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  • 1.
    Abdelgadir, Moawia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Karlsson, Anders F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Low serum adiponectin concentrations are associated with insulin sensitivity independent of obesity in Sudanese subjects with type 2 diabetes mellitus2013In: Diabetology and Metabolic Syndrome, ISSN 1758-5996, E-ISSN 1758-5996, Vol. 5, p. 15-Article in journal (Refereed)
    Abstract [en]

    Aims: Prevalence of Type 2 diabetes mellitus among Sudanese population was found to be 3.4% and associated with high rates of complications and obesity. Different adipocytokines are secreted from adipose tissues, among them adiponectin, which was shown to have insulins ensitizing properties and anti-inflammatory, anti-atherogenic effect. The aim of this study was to characterize type 2 diabetes in Sudanese diabetic subjects and controls in respect to hormones influencing or influenced by glucose metabolism. Methods: 104 type 2 diabetic patients (45 men and 59 women), and 75 matched control subjects (34 men and 41 women) were studied. Fasting serum samples were used to measure adiponectin, leptin, insulin, proinsulin, ghrelin and glucose. Body mass index, insulin/proinsulin ratio and (HOMA) insulin resistance and beta cell function were also calculated. Results: Adiponectin serum concentrations were significantly lower in subjects with type 2 diabetes compared with controls subjects (P = 0.002), comparison between males and females did not reach significant levels in both diabetic (P = 0.06) or controls (P = 0.16) groups. In the diabetic group adiponectin correlated positively with serum glucose, negatively with serum proinsulin and HOMA beta cell function (P = 0.03) respectively and serum ghrelin (P = 0.003), but not with BMI, HOMA insulin resistance, insulin or leptin. In controls serum adiponectin correlated negatively with BMI (P = 0.002) but not with other variables. Conclusions: The findings of this study suggest that, adiponectin concentrations independent on BMI as a measure of adiposity, were mostly linked to insulin sensitivity and not to insulin resistance in Sudanese type 2 diabetic subjects, where race specific regulation mechanisms or different type 2 diabetes phenotype suggested being a major contributory factor in clarification the findings of this study.

  • 2.
    Abrahamsson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Engström, Britt Edén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Gastric Bypass Surgery Elevates NT-ProBNP Levels2013In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 23, no 9, p. 1421-1426Article in journal (Refereed)
    Abstract [en]

    Background

    Brain natriuretic peptide (BNP) is produced in the heart in response to stretching of the myocardium. BNP levels are negatively correlated to obesity, and in obese subjects, a reduced BNP responsiveness has been described. Diet-induced weight loss has been found to lower or to have no effect on BNP levels, whereas gastric banding and gastric bypass have reported divergent results. We studied obese patients undergoing gastric bypass (GBP) surgery during follow-up of 1 year.

    Methods

    Twenty patients, 18 women, mean 41 (SD 9.5) years old, with a mean preoperative BMI of 44.6 (SD 5.5) kg/m2 were examined. N-terminal pro-brain natriuretic peptide (NT-ProBNP), glucose and insulin were measured preoperatively, at day 6 and months 1, 6 and 12. In 14 of the patients, samples were also taken at days 1, 2 and 4.

    Results

    The NT-ProBNP levels showed a marked increase during the postoperative week (from 54 pg/mL preop to 359 pg/mL on day 2 and fell to 155 on day 6). At 1 year, NT-ProBNP was 122 pg/mL (125 % increase, p = 0.01). Glucose, insulin and HOMA indices decreased shortly after surgery without correlation to NT-ProBNP change. Mean BMI was reduced from 44.6 to 30.5 kg/m2 at 1 year and was not related to NT-ProBNP change.

    Conclusions

    The data indicate that GBP surgery rapidly alters the tone of BNP release, by a mechanism not related to weight loss or to changes in glucometabolic parameters. The GBP-induced conversion of obese subjects, from low to high NT-ProBNP responders, is likely to influence the evaluation of cardiac function in GBP operated individuals.

  • 3. Ahrén, Bo
    et al.
    Simonsson, Erik
    Larsson, Hillevi
    Landin-Olsson, Mona
    Torgeirsson, Hlin
    Jansson, Per-Anders
    Sandqvist, Madeléne
    Båvenholm, Peter
    Efendic, Suad
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Dickinson, Sheila
    Holmes, David
    Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes.2002In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 25, no 5, p. 869-75Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has been proposed as a new treatment modality for type 2 diabetes. To circumvent the drawback of the short half-life of GLP-1, inhibitors of the GLP-1-degrading enzyme dipeptidyl peptidase IV (DPP IV) have been examined. Such inhibitors improve glucose tolerance in insulin-resistant rats and mice. In this study, we examined the 4-week effect of 1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP DPP728), a selective, orally active inhibitor of DPP IV, in subjects with diet-controlled type 2 diabetes in a placebo-controlled double-blind multicenter study.

    RESEARCH DESIGN AND METHODS: A total of 93 patients (61 men and 32 women), aged 64 +/- 9 years (means +/- SD) and with BMI 27.3 +/- 2.7 kg/m(2), entered the study. Fasting blood glucose was 8.5 +/- 1.5 mmol/l, and HbA(1c) was 7.4 +/- 0.7%. Before and after treatment with NVP DPP728 at 100 mg x 3 (n = 31) or 150 mg x 5 (n = 32) or placebo (n = 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal).

    RESULTS: Compared with placebo, NVP DPP728 at 100 mg t.i.d. reduced fasting glucose by 1.0 mmol/l (mean), prandial glucose excursions by 1.2 mmol/l, and mean 24-h glucose levels by 1.0 mmol/l (all P < 0.001). Similar reductions were seen in the 150-mg b.i.d. treatment group. Mean 24-h insulin was reduced by 26 pmol/l in both groups (P = 0.017 and P = 0.023). Although not an efficacy parameter foreseen in the study protocol, HbA(1c) was reduced to 6.9 +/- 0.7% in the combined active treatment groups (P < 0.001). Laboratory safety and tolerability was good in all groups.

    CONCLUSIONS: We conclude that inhibition of DPP IV is a feasible approach to the treatment of type 2 diabetes in the early stage of the disease.

  • 4. Axelsen, M
    et al.
    Smith, U
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Taskinen, M R
    Jansson, P A
    Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes.1999In: Annals of Internal Medicine, ISSN 0003-4819, E-ISSN 1539-3704, Vol. 131, no 1, p. 27-31Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an atherogenic trait associated with insulin resistance.

    OBJECTIVE: To assess insulin sensitivity and postprandial triglyceride metabolism in prediabetic persons.

    DESIGN: Cross-sectional study.

    SETTING: Sahlgrenska University Hospital, Göteborg, Sweden.

    PARTICIPANTS: 13 healthy, normotriglyceridemic men with two first-degree relatives with type 2 diabetes and 13 carefully matched controls without known diabetes heredity.

    MEASUREMENTS: Oral glucose tolerance test, insulin sensitivity (euglycemic clamp technique), and fasting and postprandial triglyceride levels after a mixed meal.

    RESULTS: Relatives of persons with type 2 diabetes were insulin resistant but had normal glucose tolerance. They exhibited postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under the curve was 50% higher than that of the control group (P = 0.037).

    CONCLUSIONS: These healthy male first-degree relatives of patients with type 2 diabetes are insulin resistant and exhibit postprandial lipid intolerance despite having normal fasting triglyceride levels. These characteristics, which occur in the absence of glucose intolerance, are associated with an increased risk for macroangiopathy.

  • 5. Bakhtadze, E
    et al.
    Borg, H
    Stenström, G
    Fernlund, P
    Arnqvist, H J
    Ekbom-Schnell, A
    Bolinder, J
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Gudbjörnsdottir, S
    Nyström, L
    Groop, L C
    Sundkvist, G
    HLA-DQB1 genotypes, islet antibodies and beta cell function in the classification of recent-onset diabetes among young adults in the nationwide Diabetes Incidence Study in Sweden2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 8, p. 1785-1794Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The World Health Organization considers an aetiological classification of diabetes to be essential. The aim of this study was to evaluate whether HLA-DQB1 genotypes facilitate the classification of diabetes as compared with assessment of islet antibodies by investigating young adult diabetic patients.

    SUBJECTS AND METHODS: Blood samples were available at diagnosis for 1,872 (90%) of the 2,077 young adult patients (aged 15-34 years old) over a 5-year period in the nationwide Diabetes Incidence Study in Sweden. Islet antibodies were measured at diagnosis in 1,869 patients, fasting plasma C-peptide (fpC-peptide) after diagnosis in 1,522, while HLA-DQB1 genotypes were determined in 1,743.

    RESULTS: Islet antibodies were found in 83% of patients clinically considered to have type 1 diabetes, 23% with type 2 diabetes and 45% with unclassifiable diabetes. After diagnosis, median fpC-peptide concentrations were markedly lower in patients with islet antibodies than in those without (0.24 vs 0.69 nmol/l, p<0.0001). Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one of the risk-associated HLA-DQB1 genotypes compared with patients without. Antibody-negative patients with risk-associated HLA-DQB1 genotypes had significantly lower median fpC-peptide concentrations than those without risk-associated genotypes (0.51 vs 0.74 nmol/l, p=0.0003).

