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S239-S239Article in journal (Other academic)
  • 111.
    Pereira, Maria João
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Palming, Jenny
    Rizell, Magnus
    Aureliano, Manuel
    Carvalho, Eugenia
    Svensson, Maria K.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Cyclosporine A and Tacrolimus Reduce the Amount of GLUT4 at the Cell Surface in Human Adipocytes: Increased Endocytosis as a Potential Mechanism for the Diabetogenic Effects of Immunosuppressive Agents2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 10, p. E1885-E1894Article in journal (Refereed)
    Abstract [en]

    Context: Immunosuppressive agents are associated with profound metabolic side effects including new-onset diabetes and dyslipidemia after organ transplantation. Objective: To investigate the effects of cyclosporine A (CsA) and tacrolimus on glucose uptake and insulin signaling in human adipocytes and their impact on the regulation of cellular trafficking of the glucose transporter 4 (GLUT4). Design: Isolated human adipocytes were incubated with therapeutic concentrations of either CsA or tacrolimus, and glucose uptake and expression of insulin signaling proteins were assessed. Furthermore, we studied effects of CsA and tacrolimus on the regulation of cellular trafficking of GLUT4 in differentiated human preadipocytes and L6 cells. Results: CsA and tacrolimus had a concentration-dependent inhibitory effect on basal and insulin-stimulated C-14-glucose uptake in adipocytes. Although phosphorylation at Tyr1146 of the insulin receptor was inhibited by tacrolimus, the phosphorylation and/or protein levels of the insulin signaling proteins IRS1/2, p85-PI3K, PKB, AS160, and mTORC1, as well as GLUT4 and GLUT1, were unchanged by CsA or tacrolimus. Furthermore, CsA and tacrolimus reduced the GLUT4 amount localized at the cell surface of differentiated human preadipocytes and L6 cells in the presence of insulin. This occurred by an increased rate of GLUT4 endocytosis, with no change in the exocytosis rate. Conclusions: These results suggest that therapeutic concentrations of CsA and tacrolimus can inhibit glucose uptake independent of insulin signaling by removing GLUT4 from the cell surface via an increased rate of endocytosis. This mechanism can contribute to the development of insulin resistance and diabetes associated with immunosuppressive therapy. In addition, it may provide novel pharmacological approaches for the treatment of diabetes.

  • 112.
    Persson, Frederik
    et al.
    Steno Diabet Ctr, Copenhagen, Denmark..
    Nystrom, Thomas
    Soder Sjukhuset, Karolinska Inst, Stockholm, Sweden..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Copenhagen, Denmark..
    Carstensen, Bendix
    Steno Diabet Ctr, Copenhagen, Denmark..
    Gulseth, Hanne L.
    Oslo Univ Hosp, Oslo, Norway..
    Thuresson, Marcus
    Statisticon AB, Uppsala, Sweden..
    Fenici, Peter
    AstraZeneca, Cambridge, England..
    Nathanson, David
    Soder Sjukhuset, Karolinska Inst, Stockholm, Sweden..
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Norhammar, Anna
    Karolinska Inst, Stockholm, Sweden.;Capio St Gorans Hosp, Stockholm, Sweden..
    Bodegard, Johan
    AstraZeneca Nord Balt, N-0601 Oslo, Norway..
    Birkeland, Kare I.
    Oslo Univ Hosp, Oslo, Norway.;Univ Oslo, Oslo, Norway..
    Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study2018In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, no 2, p. 344-351Article in journal (Refereed)
    Abstract [en]

    Aims

    To compare the sodium-glucose-cotransporter-2 (SGLT-2) inhibitor dapagliflozin with dipeptidyl peptidase-4 (DPP-4) inhibitors with regard to risk associations with major adverse cardiovascular (CV) events (MACE; non-fatal myocardial infarction, non-fatal stroke or cardiovascular mortality), hospitalization for heart failure (HHF), atrial fibrillation and severe hypoglycaemia in patients with type 2 diabetes (T2D) in a real-world setting.

    Methods

    All patients with T2D prescribed glucose-lowering drugs (GLDs) during 2012 to 2015 were identified in nationwide registries in Denmark, Norway and Sweden. Patients were divided into two groups: new users of dapagliflozin and new users of DPP-4 inhibitors, matched 1:3 by propensity score, calculated by patient characteristics, comorbidities and drug treatment. Cox survival models were used to estimate hazard ratio (HR) per country separately, and a weighted average was calculated.

    Results

    After matching, a total of 40908 patients with T2D were identified as new users of dapagliflozin (n=10227) or a DPP-4 inhibitor (n=30681). The groups were well balanced at baseline; their mean age was 61years and 23% had CV disease. The mean follow-up time was 0.95years, with a total of 38760 patient-years. Dapagliflozin was associated with a lower risk of MACE, HHF and all-cause mortality compared with DPP-4 inhibitors: HRs 0.79 (95% confidence interval [CI] 0.67-0.94), 0.62 (95% CI 0.50-0.77), and 0.59 (95% CI 0.49-0.72), respectively. Numerically lower, but non-significant HRs were observed for myocardial infarction (0.91 [95% CI 0.72-1.16]), stroke (0.79 [95% CI 0.61-1.03]) and CV mortality (0.76 [95% CI 0.53-1.08]) Neutral associations with atrial fibrillation and severe hypoglycaemia were observed.

    Conclusions

    Dapagliflozin was associated with lower risks of CV events and all-cause mortality compared with DPP-4 inhibitors in a real-world clinical setting and a broad T2D population.

  • 113. Rask, E
    et al.
    Eriksson, Jan W
    Medicinska kliniken, Norrlands Universitetssjukhus, Umeå, Sweden.
    Forsberg, G
    Fallbeskrivning: inhalationssteroider gav binjurebarkshämning1997In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 94, no 40, p. 3529-3530, 3533Article in journal (Refereed)
    Abstract [en]

    In one of two cases of systemic effects of high-dose inhaled corticosteroid treatment with fluticasone propionate, adrenal suppression was demonstrated in a young man, and in the other retarded growth and severe general effects were observed in connection with infection in a child. These cases illustrate the risk of systemic effects of inhaled corticosteroids, and the importance of using the lowest possible maintenance dose.

  • 114.
    Rautio, Aslak
    et al.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.;Sunderby Hosp, Dept Med, SE-97180 Lulea, Sweden..
    Boman, Kurt
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.;Skelleftea Hosp, Res Unit, Skelleftea, Sweden..
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Svensson, Maria K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Markers of fibrinolysis may predict development of lower extremity arterial disease in patients with diabetes: A longitudinal prospective cohort study with 10 years of follow-up2016In: Diabetes & Vascular Disease Research, ISSN 1479-1641, E-ISSN 1752-8984, Vol. 13, no 3, p. 183-191Article in journal (Refereed)
    Abstract [en]

    Background: A previous cross-sectional study suggested that tissue plasminogen activator-activity might be an early marker of asymptomatic lower extremity arterial disease, but the long-term relationship is unknown. Subjects and methods: This study included 96 diabetic (48 type 1/48 type 2) and 62 non-diabetic subjects aged 30-70 years without previously known lower extremity arterial disease (age: 50.3 +/- 9.3 years, gender: M/W 47.5/52.5% and body mass index: 26.6 +/- 4.5 kg/m(2)). The relationships between asymptomatic lower extremity arterial disease and fibrinolytic markers (tissue plasminogen activator-activity, tissue plasminogen activator-mass, plasminogen activator inhibitor-1 activity) at baseline and after 10 years were assessed by logistic regression analysis adjusting for age, hypertension, statin treatment, HbA1c, triglycerides and low-density lipoprotein cholesterol as fixed covariates. Results: The tissue plasminogen activator-activity at baseline and at the 10-year follow-up significantly predicted the presence of sign(s) of lower extremity arterial disease (odds ratio = 1.78, 95% confidence interval: 1.02-3.10, p = 0.043 and odds ratio = 1.78, 95% confidence interval: 1.12-2.23, p = 0.014, respectively). In addition, tissue plasminogen activator-mass at the 10-year follow-up was associated with signs of lower extremity arterial disease (odds ratio = 1.07, 95% confidence interval: 1.00-1.15, p = 0.046). Baseline age, hypertension and HbA1c were independently associated with sign(s) of lower extremity arterial disease at 10 years (odds ratio = 1.09, 95% confidence interval: 1.04-1.14, p=<0.001; odds ratio = 3.68, 95% confidence interval: 1.67-8.12, p = 0.001 and odds ratio = 1.54, 95% confidence interval: 1.21-1.95, p=<0.001, respectively). Conclusion: This long-term study supports previous findings of a significant association between asymptomatic lower extremity arterial disease and tissue plasminogen activator-activity. Thus, tissue plasminogen activator-activity may be an early marker of lower extremity arterial disease although the mechanism of this relationship remains unclear.

  • 115. Renström, F
    et al.
    Burén, J
    Svensson, M K
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Factors in serum from type 2 diabetes patients can cause cellular insulin resistance2009In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 41, no 10, p. 767-772Article in journal (Refereed)
    Abstract [en]

    This pilot study was aimed to investigate whether there are humoral factors in serum from type 2 diabetic subjects that, in addition to glucose, insulin and free fatty acids are able to induce or contribute to peripheral insulin resistance with respect to glucose transport. Isolated subcutaneous adipocytes from 11 type 2 diabetic subjects and 10 nondiabetic controls were incubated for 24-h in medium supplemented with 25 % serum from a control or a type 2 diabetic donor, in the presence of a low (5 mM) or a high (15 mM) glucose concentration, respectively. After the incubation period glucose uptake capacity was assessed. Serum from type 2 diabetic donors, compared to serum from controls, significantly reduced the maximal insulin eff ect to stimulate glucose uptake (approximately 40 %, p < 0.05) in adipocytes from control subjects, independent of surrounding glucose concentrations. Glucose uptake capacity in adipocytes isolated from type 2 diabetic subjects was similar regardless of culture condition. No significant alterations were found in cellular content of key proteins in the insulin signaling cascade (insulin receptor substrate-1 and -2, and glucose transporter 4) that could explain the impaired insulin-stimulated glucose transport in control adipocytes incubated with serum from type 2 diabetic donors. The present findings indicate the presence of biomolecules in the circulation of type 2 diabetic subjects, apart from glucose, insulin, and free fatty acids with the ability to induce peripheral insulin resistance. This further implies that even though normoglycemia is achieved other circulating factors can still negatively affect insulin sensitivity in type 2 diabetic patients.

  • 116. Ruge, Toralph
    et al.
    Lockton, J Andrew
    Renstrom, Frida
    Lystig, Theodore
    Sukonina, Valentina
    Svensson, Maria K
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Acute hyperinsulinemia raises plasma interleukin-6 in both nondiabetic and type 2 diabetes mellitus subjects, and this effect is inversely associated with body mass index2009In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 58, no 6, p. 860-866Article in journal (Refereed)
    Abstract [en]

    Hyperinsulinemia is a characteristic of type 2 diabetes mellitus (T2DM) and is believed to play a role in the low-grade inflammation seen in T2DM. The main aim was to study the effect of hyperinsulinemia on adipokines in individuals with different levels of insulin resistance, glycemia, and obesity. Three groups of sex-matched subjects were studied: young healthy subjects (YS; n = 10; mean age, 26 years; body mass index [BMI], 22 kg/m2), patients with T2DM (DS; n = 10; 61 years; BMI, 27 kg/m2), and age- and BMI-matched controls to DS (CS; n = 10; 60 years; BMI, 27 kg/m2). Plasma concentrations of adipokines were measured during a hyperinsulinemic euglycemic clamp lasting 4 hours. Moreover, insulin-stimulated glucose uptake in isolated adipocytes was analyzed to address adipose tissue insulin sensitivity. Plasma interleukin (IL)-6 increased significantly (P ≤ .01) in all 3 groups during hyperinsulinemia. However, the increase was smaller in both DS (P = .06) and CS (P < .05) compared with YS (∼2.5-fold vs ∼4-fold). A significant increase of plasma tumor necrosis factor (TNF) α was observed only in YS. There were only minor or inconsistent effects on adiponectin, leptin, and high-sensitivity C-reactive protein levels during hyperinsulinemia. Insulin-induced rise in IL-6 correlated negatively to BMI (P = .001), waist to hip ratio (P = .05), and baseline (fasting) insulin (P = .03) and IL-6 (P = .02) levels and positively to insulin-stimulated glucose uptake in isolated adipocytes (P = .07). There was no association with age or insulin sensitivity. In a multivariate analysis, also including T2DM/no T2DM, an independent correlation (inverse) was found only between BMI and fold change of IL-6 (r2 = 0.41 for model, P < .005). Hyperinsulinemia per se can produce an increase in plasma IL-6 and TNFα, and this can potentially contribute to the low-grade inflammation seen in obesity and T2DM. However, obesity seems to attenuate the ability of an acute increase in insulin to further raise circulating levels of IL-6 and possibly TNFα.

  • 117. Ruge, Toralph
    et al.
    Sukonina, Valentina
    Kroupa, Olessia
    Makoveichuk, Elena
    Lundgren, Magdalena
    Svensson, Maria K
    Olivecrona, Gunilla
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Effects of hyperinsulinemia on lipoprotein lipase, angiopoietin-like protein 4, and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 in subjects with and without type 2 diabetes mellitus2012In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 61, no 5, p. 652-660Article in journal (Refereed)
    Abstract [en]

    Our aims were to compare the systemic effects of insulin on lipoprotein lipase (LPL) in tissues from subjects with different degrees of insulin sensitivity. The effects of insulin on LPL during a 4-hour hyperinsulinemic, euglycemic clamp were studied in skeletal muscle, adipose tissue, and postheparin plasma from young healthy subjects (YS), older subjects with type 2 diabetes mellitus (DS), and older control subjects (CS). In addition, we studied the effects of insulin on the expression of 2 recently recognized candidate genes for control of LPL activity: angiopoietin-like protein 4 (ANGPTL4) and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1. As an effect of insulin, LPL activity decreased by 20% to 25% in postheparin plasma and increased by 20% to 30% in adipose tissue in all groups. In YS, the levels of ANGPTL4 messenger RNA in adipose tissue decreased 3-fold during the clamp. In contrast, there was no significant change in DS or CS. Regression analysis showed that the ability of insulin to reduce the expression of ANGPTL4 was positively correlated with M-values and inversely correlated with factors linked to the metabolic syndrome. Expression of glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 tended to be higher in YS than in DS or CS, but the expression was not affected by insulin in any of the groups. Our data imply that the insulin-mediated regulation of LPL is not directly linked to the control of glucose turnover by insulin or to ANGPTL4 expression in adipose tissue or plasma. Interestingly, the response of ANGPTL4 expression in adipose tissue to insulin was severely blunted in both DS and CS.

  • 118. Sahli, David
    et al.
    Eliasson, Björn
    Svensson, Maria
    Blohmé, Göran
    Eliasson, Mats
    Samuelsson, Pär
    Ojbrandt, Kristina
    Eriksson, Jan W
    Assessment of toe blood pressure is an effective screening method to identify diabetes patients with lower extremity arterial disease.2004In: Angiology, ISSN 0003-3197, E-ISSN 1940-1574, Vol. 55, no 6, p. 641-51Article in journal (Refereed)
    Abstract [en]

    The authors evaluated a screening program for lower extremity arterial disease (LEAD) in diabetic patients and focused on the value of toe blood pressure assessment. They recruited 437 subjects, ages 30-70 years (134 healthy controls, 166 type 1 and 137 type 2 diabetic patients; control [Ctr], DM1, and DM2) with no previous history of LEAD. They were enrolled in a longitudinal study with a planned follow-up of 10 years. Patients were consecutively enrolled from outpatient diabetes units of 2 university hospitals. Subjects were screened with respect to peripheral circulation by use of established noninvasive techniques. These included arm, ankle (AP), and toe (TP) blood pressure measurements; evaluation of peripheral neuropathy; and a standardized physical examination. Results from the baseline examination are presented in this report. The number of patients who presented peripheral pressures or indices below normal (< mean -2 SD for controls) was higher among diabetic patients; 24% of DM1 and 31% of DM2, as compared to 6% of Ctr, had at least 1 lower limb with a low TP, AP, toe/arm index (TI), or ankle/arm index (AI), and these subjects were mainly identified by using the toe/arm index. TI was independently and negatively associated with fasting blood glucose in both patient groups, and with smoking, age, and diabetes duration in DM1. The mean AP was higher in the DM1 and DM2 groups compared to Ctr, whereas overall TP, TI, and AI were similar in the groups. It was also shown that abnormally low TI was significantly more common than low AI among diabetics (p<0.001), and this was true for TP vs AP as well (p<0.05). It is beneficial to include assessment of toe blood pressure and toe/arm blood pressure index to detect early LEAD in diabetic patients. Ankle blood pressure and indices alone are less efficient, owing probably to medial sclerosis in diabetic patients. Up to 30% of diabetic patients with no ischemic symptoms may have signs of impaired arterial circulation.