    CONCLUSIONS/INTERPRETATION: Assessment of islet antibodies is necessary for the aetiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with C-peptide measurement may be of value in differentiating between idiopathic type 1 diabetes and type 2 diabetes.

  • 6.
    Barbu, Andreea
    et al.
    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, Endocrine Tumor Biology.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bodin, Bbirgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Börjesson, Joey Lau
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Blood flow in endogenous and transplanted pancreatic islets in anesthetized rats: Effects of lactate and pyruvate2012In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 41, no 8, p. 1263-1271Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The objective of this study was to evaluate the effects of exogenously administered lactate and pyruvate on blood perfusion in endogenous and transplanted islets. METHODS: Anesthetized Wistar-Furth rats were given lactate or pyruvate intravenously, and regional blood perfusion was studied 3 or 30 minutes later with a microsphere technique. Separate rats received a 30-minute infusion of pyruvate or lactate into the portal vein before blood flow measurements. We also administered these substances to islet-implanted rats 4 weeks after transplantation and measured graft blood flow with laser Doppler flowmetry. The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was analyzed. RESULTS: The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was markedly up-regulated in transplanted as compared with endogenous islets. Administration of pyruvate, but not lactate, increased mesenteric blood flow after 3 minutes. Pyruvate decreased mesenteric blood flow after 30 minutes, whereas lactate decreased only islet blood flow. These responses were absent in transplanted animals. A continuous intraportal infusion of lactate or pyruvate increased selectively islet blood flow but did not affect blood perfusion of transplanted islets. CONCLUSIONS: Lactate and pyruvate affect islet blood flow through effects mediated by interactions between the liver and the nervous system. Such a response can help adjust the release of islet hormones during excess substrate concentrations.

  • 7. Barner, C.
    et al.
    Petersson, M.
    Engström, Britt Edén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Höybye, C.
    Effects on insulin sensitivity and body composition of combination therapy with GH and IGF1 in GH deficient adults with type 2 diabetes2012In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 167, no 5, p. 697-703Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this trial was to evaluate the effect on insulin sensitivity and body composition of combination therapy with GH and IGF1 in adults with GH deficiency (GHD) and diabetes. Design, patients and methods: A 6-month randomised placebo-controlled pilot study. Fourteen adults with GHD and type 2 diabetes were included. All received rhGH (0.15 mg/day for 1 month and 0.3 mg/day for 5 months) and were randomised to rhIGF1 (15 μg/kg per day for 1 month and 30 μg/kg per day for 5 months) or placebo. Insulin sensitivity was evaluated with euglycaemic hyperinsulinaemic clamp and body composition by computed tomography of abdominal and thigh fat, as well as bioimpedance. Results: Twelve patients completed the study. They were overweight and obese; at baseline, insulin sensitivity (M-value) was low. IGF1 and IGF1 SDS increased in both groups, with the highest increase in the GH and IGF1 group. Positive changes in M-value by +1.4 mg/kg per min, in subcutaneous abdominal fat by -60.5 ml and in fat-free mass by +4.4% were seen in the GH and IGF1 group. Corresponding values in the GH and placebo-treated group were -1.5 mg/kg per min, +23 ml and -0.04% respectively (P=0.02, P=0.04 and P=0.03 for delta values between groups). No safety issues occurred. Conclusions: Combined GH and IGF1 treatment resulted in positive, but rather small effects, and might be a treatment option in a few selected patients.

  • 8. Bergfors, M
    et al.
    Barnekow-Bergkvist, M
    Kalezic, N
    Lyskov, E
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Short-term effects of repetitive arm work and dynamic exercise on glucose metabolism and insulin sensitivity.2005In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 183, no 4, p. 345-56Article in journal (Refereed)
    Abstract [en]

    AIM: To determine whether repetitive arm work, with a large component of static muscle contraction alters glucose metabolism and insulin sensitivity.

    METHOD: Euglycemic clamps (2 h) were started in ten healthy individuals 15 min after 37 min periods of: (1) repetitive arm work in a simulated occupational setting; (2) dynamic concentric exercise on a cycle ergometer at 60% of VO(2max) and (3) a resting regime as a control. During the experimental periods, blood samples were collected, blood pressure was measured repeatedly and electrocardiogram (ECG) was recorded continuously. During the clamps, euglycemia was maintained at 5 mmol l(-1) and insulin was infused at 56 mU m(-2) min(-1) for 120 min.

    RESULTS: The insulin-mediated glucose disposal rate (M-value) for the steady-state period (60-120 min) of the clamp, tended to be lower following arm work than for both cycling and resting regimes. When dividing the steady-state period into 20-min intervals, the insulin sensitivity index (ISI) was significantly lower for arm work compared with the resting control situation between 60-80 min (P = 0.04) and 80-100 min (P = 0.01), respectively. Catecholamines increased significantly for arm work and cycling compared with resting regime. Data from heart rate variability (HRV) measurements indicated significant sympathetic activation during repetitive arm work.

    CONCLUSION: The results indicate that repetitive arm work might acutely promote insulin resistance, whereas no such effect on insulin resistance was produced by dynamic concentric exercise.

  • 9.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Intensiv satsning på framtidens diabetesläkemedel2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 45, p. 2815-2819Article in journal (Refereed)
    Abstract [en]

    Adverse reactions, particularly hypoglyceamia, and the relatively modest effects of intensive glucose-lowering therapy on cardiovascular disease in recent large-scale trials have emphasized the need for a development of new therapeutic alternatives. The recently approved incretins have shown promising results but require daily injections. Therefore, intense efforts have been made to prolong the action or to find alternative routes of administration. Exenatide LAR and insulin glargine has recently been compared in a large RCT and shown similar effects on glucose control. Still, some concerns regarding risk of pancreatitis and thyroid cancers exist for GLP-1 agonists. Inhibitors of the sodium glucose cotransporter 2 have shown promising results as add-on therapy to metformin in a recent pivotal trial, with mild adverse effects. Genital infections may be a problem. A trial with an IL-1 receptor antagonist shows a new interesting concept with a putative action to preserve beta-cells. Glucokinase activators and 11_HSD1 inhibitors have shown promising results in phase II trials, but the risk of adverse phenomena with these drugs that interact with important metabolic and hormonal pathways have to be further investigated in humans.

  • 10. Biglarnia, Ali-Reza
    et al.
    Yamamoto, Shinji
    Gustafsson, Bengt I
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Wagner, Michael
    von Zur-Mühlen, Bengt
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Transplantation av pankreas botande alternativ vid typ 1-diabetes: [Transplantation of pancreas, a curative option for type 1 diabetes]2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 39-40, p. 1754-1757Article in journal (Refereed)
    Abstract [en]

    In the past decade, pancreas transplantation (PTx) has become increasingly attractive as a curative treatment in patients with labile diabetes and secondary complications. In the United Kingdom, the percentage of deceased-donors utilized for PTx increased 5-fold between 2003 and 2007. The trend towards a higher number of annual pancreas transplantations is also observed in Sweden. The increasing activity and the excellent outcome are consequences of meticulous surgery, effective immunsuppression and adequate follow-up. The present report descibes the current status of PTx and shows the short- and long-term results during the last decade in Sweden.

  • 11.
    Birkeland, Kare I.
    et al.
    Univ Oslo, Inst Clin Med.; Oslo Univ Hosp, Dept Transplantat Med..
    Jorgensen, Marit E.
    Steno Diabet Ctr Copenhagen.;Southern Denmark Univ, Natl Inst Publ Hlth..
    Carstensen, Bendix
    Steno Diabet Ctr Copenhagen..
    Persson, Frederik
    Steno Diabet Ctr Copenhagen..
    Gulseth, Hanne L.
    Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med..
    Thuresson, Marcus
    Statisticon AB..
    Fenici, Peter
    AstraZeneca..
    Nathanson, David
    Karolinska Inst, Dept Clin Sci & Educ..
    Nyström, Thomas
    Karolinska Inst, Dept Clin Sci & Educ..
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Bodegard, Johan
    AstraZeneca Nord Baltic, Med Dept..
    Norhammar, Anna
    Karolinska Inst, Södersjukhuset, Dept Med.;Capio St Görans Hosp.
    Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): A Multinational Observational Analysis2017In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 5, no 9, p. 709-717Article in journal (Refereed)
    Abstract [en]

    Background In patients with type 2 diabetes and a high cardiovascular risk profile, the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin have been shown to lower cardiovascular morbidity and mortality. Using real-world data from clinical practice, we aimed to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors versus new users of other glucose-lowering drugs, in a population with a broad cardiovascular risk profile. Methods CVD-REAL Nordic was an observational analysis of individual patient-level data from the Prescribed Drug Registers, Cause of Death Registers, and National Patient Registers in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed up until Dec 31, 2015. Patients were divided into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs. Each SGLT2 inhibitor user was matched with three users of other glucose-lowering drugs by use of propensity scores. Hazard ratios (HRs) were estimated by country (Cox survival model) and weighted averages were calculated. Cardiovascular outcomes investigated were cardiovascular mortality, major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischaemic or haemorrhagic stroke), hospital events for heart failure (inpatient or outpatient visit with a primary diagnosis of heart failure), non-fatal myocardial infarction, non-fatal stroke, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0.9 (SD 4.1) years (80 669 patient-years) and mean age of 61 (12.0) years; 40% (36 362 of 91 320) were women and prevalence of cardiovascular disease was 25% (22 686 of 91 320). 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, with 5% for empagliflozin, and 1% for canagliflozin. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with decreased risk of cardiovascular mortality (HR 0.53 [95% CI 0.40-0.71]), major adverse cardiovascular events (0.78 [0.69-0.87]), and hospital events for heart failure (0.70 [0.61-0.81]; p<0.0001 for all). We did not identify significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for non-fatal myocardial infarction, non-fatal stroke, or atrial fibrillation. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycaemia (HR 0.76 [0.65-0.90]; p=0.001). For cardiovascular mortality, the differences were similar for the 25% of individuals with cardiovascular disease at baseline and those without (HR 0.60 [0.42-0.85] vs 0.55 [0.34-0.90]), while for major adverse cardiovascular events the HR in the group with cardiovascular disease at baseline was 0.70 (0.59-0.83) versus 0.90 (0.76-1.07) in the group without. Interpretation In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs-a finding consistent with the results of clinical trials in patients at high cardiovascular risk.