  • 119. Sahli, David
    et al.
    Eriksson, Jan W
    Department of Medicine, Umeå University Hospital, Umeå, Sweden.
    Boman, Kurt
    Svensson, Maria K
    Tissue plasminogen activator (tPA) activity is a novel and early marker of asymptomatic LEAD in type 2 diabetes2009In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 123, no 5, p. 701-706Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Lower extremity arterial disease (LEAD) is often one of the first signs of a generalized atherosclerotic disease in type 1 and type 2 diabetic subjects.

    MATERIALS AND METHODS:

    We studied 143 diabetic subjects at 30-70 years of age, M/F 69/74, 74 with type 1 and 69 with type 2 diabetes, without previously known or suspected lower extremity arterial disease. The relationship between early asymptomatic lower extremity arterial disease and blood levels of HbA1c, lipids and fibrinolysis markers (tPA-activity, tPA mass, PAI-1 activity, tPA-PAI-1 complex) was assessed. In parallel, a group with non-diabetic subjects (n=80) was studied.

    RESULTS:

    35 (24%) diabetic subjects were classified as having sign(s) of LEAD, defined as having at least one reduced peripheral blood pressure measurement, 28% in type 1 vs 20% in type 2 diabetic subjects (p=NS). In univariate logistic regression analyses age, glycemic level (HbA1c), male gender (only in type 1 diabetic subjects), hypertension and tPA activity (only in type 2 diabetic subjects) were positively associated with LEAD. When markers of fibrinolysis were entered into a multivariate model adjusting for age, hypertension, and HbA1c, only tPA activity remained independently associated with LEAD (p=0.01) and this was also found in type 2 diabetic subjects (p=0.05). In type 1 diabetic subjects the increase in odds ratio was non-significant.

    CONCLUSIONS:

    Tissue plasminogen activator (tPA) activity may be an independent and early marker for asymptomatic lower extremity arterial disease in diabetic subjects, particularly in type 2 diabetes. Thus an altered fibrinolytic activity could be an early marker of atherosclerosis development in the lower extremities but the cause-effect relationship remains unclear.

  • 120. Samuelsson, P
    et al.
    Blohmé, G
    Fowelin, J
    Eriksson, Jan W
    Department of Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
    A new non-invasive method using pulse oximetry for the assessment of arterial toe pressure1996In: Clinical Physiology, ISSN 0144-5979, E-ISSN 1365-2281, Vol. 16, no 4, p. 463-467Article in journal (Refereed)
    Abstract [en]

    We evaluated a novel, simple non-invasive method to assess systolic arterial toe pressures (ATP). It was employed in 63 subjects, of which 37 had suspected or established lower extremity arterial disease (LEAD) and 26 did not. 48 of the subjects had diabetes and 15 were non-diabetic. Pulsatile toe blood flow was monitored with a regular pulse oximeter (Biox 3700TM, BOC Ohmeda, Helsingborg, Sweden) (POX) with the sensor on the tip of the great toe. A small blood pressure cuff was placed around the proximal part of the toe and was connected to a sphygmomanometer (TycosTM, Levimed AB, Höganäs, Sweden). Systolic pressure was estimated as the cuff pressure at which pulsatile blood flow ceased during cuff inflation. Toe pressure measurement was obtained, in parallel, using the established strain gauge plethysmographic technique. There was a good concordance between the two methods (linear regression: r = 0.93; y = 1.1 x x-6.4; y = pressure obtained with the pulse oximeter, x = pressure obtained with strain gauge, in mmHg). However, patients with very low systolic toe pressures, < 20 mmHg, could not be reproducibly assessed using the POX method. In conclusion, the POX method was found to be a simple and reliable method for the estimation of systolic toe pressures, at least for those above the severely ischemic level. It may provide an easily accessible and cost-effective means of vascular assessment at the bedside, as well as for out-patients.

  • 121.
    Sarsenbayeva, Assel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Marques-Santos, Cátia M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Thombare, Ketan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Di Nunzio, Giada
    Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal.
    Almby, Kristina E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lundqvist, Martin H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism2019In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 110, article id 104445Article in journal (Refereed)
    Abstract [en]

    Objective: Metabolic syndrome is prevalent in up to 50% of schizophrenia patients, which reduces their quality of life and their compliance with the treatment. It is unclear whether metabolic adverse effects of these agents are due to their direct effect on insulin-sensitive tissues or are secondary to increased adiposity. The study aimed to investigate the direct effects of the second-generation antipsychotics olanzapine and aripiprazole on human subcutaneous adipose tissue and isolated adipocyte metabolism.

    Methods: Abdominal subcutaneous adipose tissue needle biopsies were taken from 72 healthy subjects (49 F/23 M; age: 19-78 yr; BMI: 20.0-35.6 kg/m(2)). Isolated adipocytes or adipose tissue were respectively pre-incubated short- (30 min) and long-term (24 h, 72 h) with or without olanzapine (0.004 mu M - 20 mu M) and aripiprazole (0.002 mu M - 100 mu M). Pre-incubated adipose tissue was then snap-frozen for mRNA expression analysis of adipokines genes and genes involved in inflammation, adipogenesis, and mitochondrial function. Isolated adipocytes were used to measure basal and insulin-stimulated glucose uptake and lipolysis.

    Results: Acute treatment with a therapeutic concentration of olanzapine decreases basal lipolysis in isolated adipocytes; this effect was not observed after long-term incubation with the drug. Supra-therapeutic concentration of aripiprazole reduced basal and insulin-stimulated glucose uptake after short- and long-term preincubation. Both drugs at supra-therapeutic concentrations downregulated the expression of the pro-inflammatory cytokines IL6 and IL1B genes after 72 h incubation. Similarly, supra-therapeutic concentrations of both drugs and therapeutic concentration of olanzapine, reduced the expression of PPARGC1A, PDK4, and CPT1B genes involved in the regulation of mitochondria] functions. Neither of the antipsychotics affected the expression of the main adipokines LEP and ADIPOQ, genes involved in the regulation of lipid metabolism, LPL and FASN, nor the master adipogenesis regulator, PPARG.

    Conclusion: Therapheutic concentrations of olanzapine and aripiprazole have a moderate direct effect on adipocyte lipid and glucose metabolism, respectively. At supra-therapeutic concentrations, both of the antipsychotics seem to act as anti-inflammatory agents and mildly suppressed genes involved in the regulation of mitochondrial functions, which could potentially contribute to metabolic adverse effects. Alternatively, second-generation antipsychotics could induce metabolic side effects via acting on other insulin-sensitive tissues and central nervous system.

  • 122.
    Schölin, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Björklund, L
    Borg, H
    Arnqvist, H
    Björk, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Blohme, G
    Bolinder, J
    Eriksson, Jan W
    Department of Medicine, Umeå University Hospital, Umeå.
    Gudbjörnsdottir, S
    Nyström, L
    Östman, J
    Karlsson, Anders F
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundkvist, G
    Islet antibodies and remaining beta-cell function 8 years after diagnosis of diabetes in young adults: a prospective follow-up of the nationwide Diabetes Incidence Study in Sweden2004In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 255, no 3, p. 384-391Article in journal (Other academic)
    Abstract [en]

    Objectives

    To establish the prevalence of remaining β-cell function 8 years after diagnosis of diabetes in young adults and relate the findings to islet antibodies at diagnosis and 8 years later.

    Design

    Population-based cohort study.

    Setting

    Nationwide from all Departments of Medicine and Endocrinology in Sweden.

    Subjects

    A total of 312 young (15–34 years old) adults diagnosed with diabetes during 1987–88.

    Main outcome measure

    Plasma connecting peptide (C-peptide) 8 years after diagnosis. Preserved β-cell function was defined as measurable C-peptide levels. Three islet antibodies – cytoplasmic islet cell antibodies (ICA), glutamic acid decarboxylase antibodies and tyrosine phosphatase antibodies – were measured.

    Results

    Amongst 269 islet antibody positives (ab+) at diagnosis, preserved β-cell function was found in 16% (42/269) 8 years later and these patients had a higher body mass index (median 22.7 and 20.5 kg m−2, respectively; P = 0.0003), an increased frequency of one islet antibody (50 and 24%, respectively; P = 0.001), and a lower prevalence of ICA (55 and 6%, respectively; P = 0.007) at diagnosis compared with ab+ without remaining β-cell function. Amongst the 241 patients without detectable β-cell function at follow-up, 14 lacked islet antibodies, both at diagnosis and at follow-up.

    Conclusions

    Sixteen per cent of patients with autoimmune type 1 diabetes had remaining β-cell function 8 years after diagnosis whereas 5.8% with β-cell failure lacked islet autoimmunity, both at diagnosis and at follow-up.

  • 123.
    Schölin, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björklund, Linda
    Borg, Henrik
    Arnqvist, Hans
    Björk, Elisabeth
    Blohmé, Göran
    Bolinder, Jan
    Eriksson, Jan W
    Gudbjörnsdottir, Soffia
    Nyström, Lennarth
    Remaning β-cell function eight years after diagnosis of autoimmune diabetes in young adults.: Relation to islet antibodies and clinical featuresArticle in journal (Refereed)
  • 124.
    Schölin, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Törn, C
    Nyström, L
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Arnqvist, H
    Blohme, G
    Bolinder, J
    Eriksson, Jan W
    Department of Medicine, Umeå Hospital.
    Kockum, I
    Landin-Olsson, M
    Östman, J
    Karlsson, F Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundkvist, G
    Björk, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Normal weight promotes remission and low number of islet antibodies prolong the duration of remission in Type 1 diabetes2004In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 21, no 5, p. 447-455Article in journal (Other academic)
    Abstract [en]

    Aim 

    To identify clinical, immunological and biochemical factors that predict remission, and its duration in a large cohort of young adults with Type 1 diabetes mellitus (DM).

    Methods 

    In Sweden, 362 patients (15–34 years), classified as Type 1 DM were included in a prospective, nation-wide population-based study. All patients were followed at local hospitals for examination of HbA1c and insulin dosage over a median period after diagnosis of 5 years. Duration of remission, defined as an insulin maintenance dose ≤ 0.3 U/kg/24 h and HbA1c within the normal range, was analysed in relation to characteristics at diagnosis.

    Results 

    Remissions were seen in 43% of the patients with a median duration of 8 months (range 1–73). Sixteen per cent had a remission with a duration > 12 months. Among patients with antibodies (ab+), bivariate analysis suggested that adult age, absence of low BMI, high plasma C-peptide concentrations, lack of ketonuria or ketoacidosis at diagnosis and low insulin dose at discharge from hospital were associated with a high possibility of achieving remission. Multiple regression showed that normal weight (BMI of 20–24.9 kg/m2) was the only factor that remained significant for the possibility of entering remission. In survival analysis among ab+ remitters, a low number of islet antibodies, one or two instead of three or four, were associated with a long duration of remissions.

    Conclusion 

    In islet antibody-positive Type 1 DM, normal body weight was the strongest factor for entering remission, whilst a low number of islet antibodies was of importance for the duration.

  • 125.
    Schölin, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Törn, Carina
    Arnqvist, Hans
    Berne, Christian
    Blohmé, Göran
    Bolinder, Jan
    Eriksson, Jan W
    Kockum, Ingrid
    Landin-Olsson, Mona
    Nyström, Lennarth
    BMI, ketoacidosis and GADA are important factors for prediction of remission in type 1 diabetesArticle in journal (Refereed)
  • 126.
    Sidibeh, Cherno O
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abalo, Xesus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Boersma, Gretha J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Skrtic, Stanko
    AstraZeneca R&D, Molndal, Sweden;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden.
    Lundkvist, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hausch, Felix
    Tech Univ Darmstadt, Inst Organ Chem & Biochem, Darmstadt, Germany.
    Castillejo-Lopez, Casimiro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    FKBP5 expression in human adipose tissue: potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes2018In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 62, no 1, p. 116-128Article in journal (Refereed)
    Abstract [en]

    Purpose Here, we explore the involvement of FKBP51 in glucocorticoid-induced insulin resistance (IR) in human subcutaneous adipose tissue (SAT), including its potential role in type 2 diabetes (T2D). Moreover, we assess the metabolic effects of reducing the activity of FKBP51 using the specific inhibitor SAFit1. Methods Human SAT was obtained by needle biopsies of the lower abdominal region. FKBP5 gene expression was assessed in fresh SAT explants from a cohort of 20 T2D subjects group-wise matched by gender, age and BMI to 20 nondiabetic subjects. In addition, human SAT was obtained from non-diabetic volunteers (20F/9M). SAT was incubated for 24 h with or without the synthetic glucocorticoid dexamethasone and SAFit1. Incubated SAT was used to measure the glucose uptake rate in isolated adipocytes. Results FKBP5 gene expression levels in SAT positively correlated with several indices of IR as well as glucose area under the curve during oral glucose tolerance test (r = 0.33, p < 0.05). FKBP5 gene expression levels tended to be higher in T2D subjects compared to non-diabetic subjects (p = 0.088). Moreover, FKBP5 gene expression levels were found to inversely correlate with lipolytic, lipogenic and adipogenic genes. SAFit1 partly prevented the inhibitory effects of dexamethasone on glucose uptake. Conclusions FKBP5 gene expression in human SAT tends to be increased in T2D subjects and is related to elevated glucose levels. Moreover, FKBP5 gene expression is inversely associated with the expression of lipolytic, lipogenic and adipogenic genes. SAFit1 can partly prevent glucose uptake impairment by glucocorticoids, suggesting that FKBP51 might be a key factor in glucocorticoid-induced IR.

  • 127.
    Sidibeh, Cherno O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Börjesson, Joey Lau
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kamble, Prasad G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Skrtic, S.
    Univ Gothenburg, Dept Endocrinol, Gothenburg, Sweden..
    Katsogianos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Svensson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Role of cannabinoid receptor type 1 in glucocorticoid-induced insulin resistance (IR) and lipolysis regulation in human adipose tissue (AT)2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S244-S245Article in journal (Refereed)
  • 128.
    Sidibeh, Cherno O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Börjesson, Joey Lau
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kamble, Prasad G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Skrtic, Stanko
    AstraZeneca R&D, Molndal, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Endocrinol, Gothenburg, Sweden..
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Svensson, Maria K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance2017In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 55, no 3, p. 839-852Article in journal (Refereed)
    Abstract [en]

    We recently showed that the peripheral cannabinoid receptor type 1 (CNR1) gene is upregulated by the synthetic glucocorticoid dexamethasone. CNR1 is highly expressed in the central nervous system and has been a drug target for the treatment of obesity. Here we explore the role of peripheral CNR1 in states of insulin resistance in human adipose tissue. Subcutaneous adipose tissue was obtained from well-controlled type 2 diabetes subjects and controls. Subcutaneous adipose tissue gene expression levels of CNR1 and endocannabinoid synthesizing and degrading enzymes were assessed. Furthermore, paired human subcutaneous adipose tissue and omental adipose tissue from non-diabetic volunteers undergoing kidney donation or bariatric surgery, was incubated with or without dexamethasone. Subcutaneous adipose tissue obtained from volunteers through needle biopsy was incubated with or without dexamethasone and in the presence or absence of the CNR1-specific antagonist AM281. CNR1 gene and protein expression, lipolysis and glucose uptake were evaluated. Subcutaneous adipose tissue CNR1 gene expression levels were 2-fold elevated in type 2 diabetes subjects compared with control subjects. Additionally, gene expression levels of CNR1 and endocannabinoid-regulating enzymes from both groups correlated with markers of insulin resistance. Dexamethasone increased CNR1 expression dose-dependently in subcutaneous adipose tissue and omental adipose tissue by up to 25-fold. Dexamethasone pre-treatment of subcutaneous adipose tissue increased lipolysis rate and reduced glucose uptake. Co-incubation with the CNR1 antagonist AM281 prevented the stimulatory effect on lipolysis, but had no effect on glucose uptake. CNR1 is upregulated in states of type 2 diabetes and insulin resistance. Furthermore, CNR1 is involved in glucocorticoid-regulated lipolysis. Peripheral CNR1 could be an interesting drug target in type 2 diabetes and dyslipidemia.