  • 12. Bolinder, J
    et al.
    Fernlund, P
    Borg, H
    Arnqvist, H J
    Björk, E
    Blohmé, G
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Nyström, L
    Ostman, J
    Sundkvist, G
    Hyperproinsulinemia segregates young adult patients with newly diagnosed autoimmune (type 1) and non-autoimmune (type 2) diabetes.2005In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 65, no 7, p. 585-94Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate whether measurements of proinsulin and/or intermediate proinsulin degradation products could be used to differentiate between autoimmune (type 1) and non-autoimmune (type 2) diabetes in young adults.

    MATERIAL AND METHODS: Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were measured in 25 patients aged 15-34 years with type 1 diabetes, as defined by the presence of at least two positive islet autoantibodies, and in 23 antibody-negative patients of similar age with type 2 diabetes, at the time of clinical onset of diabetes and at 3-4 months thereafter. Comparisons were made with data from 25 healthy subjects matched for gender and age.

    RESULTS: Plasma levels of total proinsulin, intact proinsulin and 32,33 split proinsulin were significantly increased 2-3-fold in the patients with newly diagnosed type 2 diabetes as compared with the controls, both in absolute terms (p<0.0001) and when related to circulating insulin (p<0.01-0.0002). In contrast, absolute proinsulin and 32,33 split proinsulin concentrations were significantly lower in patients with onset of type 1 diabetes than in controls. When proinsulin and split proinsulin release were related to plasma insulin, however, similar ratios were found in the type 1 diabetes patients and in controls. Using the 90th percentile for total proinsulin in the control group as the cut-off, the sensitivity and specificity for differentiation between autoimmune and non-autoimmune diabetes were 87% and 92%, respectively. At 3-4 months after clinical onset of diabetes, proinsulin secretion was still 2-3 times higher in type 2 than in type 1 diabetes patients (p<0.001).

    CONCLUSIONS: Young adult patients with newly diagnosed type 2 diabetes display disproportionate hyperproinsulinemia, whereas proinsulin secretion appears to be normal in patients with clinical onset of type 1 diabetes. Evaluation of proinsulin and 32,33 split proinsulin concentrations may be useful as a diagnostic tool in differentiating between autoimmune and non-autoimmune diabetes in young adults, particularly in those lacking islet autoantibodies at diagnosis.

  • 13. Borg, H
    et al.
    Arnqvist, H J
    Björk, E
    Bolinder, J
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Nyström, L
    Jeppsson, J-O
    Sundkvist, G
    Evaluation of the new ADA and WHO criteria for classification of diabetes mellitus in young adult people (15-34 yrs) in the Diabetes Incidence Study in Sweden (DISS).2003In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 46, no 2, p. 173-81Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: We aimed to evaluate how an aetiology-based classification, as recommended in the ADA and WHO guidelines for classification of diabetes mellitus, matches clinical judgement in the Diabetes Incidence Study in Sweden (DISS), a study covering incident cases of diabetic patients aged 15 to 34 years.

    METHODS: During a 1-year period (1998), blood samples were taken at diagnosis and 4 months (median) thereafter. Patients were classified according to clinical judgement by the reporting physicians and assessments of islet antibodies (ICA, GADA, and IA-2A) and plasma C-peptide.

    RESULTS: In 1998, 422 patients were registered in DISS. Among the 313 patients participating in the follow-up, most with clinical Type 1 diabetes (185/218, 85%, 95% CI 79-89%) were islet antibody positive (ab+) at diagnosis. In addition, 14 out of 58 (24%, 14-37%) with clinical Type 2 diabetes and 21 out of 37 (57%, 40-73%) with unclassifiable diabetes were antibody positive at diagnosis. Further to this, 4 out of 33 (12%, 3-28%) were antibody negative with clinical Type 1 diabetes and 4 out of 44 (9%, 3-22%) with Type 2 had converted to antibody positive at follow-up. Among those who were constantly antibody negative, 10 out of 29 (34%, 18-54%) with clinical Type 1 and 1 out of 16 (6%, 0-30%) with unclassifiable diabetes had fasting plasma C-peptide concentrations below the normal range (<0.25 nmol/l) at follow-up.

    CONCLUSION/INTERPRETATION: Most young adults with clinical Type 1 diabetes (199/218, 91%) had objective Type 1 (ab+ at diagnosis/follow-up and/or low fasting plasma C-peptide concentrations at follow-up), as did one third (18/58, 31%) with clinical Type 2 diabetes and more than half (22/37, 59%) with unclassifiable diabetes. About 10% of those who were antibody negative converted to antibody positive. Our study underlines that a classification considering aetiology is superior to clinical judgement.

  • 14. Burman, P.
    et al.
    Mattsson, A. F.
    Johannsson, G.
    Höybye, C.
    Holmer, H.
    Dahlqvist, P.
    Berinder, K.
    Edén Engström, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Ekman, B.
    Erfurth, E. M.
    Svensson, J.
    Wahlberg, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, F. A.
    Deaths Among Adult Patients With Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 4, p. 1466-1475Article in journal (Refereed)
    Abstract [en]

    Context: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. Objective: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. Design and Methods: All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. Main Outcome Measures: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. Results: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. Conclusion: Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

  • 15. Burén, Jonas
    et al.
    Lindmark, Stina
    Renström, Frida
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    In vitro reversal of hyperglycemia normalizes insulin action in fat cells from type 2 diabetes patients: is cellular insulin resistance caused by glucotoxicity in vivo?2003In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 52, no 2, p. 239-45Article in journal (Refereed)
    Abstract [en]

    Chronic hyperglycemia promotes the development of insulin resistance. The aim of this study was to investigate whether cellular insulin resistance is secondary to the diabetic state in human type 2 diabetes. Subcutaneous fat biopsies were taken from 3 age-, sex-, and body mass index (BMI)-matched groups with 10 subjects in each group: type 2 diabetes patients with either good (hemoglobin A(1c) [HbA(1c)] < 7%, G) or poor (HbA(1c) > 7.5%, P) metabolic control and healthy control subjects (C). Insulin action in vitro was studied by measurements of glucose uptake both directly after cell isolation and following a 24-hour incubation at a physiological glucose level (6 mmol/L). The relationship with insulin action in vivo was addressed by employing the euglycemic clamp technique. Freshly isolated fat cells from type 2 diabetes patients with poor metabolic control had approximately 55% lower maximal insulin response (1,000 microU/mL) on glucose uptake (P <.05) compared to C. Cells from P were more insulin-resistant (P <.05) than cells from G at a low (5 microU/mL) but not at a high (1,000 microU/mL) insulin concentration, suggesting insulin insensitivity. However, following 24 hours of incubation at physiological glucose levels, insulin resistance was completely reversed in the diabetes cells and no differences in insulin-stimulated glucose uptake were found among the 3 groups. Insulin sensitivity in vivo assessed with hyperinsulinemic, euglycemic clamp (M-value) was significantly associated with insulin action on glucose uptake in fresh adipocytes in vitro (r = 0.50, P <.01). Fasting blood glucose at the time of biopsy and HbA(1c), but not serum insulin, were negatively correlated to insulin's effect to stimulate glucose uptake in vitro (r = -0.36, P =.064 and r = - 0.41, P <.05, respectively) in all groups taken together. In the in vivo situation, fasting blood glucose, HbA(1c), and serum insulin were all negatively correlated to insulin sensitivity (M-value; r = -0.62, P<.001, r= -0.61, P<.001, and r = -0.56, p <.01, respectively). Cell size, waist-to-hip ration (WHR), and BMI correlated negatively with insulin's effect to stimulate glucose uptake both in vitro (r = -0.55, P <.01, r = -0.54, P <.01, and r = -0.43, P <.05, respectively) and in vivo (r = -0.43, P <.05, r = -0.50, P <.01, and r = -0.36, P <.05, respectively). Multiple regression analyses revealed that adipocyte cell size and WHR independently predicted insulin resistance in vitro. Furthermore, insulin sensitivity in vivo could be predicted by fasting blood glucose and serum insulin levels. We conclude that insulin resistance in fat cells from type 2 diabetes patients is fully reversible following incubation at physiological glucose concentrations. Thus, cellular insulin resistance may be mainly secondary to the hyperglycemic state in vivo.

  • 16. Burén, Jonas
    et al.
    Liu, Hui-Xia
    Jensen, Jørgen
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes.2002In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 146, no 3, p. 419-29Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Glucocorticoid excess leads to insulin resistance. This study explores the effects of glucocorticoids on the glucose transport system and insulin signalling in rat adipocytes. The interaction between glucocorticoids and high levels of insulin and glucose is also addressed.

    DESIGN AND METHODS: Isolated rat adipocytes were cultured for 24 h at different glucose concentrations (5 and 15 mmol/l) with or without the glucocorticoid analogue dexamethasone (0.3 micromol/l) and insulin (10(4) microU/ml). After the culture period, the cells were washed and then basal and insulin-stimulated glucose uptake, insulin binding and lipolysis as well as cellular content of insulin signalling proteins (insulin receptor substrate-1 (IRS-1), IRS-2, phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB)) and glucose transporter isoform GLUT4 were measured.

    RESULTS: Dexamethasone in the medium markedly decreased both basal and insulin-stimulated glucose uptake at both 5 and 15 mmol/l glucose (by approximately 40-50%, P<0.001 and P<0.05 respectively). Combined long-term treatment with insulin and dexamethasone exerted additive effects in decreasing basal, and to a lesser extent insulin-stimulated, glucose uptake capacity (P<0.05) compared with dexamethasone alone, but this was seen only at high glucose (15 mmol/l). Insulin binding was decreased (by approximately 40%, P<0.05) in dexamethasone-treated cells independently of surrounding glucose concentration. Following dexamethasone treatment a approximately 75% decrease (P<0.001) in IRS-1 expression and an increase in IRS-2 (by approximately 150%, P<0.001) was shown. Dexamethasone also induced a subtle decrease in PI3-K (by approximately 20%, P<0.01) and a substantial decrease in PKB content (by approximately 45%, P<0.001). Insulin-stimulated PKB phosphorylation was decreased (by approximately 40%, P<0.01) in dexamethasone-treated cells. Dexamethasone did not alter the amount of total cellular membrane-associated GLUT4 protein. The effects of dexamethasone per se on glucose transport and insulin signalling proteins were mainly unaffected by the surrounding glucose and insulin levels. Dexamethasone increased the basal lipolytic rate (approximately 4-fold, P<0.05), but did not alter the antilipolytic effect of insulin.

    CONCLUSIONS: These results suggest that glucocorticoids, independently of the surrounding glucose and insulin concentration, impair glucose transport capacity in fat cells. This is not due to alterations in GLUT4 abundance. Instead dexamethasone-induced insulin resistance may be mediated via reduced cellular content of IRS-1 and PKB accompanied by a parallel reduction in insulin-stimulated activation of PKB.

  • 17. Burén, Jonas
    et al.
    Liu, Hui-Xia
    Lauritz, Johan
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes.2003In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 148, no 1, p. 157-67Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The purpose of this study was to investigate the cellular effects of long-term exposure to high insulin and glucose levels on glucose transport and insulin signalling proteins.

    DESIGN AND METHODS: Rat adipocytes were cultured for 24 h in different glucose concentrations with 10(4) microU/ml of insulin or without insulin. After washing, (125)I-insulin binding, basal and acutely insulin-stimulated d-[(14)C]glucose uptake, and insulin signalling proteins and glucose transporter 4 (GLUT4) were assessed.

    RESULTS: High glucose (15 and 25 mmol/l) for 24 h induced a decrease in basal and insulin-stimulated glucose uptake compared with control cells incubated in low glucose (5 or 10 mmol/l). Twenty-four hours of insulin treatment decreased insulin binding capacity by approximately 40%, and shifted the dose-response curve for insulin's acute effect on glucose uptake 2- to 3-fold to the right. Twenty-four hours of insulin treatment reduced basal and insulin-stimulated glucose uptake only in the presence of high glucose (by approximately 30-50%). At high glucose, insulin receptor substrate-1 (IRS-1) expression was downregulated by approximately 20-50%, whereas IRS-2 was strongly upregulated by glucose levels of 10 mmol/l or more (by 100-400%). Insulin treatment amplified the suppression of IRS-1 when combined with high glucose and also IRS-2 expression was almost abolished. Twenty-four hours of treatment with high glucose or insulin, alone or in combination, shifted the dose-response curve for insulin's effect to acutely phosphorylate protein kinase B (PKB) to the right. Fifteen mmol/l glucose increased GLUT4 in cellular membranes (by approximately 140%) compared with 5 mmol/l but this was prevented by a high insulin concentration.

    CONCLUSIONS: Long-term exposure to high glucose per se decreases IRS-1 but increases IRS-2 content in rat adipocytes and it impairs glucose transport capacity. Treatment with high insulin downregulates insulin binding capacity and, when combined with high glucose, it produces a marked depletion of IRS-1 and -2 content together with an impaired sensitivity to insulin stimulation of PKB activity. These mechanisms may potentially contribute to insulin resistance in type 2 diabetes.

  • 18. Carvalho, E
    et al.
    Jansson, P A
    Axelsen, M
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Huang, X
    Groop, L
    Rondinone, C
    Sjöström, L
    Smith, U
    Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM.1999In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 13, no 15, p. 2173-8Article in journal (Refereed)
    Abstract [en]

    We examined the gene and protein expression of IRS 1 (insulin receptor substrate 1) in adipocytes from two groups of healthy individuals with an increased propensity for non-insulin-dependent diabetes mellitus (NIDDM): those with two first-degree relatives with diabetes and another group with massive obesity. A low expression of IRS 1 (</=50% of the matched control group) was seen in approximately 30% of both groups and these individuals were characterized by insulin resistance and its hallmarks: higher levels of insulin, glucose, and triglycerides. Two individuals with previously unknown NIDDM were diagnosed and both had low IRS 1 expression. Low IRS 1 protein expression was associated with low mRNA levels but not with the common Gly972Arg polymorphism of the IRS 1 gene. Taken together, our present and previous findings show that a low expression of IRS 1 in fat cells predicts insulin resistance and NIDDM. Furthermore, they support the likelihood that an impaired transcriptional activation may play a key role in the pathogenesis of NIDDM.-Carvalho, E., Jansson, P.-A., Axelsen, M., Eriksson, J. W., Huang, X., Groop, L., Rondinone, C., Sjöström, L., Smith, U. Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM.

  • 19. Chu, Kwan Yi
    et al.
    Lau, Tung
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Leung, Po Sing
    Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes2006In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, no 2, p. 367-374Article in journal (Refereed)
    Abstract [en]

    We identified an angiotensin-generating system in pancreatic islets and found that exogenously administered angiotensin II, after binding to its receptors (angiotensin II type 1 receptor [AT1R]), inhibits insulin release in a manner associated with decreased islet blood flow and (pro)insulin biosynthesis. The present study tested the hypothesis that there is a change in AT1R expression in the pancreatic islets of the obesity-induced type 2 diabetes model, the db/db mouse, which enables endogenous levels of angiotensin II to impair islet function. Islets from 10-week-old db/db and control mice were isolated and investigated. In addition, the AT1R antagonist losartan was administered orally to 4-week-old db/db mice for an 8-week period. We found that AT1R mRNA was upregulated markedly in db/db islets and double immunolabeling confirmed that the AT1R was localized to beta-cells. Losartan selectively improved glucose-induced insulin release and (pro)insulin biosynthesis in db/db islets. Oral losartan treatment delayed the onset of diabetes, and reduced hyperglycemia and glucose intolerance in db/db mice, but did not affect the insulin sensitivity of peripheral tissues. The present findings indicate that AT1R antagonism improves beta-cell function and glucose tolerance in young type 2 diabetic mice. Whether islet AT1R activation plays a role in the pathogenesis of human type 2 diabetes remains to be determined.

  • 20. Denison, H
    et al.
    Nilsson, C
    Löfgren, L
    Himmelmann, A
    Mårtensson, G
    Knutsson, M
    Al-Shurbaji, A
    Tornqvist, H
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial2014In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, no 4, p. 334-343Article in journal (Refereed)
    Abstract [en]

    AIM:

    Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor.

    METHODS:

    Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 hours after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying.

    RESULTS:

    Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at end of treatment. With AZD7687doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea.

    CONCLUSIONS:

    Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

  • 21. deSchoolmeester, J
    et al.
    Palming, J
    Persson, T
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Wallerstedt, E
    Brown, H
    Gill, D
    Renström, F
    Lundgren, M
    Svensson, M K
    Rees, A
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Differences between men and women in the regulation of adipose 11β-HSD1 and in its association with adiposity and insulin resistance2013In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 15, no 11, p. 1056-1560Article in journal (Refereed)
    Abstract [en]

    This study explored sex differences in 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 ± 15.3 years, body mass index (BMI) 27.2 ± 3.9 kg/m2]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11β-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11β-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11β-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11β-HSD1 mRNA expression. This study suggests that there are sex differences in 11β-HSD1 regulation and in its associations with markers of obesity and IR.