  • 129.
    Sidibeh, Cherno O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria João
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Börjesson, Joey Lau
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kamble, Prasad G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Svensson, M. K.
    Gothenburg Univ, Dept Mol & Clin Med, S-41124 Gothenburg, Sweden..
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Role of cannabinoid receptor type 1 in glucocorticoid-induced lipolysis, insulin resistance and central obesity in human adipose tissue2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S316-S317Article in journal (Other academic)
  • 130.
    Sidibeh, Cherno O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria João
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hammar, M.
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Rizell, M.
    Svensson, M. K.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Cannabinoid receptor type 1 expression in human adipose tissue is upregulated by glucocorticoids and is associated with insulin resistance2014In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no S1, p. S250-S250Article in journal (Other academic)
  • 131. Sjöholm, Kajsa
    et al.
    Lundgren, Magdalena
    Olsson, Maja
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Association of serum amyloid A levels with adipocyte size and serum levels of adipokines: differences between men and women2009In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 48, no 3, p. 260-266Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to characterize the association between adipocyte enlargement and circulating levels of serum amyloid A (SAA). Furthermore, we wanted to search for possible associations with measures of glycemic control and levels of circulating adipokines and/or inflammatory markers in men and women with a large range in body mass index. The study cohort consisted of 167 subjects, 114 non-diabetic and 53 with Type 2 diabetes. Adipocyte diameter as well as circulating levels of SAA, C-reactive protein (CRP), adiponectin, leptin, interleukin-6, tumor necrosis factor alpha, glucose and insulin were measured. Women had higher serum levels of SAA than men (p=0.044). SAA levels were weakly but positively correlated with BMI (p=0.043) and % body fat (p=0.027) in all subjects as well as subcutaneous adipocyte diameter (p=0.034) in women. Furthermore, in all subjects we found correlations between SAA levels and levels of CRP (p<0.001), interleukin-6 (p<0.001), leptin (p=0.003), insulin (p=0.006), HbA1c (p=0.02) and HOMA-IR (p=0.002). A majority of the correlations were strongest in women. In conclusion, serum levels of SAA are strongly correlated with serum levels of inflammatory markers as well as measures of glycemic control. There seems to be large sex differences in these associations suggesting that sex-specific factors need to be considered when analyzing SAA levels in relation to metabolic disease.

  • 132. Sjöholm, Åke
    et al.
    Agardh, Carl-David
    Brismar, Kerstin
    Efendic, Suad
    Eliasson, Björn
    Eriksson, Jan W
    Institutionen för medicin, Göteborgs universitet, Sahlgrenska akademin, Göteborg.
    Frid, Anders
    Groop, Leif
    Holmgren, Jan
    Ridderstråle, Martin
    Smith, Ulf
    Replik om nya läkemedel mot typ 2-diabetes: Viktigt att vi skaffar oss erfarenhet och kunskap2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 105, no 17-18, p. 1310, 1312-Article in journal (Refereed)
  • 133. Sjörs, A
    et al.
    Jansson, P-A
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Jonsdottir, I H
    Increased insulin secretion and decreased glucose concentrations, but not allostatic load, are associated with stress-related exhaustion in a clinical patient population2013In: Stress, ISSN 1025-3890, E-ISSN 1607-8888, Vol. 16, no 1, p. 24-33Article in journal (Refereed)
    Abstract [en]

    Allostatic load (AL) has been shown to be a useful marker of physiological strain during chronic stress and burnout in non-clinical working populations. The usability of the AL index for a clinical population with severe stress-related exhaustion was tested in this study. Thirteen biomarkers assembled as an AL index were analysed using blood samples from 90 patients with stress-related exhaustion (43 men and 47 women, age 31-61 years) and 90 healthy controls (46 men and 44 women, age 25-56 years). The AL scores did not differ between patients and controls. For men, some indication of higher cardiovascular risk was seen in the patient group: male patients had higher body mass index and waist-hip ratio and a poorer blood lipid status than male controls. We found lower plasma glucose concentrations in both female and male patients than those in controls. The male patients also showed increased fasting serum insulin concentrations. Further analysis using homeostasis model assessment for insulin resistance and β-cell function showed indications of insulin resistance in the patient group, particularly in the males, and an increased insulin secretion in both male and female patients. In conclusion, AL index does not seem to capture plausible physiological strain in patients diagnosed with stress-related exhaustion. The finding of lower plasma glucose concentrations, probably due to higher insulin secretion, in patients with severe stress-related exhaustion, needs to be further investigated, including mechanisms and the clinical relevance.

  • 134. Sjöstrand, M
    et al.
    Carlson, K
    Arnqvist, H J
    Gudbjörnsdottir, S
    Landin-Olsson, M
    Lindmark, S
    Nyström, L
    Svensson, M K
    Eriksson, Jan W
    Sahlgrenska Academy Hospital, Gothenburg, Sweden.
    Bolinder, J
    Assessment of beta-cell function in young patients with type 2 diabetes: arginine-stimulated insulin secretion may reflect beta-cell reserve2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 1, p. 39-48Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Simple methods for the evaluation of dynamic b-cell function in epidemiological and clinical studies of patients with type 2 diabetes (T2D) are needed. The aim of this study was to evaluate the dynamic beta-cell function in young patients with T2D with different disease durations and treatments.

    METHODS: Overall, 54 subjects with T2D from the Diabetes Incidence Study in Sweden (DISS) and 23 healthy control participants were included in this cross-sectional study. Beta-cell function was assessed by intravenous (i.v.) administration of arginine followed by i.v. glucose. The acute insulin and C-peptide responses to arginine (AIRarg and Ac-pepRarg, respectively) and to glucose (AIRglu and Ac-pepRglu, respectively)were estimated.Homeostasis model assessment of b-cell function(HOMA-b) andCpeptide assessments were also used for comparisons between patients with T2D and control participants.

    RESULTS: AIRarg and Ac-pepRarg, but not AIRglu and Ac-pepRglu, could differentiate between patients with different disease durations. AIRglu values were 89% (P < 0.001) lower and AIRarg values were 29% (P < 0.01) lower in patients with T2D compared with control participants. HOMA-b and fasting plasma C-peptide levels did not differ between the T2D and control groups.

    CONCLUSION: In young patients with T2D, the insulin secretory response to i.v. glucose is markedly attenuated, whereas i.v. arginine-stimulated insulin release is better preserved and can distinguish between patients with different disease duration and antidiabetic therapies. This suggests that the i.v. arginine stimulation test may provide an estimate of functional beta-cell reserve.

  • 135. Sjöstrand, M
    et al.
    Jansson, P-A
    Palming, J
    de Schoolmeester, J
    Gill, D
    Rees, A
    Sjögren, L
    Persson, T
    Eriksson, Jan W
    The Lundberg Laboratory for Diabetes Research, Dept of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Repeated measurements of 11β-HSD-1 activity in subcutaneous adipose tissue from lean, abdominally obese, and type 2 diabetes subjects: no change following a mixed meal2010In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 42, no 11, p. 798-802Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to measure 11β-HSD-1 activity in subcutaneous adipose tissue by an ex vivo method in three subgroups; lean, obese, and type 2 diabetes subjects, both in the fasting state and after a mixed meal and to determine the variability and reproducibility of this method. Eighteen subjects were investigated; 6 lean, 6 abdominally obese, and 6 type 2 diabetes subjects (BMI 22±1, 30±3 and 31±3 kg/m2, respectively). Needle biopsies were taken repeatedly and an index of 11β-HSD-1 activity was measured as percent conversion of 3H-cortisone to 3H-cortisol/100 mg tissue. For two separate biopsies taken in the fasting state on the same day, the within subjects CV was 16% and the between CV was 36% for 11β-HSD-1 activity for all subjects. For two biopsies taken in the fasting state at two different days, the total within subjects CV was 38% and the between subjects CV was 46%. Lean subjects had lower 11β-HSD-1 activity (4.8±1.5% conversion of 3H-cortisone to 3H-cortisol/100 mg tissue) than both obese (14.4±1.6% conversion, p<0.01) and type 2 diabetes subjects (11.7±1.9% conversion, p<0.05) in the fasting state. There was no effect of a meal on 11β-HSD-1 activity in any of the three groups. The conclusions from this study are: 1) the variation coefficient for the ex vivo adipose tissue 11β-HSD-1 activity method was ∼25% for repeat measures within subjects; 2) food intake had no major impact on enzyme activity; and 3) 11β-HSD-1 activity in subcutaneous adipose tissue was significantly increased in obese subjects with or without T2DM compared to lean subjects without diabetes.