  • 22.
    Drott, Carl Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Olerud, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Emanuelsson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Christoffersson, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Sustained Beta-Cell Dysfunction but Normalized Islet Mass in Aged Thrombospondin-1 Deficient Mice2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47451-Article in journal (Refereed)
    Abstract [en]

    Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1), that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only similar to 15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.

  • 23.
    Edholm, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Svensson, Felicity
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Näslund, Ingmar
    Karlsson, F Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Rask, Eva
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Long-term results 11 years after primary gastric bypass in 384 patients2013In: Surgery for Obesity and Related Diseases, ISSN 1550-7289, E-ISSN 1878-7533, Vol. 9, no 5, p. 708-713Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Roux-en-Y gastric bypass surgery (RYGB) as treatment of morbid obesity results in substantial weight loss. Most published long-term studies have included few patients at the last follow-up point. The aim of the present study was to explore long-term results in a large cohort of patients 7-17 years after gastric bypass.

    METHODS:

    All 539 patients who had undergone primary RYGB from 1993 to 2003 at Uppsala and Örebro University Hospitals received a questionnaire regarding their postoperative status. Blood samples were obtained and the medical charts studied.

    RESULTS: 

    Of the 539 patients, 384 responded (71.2% response rate, mean age 37.9 yr, body mass index 44.5 kg/m2 at surgery, 317 women, and 67 men). At a mean follow-up of 11.4 years (range 7-17), the body mass index had decreased to 32.5 kg/m2, corresponding to an excess body mass index loss of 63.3%. Similar weight loss was observed, regardless of the length of follow-up. Orally treated diabetes resolved in 72% and sleep apnea and hyperlipidemia were improved. Revisional bariatric surgery had been performed in 2.1% and abdominoplasty in 40.2%. The gastrointestinal symptoms were considered tolerable. The overall result was satisfactory for 79% of the patients and 92% would recommend Roux-en-Y gastric bypass to a friend. Attendance to the annual checkups was 37%. Vitamin B12 supplements were taken by 72% and multivitamins by 24%.

    CONCLUSION:

    At 11 years, substantial weight loss was maintained and revisional surgery was rare. Surprisingly few patients were compliant with the recommendation of lifelong supplements and yearly evaluations; however, patient satisfaction was high.

  • 24. Elvanides, H
    et al.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    [Ketoacidosis also occurs in type 2 diabetes. Important risk factors are other concomitant diseases]].1999In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 96, no 34, p. 3529-32, 3534Article in journal (Refereed)
    Abstract [sv]

    Although ketoacidosis has traditionally been regarded as a complication occurring only in conjunction with type I diabetes, there have recently been reports of its occurrence in cases of type II diabetes, e.g. in Afro-American and Japanese patients. The article reports a few cases suggesting that ketoacidosis may not be a rare phenomenon even in Swedish type II diabetes patients. This severe complication is usually precipitated by the occurrence of other concomitant disease.

  • 25.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    [Exciting findings can change the view on the pathogenesis of type 2 diabetes. Impaired mitochondrial function can explain metabolic disorders in several organs].2004In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 101, no 39, p. 2992-3Article in journal (Refereed)
  • 26.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Metabolic stress in insulin's target cells leads to ROS accumulation - a hypothetical common pathway causing insulin resistance.2007In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 581, no 19, p. 3734-42Article in journal (Refereed)
    Abstract [en]

    The metabolic syndrome is a cluster of cardiovascular risk factors, and visceral adiposity is a central component that is also strongly associated with insulin resistance. Both visceral obesity and insulin resistance are important risk factors for the development of type 2 diabetes. It is likely that adipose tissue, particularly in the intra-abdominal depot, is part of a complex interplay involving several tissues and that dysregulated hormonal, metabolic and neural signalling within and between organs can trigger development of metabolic disease. One attractive hypothesis is that many factors leading to insulin resistance are mediated via the generation of abnormal amounts of reactive oxygen species (ROS). There is much evidence supporting that detrimental effects of glucose, fatty acids, hormones and cytokines leading to insulin resistance can be exerted via such a common pathway. This review paper mainly focuses on metabolic and other 'stress' factors that affect insulin's target cells, in particular adipocytes, and it will highlight oxidative stress as a potential unifying mechanism by which these stress factors promote insulin resistance and the development and progression of type 2 diabetes.

  • 27.
    Eriksson, Jan W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Burén, Jonas
    Svensson, Maria
    Olivecrona, Thomas
    Olivecrona, Gunilla
    Postprandial regulation of blood lipids and adipose tissue lipoprotein lipase in type 2 diabetes patients and healthy control subjects.2003In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 166, no 2, p. 359-67Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIM: In type 2 diabetes and other insulin-resistant conditions, postprandial hypertriglyceridaemia is an important metabolic perturbation. To further elucidate alterations in the clearance of triglyceride-rich lipoproteins in type 2 diabetes we focused on the nutritional regulation of adipose tissue lipoprotein lipase (LPL).

    SUBJECTS AND METHODS: Eight subjects with type 2 diabetes and eight age-, sex- and body mass index (BMI)-matched control subjects underwent subcutaneous abdominal adipose tissue biopsies in the fasting state and 3.5 h following a standardized lipid-enriched meal. LPL activity and mass were measured in adipose tissue and also in plasma after an intravenous injection of heparin.

    RESULTS: Postprandial, but not fasting, triglycerides were significantly higher in the diabetic subjects than in the control subjects (3.0+/-0.4 vs 2.0+/-0.2 mmol/l, P=0.028). Adipose tissue LPL activity was increased following the meal test by approximately 35-55% (P=0.021 and 0.004, respectively). There was no significant difference between the groups in this respect. The specific enzyme activity of LPL was not altered in the postprandial state. Fasting and postprandial adipose tissue LPL activity as well as post-heparin plasma LPL activity tended to be lower among the diabetes patients (NS). There was a significant and independent inverse association between insulin resistance (homeostasis model assessment insulin resistance (HOMA-IR) index) vs post-heparin plasma LPL activity and postprandial triglyceride levels, respectively. Adipose tissue LPL activity was related to insulin action in vitro on adipocyte glucose transport, but not to HOMA-IR.

    CONCLUSION: Following food intake adipose tissue LPL activity is enhanced to a similar degree in patients with type 2 diabetes and in healthy control subjects matched for BMI, age and gender. If LPL dysregulation is involved in the postprandial hypertriglyceridaemia found in type 2 diabetes, it should occur in tissues other than subcutaneous fat.

  • 28.
    Eriksson, Jan W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Carlberg, B
    Hillörn, V
    Life-threatening ventricular tachycardia due to liquorice-induced hypokalaemia.1999In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 245, no 3, p. 307-10Article in journal (Refereed)
    Abstract [en]

    We report on a patient with hypokalaemia and severe ventricular tachycardia of torsades de pointes type which turned out to be caused by an apparent mineralocorticoid excess syndrome associated with liquorice consumption. The patient, a 44-year-old woman, attended the hospital because of irregular heart rhythm and she displayed repeated episodes of life-threatening torsades de pointes ventricular tachycardia. The initial serum potassium was low: 2.3 mmol L-1. The patient was treated with potassium and magnesium infusions, and the dysrhythmias eventually ceased. Endocrinological investigations showed no indication of Cushing's syndrome or hyperaldosteronism. After some time it became clear that the patient had ingested moderately large amounts of liquorice every day for 4 months. After the patient stopped this habit the hypokalaemia and dysrhythmias did not recur and after more than 1 year there are no signs of cardiac illness.

  • 29.
    Eriksson, Jan W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Smith, U
    Waagstein, F
    Wysocki, M
    Jansson, P A
    Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon?1999In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 48, no 8, p. 1572-8Article in journal (Refereed)
    Abstract [en]

    To elucidate potential mechanisms for insulin resistance occurring early in the development of type 2 diabetes, we studied 10 young healthy individuals, each with two first-degree relatives with type 2 diabetes, and 10 control subjects without known type 2 diabetic relatives. They were pairwise matched for age (35 +/- 1 vs. 35 +/- 1 years), BMI (23.6 +/- 0.6 vs. 23.1 +/- 0.4 kg/m2), and sex (four men, six women). Glucose turnover was assessed during a euglycemic clamp at two insulin levels (low approximately 20 mU/l; high approximately 90 mU/l), and abdominal subcutaneous adipose tissue (SAT) lipolysis and blood flow were concomitantly studied with microdialysis and 133Xe clearance. HbA1c was higher in patients with type 2 diabetic relatives than in control subjects (4.8 +/- 0.1 vs. 4.5 +/- 0.1%, P < 0.02), but fasting glucose, insulin, and C-peptide levels were similar. During the clamp, the insulin sensitivity index for glucose disposal was lower (P < 0.03) in relatives than in control subjects (low 12.0 +/- 1.6 vs. 18.1 +/- 1.4; high 9.4 +/- 0.8 vs. 12.9 +/- 0.6 [100 x mg x l x kg(-1) x mU(-1) x min(-1)]). This difference was partially attributed to slightly higher clamp insulin levels in the relatives (P < 0.03), suggesting an impaired rate for insulin clearance. SAT lipolysis measured as in situ glycerol release did not differ under basal conditions (2.0 +/- 0.2 vs. 2.1 +/- 0.2 micromol x kg(-1) x min(-1)), but the suppression during the insulin infusion was less marked in relatives than in control subjects (glycerol release: low 0.92 +/- 0.09 vs. 0.68 +/- 0.16; high 0.71 +/- 0.10 vs. 0.34 +/- 0.10 micromol x kg(-1) x min(-1); P < 0.03). Plasma nonesterified fatty acids also tended to be higher in relatives than in control subjects during the insulin infusion (NS). In contrast, in vitro experiments with isolated subcutaneous adipocytes displayed similar effects of insulin in relatives and control subjects with respect to both glucose uptake and antilipolysis. In conclusion, insulin action in vivo on both lipolysis and glucose uptake is impaired early in the development of type 2 diabetes. Since this impairment was not found in isolated adipocytes, it may be suggested that neural or hormonal perturbations precede cellular insulin resistance in type 2 diabetes.

  • 30.
    Espes, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Engström, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Reinius, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Severe diabetic ketoacidosis in combination with starvation and anorexia nervosa at onset of type 1 diabetes: A case report2013In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, no 2, p. 130-133Article in journal (Refereed)
    Abstract [en]

    We here report a case of diabetic ketoacidosis at onset of type 1 diabetes after a prolonged period of starvation due to anorexia nervosa. A 53-year-old female with a history of anorexia nervosa was admitted to the psychiatric clinic due to psychotic behaviour and inability to take care of herself. Twenty-four hours after admission she was transferred to the clinic of internal medicine due to altered mental status, and laboratory screening revealed a pH of 6.895 and blood glucose concentration of 40 mmol/L. Due to the unusual combination of prolonged starvation and diabetic ketoacidosis we implemented some modifications of existing treatment guidelines and some special considerations regarding nutrition in order to prevent a re-feeding syndrome.

  • 31. Fall, T.
    et al.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    The role of obesity-related genetic loci in insulin sensitivity2012In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 29, no 7, p. E62-E66Article in journal (Refereed)
    Abstract [en]

    Aims Despite rapid advancements and many new diabetes susceptibility loci found in the past few years, few genetic variants associated with insulin sensitivity have been described, potentially attributable to the lack of larger cohorts examined with gold standard methods for insulin sensitivity assessment. There is a strong link between obesity and insulin sensitivity, and we hypothesized that known obesity susceptibility loci may act via effects on insulin sensitivity. Methods A cohort of 71-year-old men without diabetes (Uppsala Longitudinal Study of Adult Men) underwent a euglycaemichyperinsulinaemic clamp and genotyping for genetic variants representing 32 loci recently reported to be associated with BMI (n = 926). The effect of these loci on the insulin sensitivity index (M/I ratio) was examined using linear regression. An in silico replication was performed in publically available data for the three top single-nucleotide polymorphisms from the Meta-Analyses of Glucose and Insulin-related traits Consortium analyses of homeostasis model assessment of insulin resistance (n = 37 037). Results Three loci (SH2B1, MTCH2 and NEGR1) were associated with decreased insulin sensitivity at a nominal significance (P = 0.05) after adjustment for BMI, but did not hold for multiple comparison correction. SH2B1 rs7359397 was also associated with homeostasis model assessment of insulin resistance in the Meta-Analyses of Glucose and Insulin-related traits Consortium data set (P = 3.9 x 10(3)). Conclusions Our study supports earlier reports of SH2B1 to be of importance in insulin sensitivity and, in addition, suggests potential roles of NEGR1 and MTCH2.

  • 32. Forst, T
    et al.
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Strotmann, H-J
    Bai, S
    Brunelle, R
    Gulliya, K S
    Gack, S
    Gudat, U
    Metabolic effects of mealtime insulin lispro in comparison to glibenclamide in early type 2 diabetes.2003In: Experimental and clinical endocrinology & diabetes, ISSN 0947-7349, E-ISSN 1439-3646, Vol. 111, no 2, p. 97-103Article in journal (Refereed)
    Abstract [en]

    The efficacy and safety of the preprandial injection of insulin lispro was compared with the oral administration of glibenclamide in patients with early type 2 diabetes. In this open-label, multicenter study, 143 patients with a glucagon-stimulated increase in C-peptide of at least 0.4 nmol/L were randomized to receive preprandial insulin lispro (LP) or glibenclamide (GB) for 26 weeks. Seventy-five patients received LP (51 male/24 female; age 40 to 70 years, duration of diabetes 4.4 +/- 2.9 years) and 68 patients received GB (39 male/29 female; age 39 to 70 years; duration of diabetes 4.3 +/- 3.4 years). After 12 weeks, mean 90 minute blood glucose excursions were 0.9 +/- 1.0 mmol/L for LP and 1.8 +/- 1.2 mmol/L for GB (p < 0.0001). After 24 weeks, mean blood glucose excursions were 1.0 +/- 1.1 mmol/L for LP and 1.7 +/- 1.2 mmol/L for GB (p = 0.002). Body weight decreased slightly from 87.2 +/- 2.3 to 86.5 +/- 12.2 kg in the LP group and increased from 84.1 +/- 13.7 to 84.4 +/- 13.3 kg in the GB group. LP versus GB induced changes from baseline to endpoint in fasting C-peptide (nmol/L), proinsulin and insulin levels (pmol/L) were - 0.2 +/- 0.4 versus - 0.1 +/- 0.6 (p = 0.04), - 11.2 +/- 26.0 versus - 1.1 +/- 17.3 (p = 0.03), and - 27.8 +/- 147.4 versus + 32.6 +/- 286.2 (not significant), respectively. HbA 1c at baseline was 7.5 +/- 1.0 % for LP and 7.7 +/- 1.2 % for GB and did not change significantly in either group during the investigation. No significant difference was observed between the groups with respect to hypoglycemic episodes. Treatment with LP improved postprandial blood glucose control more than GB without increasing body weight or hypoglycemic episodes. In addition, use of LP was associated with a decrease in fasting C-peptide and proinsulin levels, suggesting a potential down regulation of endogenous insulin production and improved proinsulin processing efficiency.

  • 33. Giorgino, F
    et al.
    Laviola, L
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies.2005In: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 183, no 1, p. 13-30Article in journal (Refereed)
    Abstract [en]

    Adipose tissue is now recognized to have a multitude of functions that are of importance in the regulation of energy balance and substrate metabolism. Different hormones, in particular insulin and catecholamines, govern the storage and utilization of energy in the triglyceride depots. In addition, adipocytes produce several different substances with endocrine or paracrine functions, which regulate the overall energetic homeostasis. With excess energy storage, obesity develops, leading to increased risk for type 2 diabetes and cardiovascular disease. The distribution of body fat appears to be even more important than the total amount of fat. Abdominal and, in particular, visceral adiposity is strongly linked to insulin resistance, type 2 diabetes, hypertension and dyslipidaemia, leading to increased risk of cardiovascular disease. The adverse metabolic impact of visceral fat has been attributed to distinct biological properties of adipocytes in this depot compared with other adipose tissue depots. Indeed, regional variations in the metabolic activity of fat cells have been observed. Furthermore, expression studies aiming at defining the unique biological properties of adipose tissues from distinct anatomical sites have identified depot-related differences in the protein content of fat-produced molecules. In this review we wish to summarize important results from the literature and also some recent data from our own work. The main scope is to describe the biological functions of adipose tissue, and to focus on metabolic, hormonal, and signalling differences between fat depots.

  • 34. Henricsson, Marianne
    et al.
    Nyström, Lennarth
    Blohmé, Göran
    Ostman, Jan
    Kullberg, Carin
    Svensson, Maria
    Schölin, Anna
    Arnqvist, Hans J
    Björk, Elisabeth
    Bolinder, Jan
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Sundkvist, Göran
    The incidence of retinopathy 10 years after diagnosis in young adult people with diabetes: results from the nationwide population-based Diabetes Incidence Study in Sweden (DISS).2003In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 26, no 2, p. 349-54Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To estimate the prevalence and severity of diabetic retinopathy (DR) 10 years after diagnosis in a nationwide population-based cohort study of young adult diabetic patients in Sweden.

    RESEARCH DESIGN AND METHODS: The Diabetes Incidence Study in Sweden (DISS) aims to register all incident cases of diabetes aged 15-34 years in Sweden. In 1987-1988, 806 cases were reported, and 627 (78%) of them were followed up with regard to retinopathy 8-10 years later. The assessment was based on retinal photographs in most cases (86%).

    RESULTS: Ten years after diagnosis, retinopathy was found in 247 patients (39%). The retinopathy was mild in 206 (33%), whereas 30 (4.8%) patients had moderate nonproliferative DR (NPDR) and 11 (1.8%) had proliferative DR (PDR). Patients with retinopathy had worse glycemic control during the years than patients without (HbA(1c) 8.1 +/- 1.5% and 6.8 +/- 1.2%, respectively; P < 0.001). In a Cox regression analysis, time to retinopathy was related to high HbA(1c) (P < 0.001) and high BMI (P = 0.001). Patients with type 2 diabetes had an increased prevalence of severe retinopathy (NPDR or PDR) compared with those with type 1 diabetes (14 of 93 [15%] versus no or mild 24 of 471 [5%], respectively; P < 0.001).