  • 136. Sjöstrand, Mikaela
    et al.
    Eriksson, Jan W
    The Lundberg Laboratory for Diabetes Research, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Neuroendocrine mechanisms in insulin resistance2009In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 297, no 1-2, p. 104-111Article in journal (Refereed)
    Abstract [en]

    Dysregulated hormonal, metabolic and neural signalling within and between organs can contribute to development of metabolic diseases including type 2 diabetes. Insulin-antagonistic effects of hormones, cytokines and excess metabolic substrates such as glucose and fatty acids may be exerted via common mechanisms involving for example reactive oxygen species (ROS) accumulation and associated inflammatory responses. Visceral adiposity is a central component of the metabolic syndrome and it is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. In the development of insulin resistance, it is likely that intra-abdominal adipose tissue plays a critical role in a complex endocrine and neural network involving several tissues. This review paper focuses on neuroendocrine 'stress' factors that target insulin-responsive tissues, in particular adipose tissue. We propose that there are common pathways by which dysregulation in different endocrine systems may contribute to the development of type 2 diabetes.

  • 137. Stephenson, M C
    et al.
    Leverton, E
    Khoo, E Y H
    Poucher, S M
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lockton, J A
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Mansell, P
    Morris, P G
    Macdonald, I A
    Variability in fasting lipid and glycogen contents in hepatic and skeletal muscle tissue in subjects with and without type 2 diabetes: a 1H and 13C MRS study2013In: NMR in Biomedicine, ISSN 0952-3480, E-ISSN 1099-1492, Vol. 26, no 11, p. 1518-1526Article in journal (Refereed)
    Abstract [en]

    The measurement of tissue lipid and glycogen contents and the establishment of normal levels of variability are important when assessing changes caused by pathology or treatment. We measured hepatic and skeletal muscle lipid and glycogen levels using 1H and 13C MRS at 3 T in groups of subjects with and without type 2 diabetes. Within-visit reproducibility, due to repositioning and instrument errors was determined from repeat measurements made over 1 h. Natural variability was assessed from separate measurements made on three occasions over 1 month. Hepatic lipid content was greater in subjects with diabetes relative to healthy subjects (p = 0.03), whereas levels of hepatic and skeletal muscle glycogen, and of intra- and extra-myocellular lipid, were similar. The single-session reproducibility values (coefficient of variation, CV) for hepatic lipid content were 12% and 7% in groups of subjects with and without diabetes, respectively. The variability of hepatic lipid content over 1 month was greater than the reproducibility, with CV = 22% (p = 0.08) and CV = 44% (p = 0.004) in subjects with and without diabetes, respectively. Similarly, levels of variation in basal hepatic glycogen concentrations (subjects with diabetes, CV = 38%; healthy volunteers, CV = 35%) were significantly larger than single-session reproducibility values (CV = 17%, p = 0.02 and CV = 13%, p = 0.05, respectively), indicating substantial biological changes in basal concentrations over 1 month. There was a decreasing correlation in measurements of both hepatic lipid and glycogen content with increasing time between scans. Levels of variability in intra- and extra-myocellular lipid in the soleus muscle, and glycogen concentrations in the gastrocnemius muscle, tended to be larger than expected from single-session reproducibility, although these did not reach significance.

  • 138. Svensson, M K
    et al.
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Change in the amount of body fat and IL-6 levels is related to altered insulin sensitivity in type 1 diabetes patients with or without diabetic nephropathy2011In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 43, no 3, p. 209-215Article in journal (Refereed)
    Abstract [en]

    Insulin resistance (IR) is found early-on in renal disease. The aim of this study was to prospectively evaluate if a change in glomerular filtration rate (GFR) or in endocrine and inflammatory factors over time alters insulin sensitivity in patients with type 1 diabetes (T1D) or without diabetic nephropathy (DN) at baseline. 20 T1D with (DN+, n=12) or without DN (DN–, n=8) were re-examined after 5.0±0.4 years. GFR was determined by 51Cr-EDTA clearance. Insulin sensitivity was assessed by hyperinsulinemic (56 mU/m2/min), euglycemic clamp (M-value at steady state during clamp) and calculated per lean body mass. Body composition was determined by bioimpedance. No association was found between change in GFR and change in M-value over time. Instead, change in M-value was associated to change in fat mass (%) and change in IL-6 levels in all subjects taken together (r=−0.55, p=0.012 and r=−0.62, p=0.006). These association were verified in the multivariate regression analyses. Findings were similar in DN − and DN +, respectively, but the change in IL-6 was only significantly associated with altered M-value in DN+ subjects. This prospective study indicates that change in amount body fat and levels of inflammatory cytokines, such as IL-6, contribute to change in insulin resistance over time in type 1 diabetes patients with and without diabetic nephropathy.

  • 139. Svensson, M K
    et al.
    Jansson, P-A
    Persson, A L
    Sjöstrand, M
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Atropine improves insulin sensitivity in both lean and abdominally obese subjects2011In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, no 11, p. E1843-E1847Article in journal (Refereed)
    Abstract [en]

    Background:

    Dysregulated autonomic nerve activity may contribute to the development of type 2 diabetes. The aim of this study was to assess the effects of an anticholinergic agent, atropine, and a cholinergic agent, physostigmine, on insulin sensitivity in lean and abdominally obese subjects.

    Subjects and Methods:

    In a single-blinded three-way crossover study, six lean and six abdominally obese nondiabetic subjects [three males and three females in each group; age, 43.8 ± 14.8 vs. 46.8 ± 4.8 yr (mean ± sd); body mass index, 22.6 ± 1.7 vs. 28.8 ± 1.3 kg/m2; and waist circumference, 85 ± 2 vs. 99 ± 6 cm, respectively] were given iv infusions with atropine (15 μg/kg bolus, 4 μg/kg · h infusion), physostigmine (0.12 μg/kg · min) or saline (0.9% NaCl) in a randomized treatment order. Infusions were started 30 min before and continued throughout a 120-min euglycemic (5.6 mm) hyperinsulinemic (40 mU/m2 · min) clamp.

    Results:

    Insulin sensitivity (M-value, i.e. glucose infusion rate divided by lean body mass) during the last 60 min of the clamp was higher during infusion with atropine than saline (9.2 ± 1.0 vs. 7.6 ± 1.0 mg/kg lean body mass · min, mean ± sem; P = 0.015) in all subjects. Physostigmine did not differ significantly from saline (8.2 ± 1.0). M-values were significantly higher in lean vs. obese [atropine, 11.6 ± 1.4 vs. 7.6 ± 1.3; physostigmine, 10.8 ± 1.3 vs. 6.3 ± 1.3; and saline, 9.1 ± 1.4 vs. 6.4 ± 1.3, respectively (all P < 0.05)], but the incremental effect of atropine vs. saline did not differ consistently between groups.

    Conclusion:

    Insulin sensitivity was higher during a short-term atropine infusion compared with saline in both lean and abdominally obese subjects. This insulin-sensitizing effect of cholinergic blockade is unexpected, and the underlying mechanisms should be further investigated.

  • 140. Svensson, M K
    et al.
    Tyrberg, M
    Nyström, L
    Arnqvist, H J
    Bolinder, J
    Östman, J
    Gudbjörnsdottir, S
    Landin-Olsson, M
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    The risk for diabetic nephropathy is low in young adults in a 17-year follow-up from the Diabetes Incidence Study in Sweden (DISS). Older age and higher BMI at diabetes onset can be important risk factors.2015In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 31, no 2, p. 138-146Article in journal (Refereed)
    Abstract [en]

    AIMS: The main objective of this study was to estimate the occurrence of diabetic nephropathy in a population-based cohort of patients diagnosed with diabetes as young adults (15-34 years).

    METHODS: All 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) were invited to a follow-up study 15-19 years after diagnosis, and 468 (58%) participated. Analysis of islet antibodies was used to classify type of diabetes.

    RESULTS: After median 17 years of diabetes, 15% of all patients, 14% T1DM and 25% T2DM, were diagnosed with diabetic nephropathy. Ninety-one percent had microalbuminuria and 8.6% macroalbuminuria. Older age at diagnosis (HR 1.05; 95% CI 1.01-1.10 per year) was an independent and a higher BMI at diabetes diagnosis (HR 1.04; 95% CI 1.00-1.09 per 1 kg/m(2) ), a near-significant predictor of development of diabetic nephropathy. Age at onset of diabetes (p = 0.041), BMI (p = 0.012) and HbA1c (p < 0.001) were significant predictors of developing diabetic nephropathy between 9 and 17 years of diabetes. At 17 years of diabetes duration, a high HbA1c level (OR 1.06; 95% CI 1.03-1.08 per 1 mmol/mol increase) and systolic blood pressure (OR 1.08; 95% CI 1.05 1.12 per 1 mmHg increase) were associated with DN.

    CONCLUSIONS: Patients with T2DM diagnosed as young adults seem to have an increased risk to develop diabetic nephropathy compared with those with T1DM. Older age and higher BMI at diagnosis of diabetes were risk markers for development of diabetic nephropathy. In addition, poor glycaemic control but not systolic blood pressure at 9 years of follow-up was a risk marker for later development of diabetic nephropathy. Copyright © 2014 John Wiley & Sons, Ltd.

  • 141. Svensson, Maria
    et al.
    Eriksson, Jan W
    Insulin resistance in diabetic nephropathy - cause or consequence?2006In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 22, no 5, p. 401-410Article in journal (Refereed)
    Abstract [en]

    Insulin resistance (IR) is associated with multiple risk factors for cardiovascular disease. Many studies have shown that IR is present in chronic renal failure (CRF), and recent evidence suggests that IR can also occur in the early stages of renal disease. Patients with diabetic nephropathy (DN) have an increase in cardiovascular mortality, and since IR may be a contributing factor, this emphasizes the importance of a detailed understanding of the mechanisms linking IR and renal dysfunction at different stages of DN. IR can be detected early on in DN, e.g. at the stage of microalbuminuria (MA) and this could indicate a common genetic trait for IR and DN. As DN progresses further, IR is aggravated and it may, in addition to other factors, possibly accelerate the decline in renal function toward end-stage renal disease (ESRD). Several potentially modifiable mechanisms including circulating hormones, neuroendocrine pathways and chronic inflammation, are said to contribute to the worsening of IR. In ESRD, uremic toxins are of major importance. In this review article, we address the association between different stages of DN and IR and attempt to summarize major findings on potential mechanisms linking DN and IR. We conclude that IR is a consequence, and potentially also a cause of DN. In addition, there are probably genetic and environmental background factors that predispose to both IR and DN.

  • 142. Svensson, Maria
    et al.
    Eriksson, Jan W
    Department of Medicine, Umeå University Hospital, Sweden.
    No direct link between albumin excretion rate and insulin resistance: A study in type 1 diabetes patients with mild nephropathy2002In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 34, no 5, p. 254-259Article in journal (Refereed)
    Abstract [en]

    Aims:

    Albuminuria is thought to be associated with insulin resistance in patients with type 1 and type 2 diabetes as well as in non-diabetic subjects. The aim of this study was to find out about any direct correlation between the albumin excretion rate (AER) and insulin resistance; this was investigated in patients with type 1 diabetes.

    Methods:

    Euglycemic hyperinsulinemic clamps were performed in 18 patients with type 1 diabetes and incipient nephropathy - elevated albumin excretion rate (AER > 20 µg/min) but normal glomerular filtration rate (GFR) (81 - 135 ml/min/1.73 m2).

    Results:

    AER, determined as mean of two overnight urine collections, was 137 ± 157 (mean ± S.D.) µg/min (range 24 - 447). Insulin sensitivity, expressed as the M-value, was 6.8 ± 2.9 mg/kg/min, insulin sensitivity index (ISI = 100 × M/plasma insulin) 7.9 ± 3.4 and insulin clearance (MCRins) 17.0 ± 4.0 ml/kg/min. Simple regression analyses showed no direct association between AER and M, ISI or MCRins. GFR was not associated with M, ISI or MCRins in this group, either. AER was, however, positively associated with poor glucose control (high HbAlc) and tobacco use.

    Conclusions:

    These results suggest that the degree of albuminuria is not directly linked to insulin resistance. This was shown in type 1 diabetics, but could possibly be applicable in other subjects as well.

  • 143. Svensson, Maria K
    et al.
    Eriksson, Jan W
    Institution för medicin, Sahlgrenska universitetssjukhuset, Göteborg.
    Bättre mäta tåblodtryck än ankelblodtryck hos patienter med diabetes2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 105, no 12-13, p. 925-926Article in journal (Refereed)
  • 144.
    Svensson, Maria K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lindmark, Stina
    Umea Univ Hosp, Dept Med, Umea, Sweden..
    Wiklund, Urban
    Umea Univ Hosp, Dept Biomed Engn & Informat, Umea, Sweden..
    Rask, Peter
    Orebro Univ Hosp, Dept Clin Physiol, Orebro, Sweden..
    Karlsson, Marcus
    Umea Univ Hosp, Dept Biomed Engn & Informat, Umea, Sweden..
    Myrin, Jan
    Orebro Univ Hosp, Dept Clin Physiol, Orebro, Sweden..
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Alterations in heart rate variability during everyday life are linked to insulin resistance. A role of dominating sympathetic over parasympathetic nerve activity?2016In: Cardiovascular Diabetology, ISSN 1475-2840, E-ISSN 1475-2840, Vol. 15, article id 91Article in journal (Refereed)
    Abstract [en]

    Aims: To evaluate the role of the autonomic nervous system (ANS) in the development of insulin resistance (IR) and assess the relationship between IR and activity of ANS using power spectrum analysis of heart rate variability (HRV). Subjects and methods: Twenty-three healthy first-degree relatives of patients with type 2 diabetes (R) and 24 control subjects without family history of diabetes (C) group-matched for age, BMI and sex were included. Insulin sensitivity (M value) was assessed by hyperinsulinemic (56 mU/m(2)/min) euglycemic clamp. Activity of the ANS was assessed using power spectrum analysis of HRV in long-term recordings, i.e., 24-h ECG monitoring, and in short-term recordings during manoeuvres activating the ANS. Computed tomography was performed to estimate the amount and distribution of abdominal adipose tissue. Results: Insulin sensitivity (M value, mg/kg lbm/min) did not differ significantly between the R and C groups. Total spectral power (P-tot) and very low-frequency (P-VLF) power was lower in R than C during 24 h ECG-recordings (p = 0.02 and p = 0.03). The best fit multiple variable linear regression model (r(2) = 0.37, p < 0.001 for model) indicated that body composition (BMI) and long-term low to high frequency (LF/HF) power ratio (std beta = -0.46, p = 0.001 and std beta = -0.28, p = 0.003, respectively) were significantly and independently associated with the M value. Conclusion: Altered heart rate variability, assessed by power spectrum analysis, during everyday life is linked to insulin resistance. The data suggest that an increased ratio of sympathetic to parasympathetic nerve activity, occurring via both inherited and acquired mechanisms, could potentially contribute to the development of type 2 diabetes.

  • 145. Taube, Magdalena
    et al.
    Andersson-Assarsson, Johanna C
    Lindberg, Kristin
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Gäbel, Markus
    Svensson, Maria K
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Svensson, Per-Arne
    Evaluation of reference genes for gene expression studies in human brown adipose tissue2015In: Adipocyte, ISSN 2162-3945, E-ISSN 2162-397X, Vol. 4, no 4, p. 280-285Article in journal (Refereed)
    Abstract [en]

    Human brown adipose tissue (BAT) has during the last 5 year been subjected to an increasing research interest, due to its putative function as a target for future obesity treatments. The most commonly used method for molecular studies of human BAT is the quantitative polymerase chain reaction (qPCR). This method requires normalization to a reference gene (genes with uniform expression under different experimental conditions, e.g. similar expression levels between human BAT and WAT), but so far no evaluation of reference genes for human BAT has been performed. Two different microarray datasets with samples containing human BAT were used to search for genes with low variability in expression levels. Seven genes (FAM96B, GNB1, GNB2, HUWE1, PSMB2, RING1 and TPT1) identified by microarray analysis, and 8 commonly used reference genes (18S, B2M, GAPDH, LRP10, PPIA, RPLP0, UBC, and YWHAZ) were selected and further analyzed by quantitative PCR in both BAT containing perirenal adipose tissue and subcutaneous adipose tissue. Results were analyzed using 2 different algorithms (Normfinder and geNorm). Most of the commonly used reference genes displayed acceptably low variability (geNorm M-values <0.5) in the samples analyzed, but the novel reference genes identified by microarray displayed an even lower variability (M-values <0.25). Our data suggests that PSMB2, GNB2 and GNB1 are suitable novel reference genes for qPCR analysis of human BAT and we recommend that they are included in future gene expression studies of human BAT.

  • 146. Torffvit, Ole
    et al.
    Eriksson, Jan W
    Henricsson, Marianne
    Sundkvist, Göran
    Arnqvist, Hans J
    Blohmé, Göran
    Bolinder, Jan
    Nyström, Lennarth
    Ostman, Jan
    Svensson, Maria
    Early changes in glomerular size selectivity in young adults with type 1 diabetes and retinopathy. Results from the Diabetes Incidence Study in Sweden.2007In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 21, no 4, p. 246-51Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the relationship between early-onset retinopathy and urinary markers of renal dysfunction.