    CONCLUSIONS: Despite modern diabetes management, 39% of young adult diabetic patients developed retinopathy within the first 10 years of the disease. Nevertheless, compared with the prevalence of retinopathy (63%), after a similar duration of diabetes before the Diabetes Control and Complications Trial, this prevalence was clearly lower. Current treatment aimed to achieve strict glycemic control has reduced the risk for developing retinopathy.

  • 35.
    Hudecova, Miriam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Holte, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Moby, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Androgen levels, insulin sensitivity, and early insulin response in women with polycystic ovary syndrome: a long-term follow-up study2011In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 95, no 3, p. 1146-1148Article in journal (Refereed)
    Abstract [en]

    Thirty-four women with polycystic ovary syndrome who previously had participated in studies with intravenous glucose tolerance test and hyperinsulinemic, euglycemic clamp between 1987 and 1995 underwent anthropometric, endocrine (T and sex-hormone binding globulin serum concentration), and metabolic (intravenous glucose tolerance test, hyperinsulinemic, euglycemic clamp, and androgens) measurements. Free androgen levels and β-cell function decreased over time in women with polycystic ovary syndrome, but insulin sensitivity remained unaltered.

  • 36.
    Hudecova, Miriam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Jan, Holte
    Christian, Berne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Long-term Reproductive and Metabolic Consequences of PCOS2012In: Current diabetes reviews, ISSN 1875-6417, Vol. 8, no 6, p. 444-451Article in journal (Refereed)
    Abstract [en]

    Polycystic ovary syndrome (PCOS) is associated with reproductive and metabolic consequences. The review of findings indicate that the long-term reproductive outcomes of women with PCOS are surprisingly similar compared to women with normal ovaries, and that they have an ovarian reserve possibly superior to women with normal ovaries. The typical features of PCOS, specifically the anovulatory cycles tend to normalize over time, but in spite of a decrease over time, free androgen levels remain elevated compared to age-matched control subjects. Women with PCOS diagnosed at young age continue to display reduced insulin sensitivity in the perimenopausal age, independent from phenotypic expression of PCOS, both at diagnosis and at follow-up. Insulin resistance does not seem to deteriorate further, however. Overall, the accumulated data from several European cohort studies of older women with a previous diagnosis of PCOS suggest an increased incidence of type 2 diabetes, increased prevalence of several features of the metabolic syndrome, but no increased incidence of mortality from CVD.

  • 37.
    Högberg, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Stenbäck, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Engstrand Lilja, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
    Intraluminal intestinal microdialysis detects markers of hypoxia and cell damage in experimental necrotizing enterocolitis2012In: Journal of Pediatric Surgery, ISSN 0022-3468, E-ISSN 1531-5037, Vol. 47, no 9, p. 1646-1651Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/PURPOSE:

    Necrotizing enterocolitis (NEC) represents one of the gravest complications in premature infants and carries significant morbidity and mortality. There is a great need for improved diagnostic methods to reduce the severity and incidence of NEC. The aim of the study was to investigate if intraluminal microdialysis can detect intestinal ischemia in newborn rats with induced experimental NEC.

    METHODS:

    The studies were performed on 1-day-old Sprague-Dawley rat pups. Experimental NEC was induced using hypoxia/reoxygenation treatment. Microdialysis catheters were rectally inserted and placed in the rectosigmoid part of the colon. Microdialysate levels of glucose, lactate, pyruvate, and glycerol were measured. Intestinal specimens were collected at the end of the experiments for microscopic evaluation.

    RESULTS:

    Intraluminal microdialysis revealed signs of intestinal hypoxia and cellular damage, with a marked increase of lactate and glycerol. Microscopic evaluation confirmed intestinal damage in the NEC group.

    CONCLUSION:

    Intraluminal microdialysis can detect intestinal hypoxic stress and mucosal cell membrane decay in a rat model of NEC. Intestinal intraluminal microdialysis is easily accessible through the rectum and may be a useful noninvasive complement to other methods in the assessment of NEC.

  • 38. Jansson, P-A
    et al.
    Eliasson, B
    Lindmark, S
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Endocrine abnormalities in healthy first-degree relatives of type 2 diabetes patients--potential role of steroid hormones and leptin in the development of insulin resistance.2002In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 32, no 3, p. 172-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: First-degree relatives of type 2 diabetes patients are at risk of developing diabetes and they display several metabolic and hormonal perturbations. The interplay between insulin resistance, steroid hormones and circulating leptin is, however, still not fully explored in this group.

    DESIGN: Thirty-three healthy first-degree relatives of type 2 diabetic patients (relatives; M/F 19/14) were compared to 33 healthy subjects without a family history of diabetes (controls) and the groups were matched for gender, age and body mass index (BMI). We performed euglycaemic hyperinsulinaemic clamps and blood was sampled for hormone analyses.

    RESULTS: Relatives exhibited decreased insulin sensitivity (index of metabolic clearance rate of glucose; MCRI) but when genders were analysed separately, this difference was significant only in males (11.3 +/- 1.3 vs. 15.0 +/- 1.5 units, means +/- SEM, P = 0.030). In male relatives morning cortisol and testosterone levels were lower, whereas leptin was higher than in male controls (P = 0.018, 0.008 and 0.063, respectively). In male relatives plasma testosterone levels were significantly associated with insulin sensitivity (r = 0.48, P = 0.040). Circulating leptin levels were inversely correlated with insulin sensitivity in all subject groups (r-values -0.49 to -0.66; P < 0.05, except in female control subjects P = 0.063). These associations were present also when age and BMI or waist:hip ratio were included in stepwise multiple regression analyses.

    CONCLUSION: Male subjects genetically predisposed for type 2 diabetes display several endocrine abnormalities including leptin, cortisol and testosterone levels. Dysregulation of these hormones may be important in the development of insulin resistance and type 2 diabetes.

  • 39. Kalani, Majid
    et al.
    Apelqvist, Jan
    Blombäck, Margareta
    Brismar, Kerstin
    Eliasson, Björn
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Fagrell, Bengt
    Hamsten, Anders
    Torffvit, Ole
    Jörneskog, Gun
    Effect of dalteparin on healing of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease: a prospective, randomized, double-blind, placebo-controlled study.2003In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 26, no 9, p. 2575-80Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Chronic foot ulcers are a common, severe, and expensive complication threatening life and limb in patients with diabetes. The aim of the present study was to investigate the effect of dalteparin on ulcer outcome in patients with diabetes, peripheral arterial occlusive disease, and chronic foot ulcers.

    RESEARCH DESIGN AND METHODS: A total of 87 patients were investigated in a prospective, randomized, double-blind, placebo-controlled trial. Participants were randomized to treatment with subcutaneous injection of 5000 units dalteparin (Fragmin, Pharmacia Corporation; n = 44) or an equivalent volume of physiological saline (n = 43) once daily until ulcer healing or for a maximum of 6 months. Ulcer outcome was investigated by evaluating the number of patients 1). who healed with intact skin; 2). in whom the study ulcer was improved, unchanged, or impaired; or 3). who were amputated above or below the ankle level, as compared with control subjects.

    RESULTS: Two patients, one on dalteparin and one on placebo, dropped out of the study. Ulcer outcome was significantly better (P = 0.042, two-sided chi(2) test for trend) in the dalteparin group (n = 43) compared with the placebo group (n = 42). A total of 29 patients healed with intact skin (n = 14) or decreased the ulcer area >or=50% (n = 15) in the dalteparin group compared with 20 (n = 9 and 11, respectively) in the placebo group. Five patients in each group showed impaired ulcer healing, i.e., the ulcer area increased >or=50%. Two patients in the dalteparin group were amputated compared with eight in the placebo group. Time to healing with intact skin was 17 +/- 8 weeks in the dalteparin group compared with 16 +/- 7 weeks in placebo group (NS).

    CONCLUSIONS: The results of the present study indicate that dalteparin improves the outcome of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease.

  • 40. Kalani, Majid
    et al.
    Silveira, Angela
    Blombäck, Margareta
    Apelqvist, Jan
    Eliasson, Björn
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Fagrell, Bengt
    Torffvit, Ole
    Hamsten, Anders
    Jörneskog, Gun
    Beneficial effects of dalteparin on haemostatic function and local tissue oxygenation in patients with diabetes, severe vascular disease and foot ulcers.2007In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 120, no 5, p. 653-61Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: A state of hypercoagulation and fibrinolytic dysfunction is present in individuals with diabetes, which may contribute to disturbed skin microcirculation and impaired ulcer healing. We have previously reported an improved outcome of chronic diabetic foot ulcers during treatment with dalteparin. In the present study we investigated the effects of dalteparin on skin microcirculation and haemostatic function.