    RESEARCH DESIGN AND METHODS: The Diabetes Incidence Study in Sweden (DISS) aims to register all new cases of diabetes in young adults (15-34 years). In 1987-1988, 806 patients were reported and later invited to participate in a follow-up study focusing on microvascular complications after approximately 10 years of diabetes. In the present study, 149 patients with type 1 diabetes, completed eye examination, and urine sampling were included.

    RESULTS: The patients with retinopathy (n=58, 39%) had higher HbA(1c) (P<.001) and urinary IgG2/creatinine (P<.05) and IgG2/IgG4 ratios (P<.05). Patients with maculopathy had the highest levels. No significant differences in urinary albumin/creatinine, glycosaminoglycans (GAGs)/creatinine, Tamm-Horsfall protein (THP)/creatinine, and IgG4/creatinine ratios were found. Women had higher urinary albumin/creatinine (P<.01) and urinary IgG2/creatinine ratios (P<.01) than men.

    CONCLUSIONS: Young adults with type 1 diabetes and early-onset retinopathy had higher IgG2/creatinine and IgG2/IgG4 ratios than patients without retinopathy indicating that retinopathy is associated with a change in glomerular size selectivity. This was found in association with normal urinary albumin and THP excretion and may be suspected to reflect early general vascular changes.

  • 147. Torffvit, Ole
    et al.
    Kalani, Majid
    Apelqvist, Jan
    Eliasson, Björn
    Eriksson, Jan W
    Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
    Brismar, Kerstin
    Jörneskog, Gun
    Increased Urine IgM and IgG2 Levels, Indicating Decreased Glomerular Size Selectivity, Are Not Affected by Dalteparin Therapy in Patients with Type 2 Diabetes2012In: Biochemistry Research International, ISSN 2090-2247, E-ISSN 2090-2255, Vol. 2012, p. 480529-Article in journal (Refereed)
    Abstract [en]

    Fifty-four type 2 diabetic patients with neuroischemic foot ulcers were randomised to treatment with 5000 IU of dalteparin, (n = 28), or physiological saline, (n = 26), once daily until ulcer healing or for a maximum of 6 months. Thirty-three patients had normo-, 15 micro-, and 6 macroalbuminuria. The urinary levels of IgM and IgG2 were elevated in 47 and 50 patients, respectively. Elevated urinary levels of IgM and IgG2 indicate decreased glomerular size selectivity. Urine IgM levels were associated with IGF-1/IGFBP-1 and IGFBP-1 levels. Dalteparin treatment increased urinary levels of glycosaminoglycans (P < 0.001) and serum IGFBP-1 (P < 0.05) while no significant effects were seen in any of the other studied parameters. In conclusion, dalteparin therapy in patients with type 2 diabetes had no effects on urinary levels of albumin, IgM, or IgG2 despite significantly increased glycosaminoglycans in urine. Elevated urinary levels of IgM and IgG2 might be more sensitive markers of renal disease than albuminuria in patients with type 2 diabetes and antihypertensive therapy.

  • 148.
    Tyrberg, M.
    et al.
    Lund Univ, Helsingborg Hosp, Dept Ophthalmol, Helsingborg, Sweden..
    Nystrom, L.
    Umea Univ, Epidemiol, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Arnqvist, H. J.
    Linkoping Univ, Dept Endocrinol, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Bolinder, J.
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Endocrinol Metab & Diabet, Huddinge, Sweden..
    Gudbjornsdottir, S.
    Univ Gothenburg, Sahlgrenska Acad, Dept Med, Gothenburg, Sweden..
    Landin-Olsson, M.
    Lund Univ, Dept Clin Sci, Lund, Sweden..
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Svensson, Maria K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Overweight, hyperglycemia and tobacco use are modifiable risk factors for onset of retinopathy 9 and 17 years after the diagnosis of diabetes: A retrospective observational nation-wide cohort study2017In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 133, p. 21-29Article in journal (Refereed)
    Abstract [en]

    Background: The aims of this study were to estimate the risk for diabetic retinopathy (DR) and to identify risk factors. We investigated a nationwide population-based cohort with diabetes diagnosed at age 15-34 years. Patients and methods: Of 794 patients registered 1987-1988 in the Diabetes Incidence Study in Sweden (DISS) 444 (56%) patients with retinal photos available for classification of retinopathy participated in a follow-up study 15-19 (median 17) years after diagnosis. Mean age was 42.3 +/- 5.7 years, BMI 26.1 +/- 4.1 kg/m(2), 62% were male and 91% had type 1 diabetes. A sub-study was performed in 367 patients with retinal photos from both the 9 and 17 year follow up and the risk for development of retinopathy between 9 and 17 years of follow up was calculated. Results: After median 17 years 324/444 (73%, 67% of T1D and 71% of T2D), had developed any DR but only 5.4% proliferative DR. Male sex increased the risk of developing retinopathy (OR 1.9, 95% CI 1.2-2.9). In the sub-study obesity (OR 1.2, 95% CI 1.04-1.4), hyperglycemia (OR 2.5, 95% CI 1.6-3.8) and tobacco use (OR 2.9, 95% CI 1.1-7.3) predicted onset of retinopathy between 9 and 17 years after diagnosis of diabetes. Conclusion: The number of patients with severe retinopathy after 17 years of diabetes disease was small. The risk of developing retinopathy with onset between 9 and 17 years after diagnosis of diabetes was strongly associated to modifiable risk factors such as glycemic control, obesity and tobacco use.

  • 149. Wang, Z H
    et al.
    Kihl-Selstam, E
    Eriksson, Jan W
    The Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden.
    Ketoacidosis occurs in both Type 1 and Type 2 diabetes: a population-based study from Northern Sweden2008In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 25, no 7, p. 867-870Article in journal (Refereed)
    Abstract [en]

    AIMS:

    To determine the occurrence of diabetic ketoacidosis (DKA) in adult Type 2 and Type 1 diabetic patients in Northern Sweden and to determine whether DKA presents with a different clinical picture in Type 2 compared with Type 1 diabetic subjects.

    METHODS:

    All adult patients from a hospital catchment area in Northern Sweden with diagnosed DKA episodes during 1997-2000 were included in a retrospective study. Medical records and laboratory reports were analysed.

    RESULTS:

    During the years 1997 to 2000, the average annual incidence rate for DKA was 5.9 per 100 000 adult inhabitants. Twenty-five patients developed DKA, eight (32%) had Type 2 diabetes, while 17 (68%) had Type 1 diabetes. Type 2 diabetic patients with DKA were older and had higher levels of C-peptide than Type 1 diabetic patients. On admission because of DKA, a similar degree of hyperglycaemia was present in Type 1 and Type 2 patients. Metabolic acidosis was more severe in Type 1 compared with Type 2 diabetic patients. In 50% of the Type 2 diabetic patients, diabetes was diagnosed at the episode of DKA.

    CONCLUSIONS:

    DKA occurs in Caucasian Type 2 diabetic patients within a Swedish population. Although the frequency of DKA is much higher in Type 1 diabetic patients, Type 2 diabetes may account for as much as one-third of the overall DKA cases.

  • 150. Wesslau, C
    et al.
    Eriksson, Jan W
    Gothenburg University, Sahlgrens Hospital, Department of Medicine, Gothenburg, Sweden.
    Smith, U
    Cellular cyclic AMP levels modulate insulin sensitivity and responsiveness: evidence against a significant role of Gi in insulin signal transduction1993In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 196, no 1, p. 287-293Article in journal (Refereed)
    Abstract [en]

    Treating rats with pertussis toxin (PTX) both elevated the adipocyte cAMP levels and impaired sensitivity and responsiveness to the antilipolytic effect of insulin in the presence of different beta-adrenergic agonists. However, in the presence of a fixed medium concentration of the degradable cAMP analogue, 8-bromo-cAMP, the effect of insulin was similar in PTX- and control cells. Elevating the cAMP levels in control cells either through different concentrations of the cAMP analogue or addition of adenosine deaminase impaired both insulin sensitivity and responsiveness to a similar extent as that seen in PTX-treated cells. The antilipolytic effect of insulin was exerted through the activation of the cGMP-inhibitable phosphodiesterase (cGI-PDE) as it was dose-dependently impaired by the specific cGI-PDE inhibitor OPC 3911. The results show the importance of the cellular cAMP levels in modulating insulin sensitivity and action. Gi plays a minor role, if any, for the signal transduction of the antilipolytic effect of insulin.

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