    MATERIALS AND METHODS: 87 patients with diabetes, peripheral arterial obliterative disease and chronic foot ulcers were investigated in a prospective, randomised, double-blind and placebo-controlled study. They were randomised to treatment with subcutaneous injections of 5000 U dalteparin (n=44) or placebo (n=43), once daily until ulcer healing or for a maximum of six months. Plasma fibrinogen, fibrin gel structure [permeability coefficient (Ks) and fiber mass/length ratio (mu)], prothrombin fragment 1+2 (F1+2) antigen, plasminogen activator inhibitor-1 (PAI-1) activity and tissue plasminogen activator (tPA) antigen were analysed before randomization (baseline value), and at the end of the treatment period. The skin microcirculation of the foot was investigated by transcutaneous oxygen tension (TcPO(2)) and laser Doppler fluxmetry (LDF).

    RESULTS: The changes (Delta-values) of Ks, mu, tPA and TcPO(2) were higher (p<0.05) during treatment with dalteparin, as compared to the changes during treatment with placebo. At baseline, plasma fibrinogen and Ks were significantly correlated to TcPO(2).

    CONCLUSIONS: Local skin oxygenation improved and a less thrombogenic fibrin gel structure was formed in patients treated with dalteparin. Beneficial effects on haemostatic function are likely to contribute to the improved skin oxygenation observed during treatment with dalteparin.

  • 41. Leung, Po Sing
    et al.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus2005In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 30, no 4, p. 293-298Article in journal (Refereed)
    Abstract [en]

    Several regulatory systems are implicated in the regulation of islet function and [beta] cell mass. Of great interest in this context are some endocrine, paracrine/autocrine, and intracrine regulators. These include, to name but a few, the gut peptides, growth factors, prostaglandins, and some vasoactive mediators such as nitric oxide, bradykinins, endothelins, and angiotensins. Apart from its potent vasoconstrictor actions, the renin-angiotensin system (RAS) that generates angiotensin II has several novel functions-stimulation and inhibition of cell proliferation; induction of apoptosis; generation of reactive oxygen species; regulation of hormone secretion; and proinflammatory and profibrogenic actions. In the pancreas, recent evidence supports the presence of an islet RAS, which is subject to activation by islet transplantation and diabetes. Such a local islet RAS, if activated, may drive islet fibrosis and reduce islet blood flow, oxygen tension, and insulin biosynthesis. Moreover, activation of an islet RAS may drive the synthesis of reactive oxygen species, cause oxidative stress-induced [beta] cell dysfunction and apoptosis, and thus contribute to the islet dysfunction seen in type 2 diabetes and after islet transplantation. Blockade of the RAS could contribute to the development of novel therapeutic strategies in the prevention and treatment of patients with diabetes and in islet transplantation.

  • 42. Lindmark, S
    et al.
    Burén, J
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Insulin resistance, endocrine function and adipokines in type 2 diabetes patients at different glycaemic levels: potential impact for glucotoxicity in vivo.2006In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 65, no 3, p. 301-9Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the interplay between hyperglycaemia, insulin resistance, hormones and adipokines in patients with type 2 diabetes mellitus (T2DM).

    DESIGN AND METHODS: Ten patients with T2DM with good glycaemic control (G), 10 with poor control (P) and 10 nondiabetic control subjects (C) were matched for sex (M/F 6/4), age and body mass index. A hyperinsulinaemic, euglycaemic clamp was performed and cytokines and endocrine functions, including cortisol axis activity were assessed.

    RESULTS: Patients with diabetes were more insulin resistant than group C, and group P exhibited the highest degree of insulin resistance (P = 0.01, P vs C). Tumour necrosis factor (TNF)-alpha levels were elevated in patients with diabetes (P = 0.05) and group P had the highest levels of fasting serum cortisol (P = 0.05), nonesterified fatty acids (NEFA; P = 0.06) and C-reactive protein (CRP; P = 0.01). Adiponectin levels were lower in the P group. In partial correlation analyses, significant associations were found: glycaemic level (HbA1c) with insulin resistance, TNF-alpha, CRP and basal and ACTH-stimulated cortisol levels, insulin resistance with plasma NEFA, TNF-alpha and stimulated cortisol levels.

    CONCLUSION: Poor glycaemic control in patients with T2DM was associated with insulin resistance and with elevated TNF-alpha, CRP and basal as well as stimulated cortisol levels. Inflammatory mediators, e.g. TNF-alpha, may contribute to insulin resistance in hyperglycaemic patients with T2DM and this might be a partial explanation for glucotoxicity.

  • 43. Lindmark, S
    et al.
    Wiklund, U
    Bjerle, P
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Does the autonomic nervous system play a role in the development of insulin resistance? A study on heart rate variability in first-degree relatives of Type 2 diabetes patients and control subjects.2003In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 20, no 5, p. 399-405Article in journal (Refereed)
    Abstract [en]

    AIMS: To investigate dysregulation of the autonomic nervous system as a potential mechanism for early insulin resistance in the development of Type 2 diabetes.

    METHODS: Thirteen healthy individuals with first-degree relatives with Type 2 diabetes (R) were compared with 14 control subjects without family history of diabetes (C), matched for age, body mass index and sex. An oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp were performed. Analysis of heart rate variability during rest, controlled breathing, an orthostatic manoeuvre and a standardized physical stress (cold pressor test (CPT)), were used to evaluate the activity of the autonomic nervous system.

    RESULTS: Fasting blood glucose, HbA1c and serum insulin were similar in the R and C groups. The M-value, reflecting insulin sensitivity, did not differ significantly between the groups. Total spectral power and high-frequency power were lower in R during controlled breathing (P = 0.05 and P = 0.07, respectively), otherwise there were no significant differences between R and C in heart rate variability. However, low-frequency (LF)/high-frequency (HF) spectral power ratio during CPT, reflecting sympathetic/parasympathetic balance, was negatively associated with insulin sensitivity (r = -0.53, P = 0.006). When all subjects were divided into two groups by the mean M-value, the low M-value group displayed an overall higher LF/HF ratio (P = 0.04). HF power was lower in the low M-value group during controlled breathing and CPT (P = 0.01 and P = 0.03, respectively).

    CONCLUSION: An altered balance of the parasympathetic and sympathetic nervous activity, mainly explained by an attenuated parasympathetic activity, might contribute to the development of insulin resistance and Type 2 diabetes.

  • 44. Lindmark, Stina
    et al.
    Lönn, Lars
    Wiklund, Urban
    Tufvesson, Magnus
    Olsson, Tommy
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Dysregulation of the autonomic nervous system can be a link between visceral adiposity and insulin resistance.2005In: Obesity Research, ISSN 1071-7323, E-ISSN 1550-8528, Vol. 13, no 4, p. 717-28Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the interplay among abdominal adipose tissue distribution, the cortisol axis, the autonomic nervous system, and insulin resistance.

    RESEARCH METHODS AND PROCEDURES: Two age-, sex-, and BMI-matched groups were studied. Fifteen subjects were first-degree relatives of patients with type 2 diabetes (R), and 15 had no family history of diabetes (controls, C). A hyperinsulinemic euglycemic clamp, cortisol measurements, and analysis of heart rate variability (HRV) were performed. Computed tomography was performed in a subgroup (n = 9 + 9) to determine abdominal adipose tissue distribution.

    RESULTS: R tended to be less insulin-sensitive than C (M value 9.2 +/- 1.0 vs 10.3 +/- 0.7 mg/kg per minute, not significant). Stimulation with tetracosactin or corticotropin releasing hormone yielded lower peak serum cortisol levels in R (p = 0.03 and p = 0.06, respectively). The amount of visceral abdominal fat (VAT) tended to be greater in R. In all subjects, VAT was negatively correlated to insulin sensitivity (r = -0.93, p < 0.001). There was a positive association between VAT and resting heart rate (r = 0.70, p = 0.003) and sympathetic/parasympathetic ratio in HRV assessment after tilt (r = 0.53, p = 0.03). Subcutaneous abdominal tissue was not associated with insulin sensitivity or any of the hormonal or HRV assessments.

    DISCUSSION: Subjects genetically predisposed for type 2 diabetes had a tendency toward a larger amount of VAT and to lower insulin sensitivity compared with control subjects. The amount of visceral fat was strongly associated with insulin resistance and signs of a high ratio of sympathetic vs. parasympathetic reactivity. A large amount of visceral fat may act in concert with sympathetic/parasympathetic imbalance to promote the development of insulin resistance, and this may be partly independent of genetic background.

  • 45. Littorin, B
    et al.
    Nyström, L
    Gullberg, B
    Råstam, L
    Ostman, J
    Arnqvist, H J
    Björk, E
    Blohmé, G
    Bolinder, J
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Scherstén, B
    Sundkvist, G
    Increasing body mass index at diagnosis of diabetes in young adult people during 1983-1999 in the Diabetes Incidence Study in Sweden (DISS).2003In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 254, no 3, p. 251-6Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study trends in body mass index (BMI) at diagnosis of diabetes in all young Swedish adults in the age range of 15-34 years registered in a nation-based registry.

    DESIGN: The BMI was assessed at diagnosis in diabetic patients 15-34 years of age at diagnosis, for a period of 17 years (1983-1999). Islet cell antibodies (ICA) were measured during three periods (1987-1988, 1992-1993 and 1998-1999).

    SETTING: