Jan W. Eriksson

Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’

Aims/hypothesisThe aim of this study was to explore whether fat cell size in human subcutaneous and omental adipose tissue is independently related to insulin action and adipokine levels.Materials and methodsFat cells were prepared from abdominal subcutaneous biopsies obtained from 49 type 2 diabetic and 83 non-diabetic subjects and from omental biopsies obtained from 37 non-diabetic subjects. Cell size and insulin action on glucose uptake capacity in vitro were assessed in isolated fat cells. Insulin sensitivity in vivo was assessed with euglycaemic-hyperinsulinaemic clamps. Fasting blood samples were collected and adipokines and NEFA were measured.ResultsNegative correlations were found between subcutaneous fat cell size and insulin sensitivity assessed as M-value during clamp and as insulin action on glucose uptake in fat cells in vitro. This was seen in non-diabetic subjects after including age, sex and BMI in the analyses. No such relationship was found in type 2 diabetic subjects. In both groups, subcutaneous fat cell size correlated positively and independently with plasma levels of leptin but not to any of the other assessed adipokines. In non-diabetic subjects, omental fat cell size was independently and negatively correlated with insulin action in subcutaneous, but not omental, fat cells in vitro.Conclusions/interpretationFat cell enlargement is associated with insulin resistance in non-diabetic individuals independently of BMI. This was not seen in type 2 diabetic subjects, suggesting that after development of type 2 diabetes other factors, not related to fat cell size, become more important for the modulation of insulin resistance.

The risk of venous thromboembolism is markedly elevated in patients with diabetes

Aims/hypothesisDiabetes mellitus is associated with several changes in coagulation and fibrinolysis that may lead to a thrombogenic propensity. However, it is not known whether these perturbations actually cause increased risk of venous thromboembolism.MethodsIn a retrospective population-based study we evaluated the medical records of all 302 adult patients who were admitted to the Umeå University Hospital with verified deep vein thrombosis or pulmonary embolism during the years 1997 to 1999. The patients were classified as diabetic (n=56) and non-diabetic (n=246) according to clinical information. The total number of diagnosed diabetic patients in different age groups in the catchment area was obtained from computerised registries in the primary health care centres and the Umeå University Hospital, and data on the background population were collected from the Swedish population registry.ResultsThe annual incidence rate of venous thromboembolism among diabetic patients in the population was 432 per 100,000 individuals (95% CI 375–496). In non-diabetic individuals it was 78 (95% CI 68–88). The age-adjusted incidence rate among the diabetic population was 274 (95% CI 262–286). The annual incidence rate of venous thromboembolism was elevated in type 1 and type 2 diabetic patients and the incidence rates were 704 (95% CI 314–1,566) and 412 (95% CI 312–544) respectively. The overall standardised morbidity ratio was 2.27 (95% CI 1.75–2.95), i.e. diabetic patients were more prone to venous thromboembolism after adjustment for age differences.Conclusions/interpretationThese results suggest that the age-adjusted risk for venous thromboembolism is more than two-fold higher among diabetic patients than in the non-diabetic background population.

Metabolic stress in insulin’s target cells leads to ROS accumulation – A hypothetical common pathway causing insulin resistance

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 insulins 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.

Insulin action and signalling in fat and muscle from dexamethasone-treated rats.

Glucocorticoids initiate whole body insulin resistance and the aim of the present study was to investigate effects of dexamethasone on protein expression and insulin signalling in muscle and fat tissue. Rats were injected with dexamethasone (1mg/kg/day, i.p.) or placebo for 11 days before insulin sensitivity was evaluated in vitro in soleus and epitrochlearis muscles and in isolated epididymal adipocytes. Dexamethasone treatment reduced insulin-stimulated glucose uptake and glycogen synthesis by 30-70% in epitrochlearis and soleus, and insulin-stimulated glucose uptake by approximately 40% in adipocytes. 8-bromo-cAMP-stimulated lipolysis was approximately 2-fold higher in adipocytes from dexamethasone-treated rats and insulin was less effective to inhibit cAMP-stimulated lipolysis. A main finding was that dexamethasone decreased expression of PKB and insulin-stimulated Ser(473) and Thr(308) phosphorylation in both muscles and adipocytes. Expression of GSK-3 was not influenced by dexamethasone treatment in muscles or adipocytes and insulin-stimulated GSK-3beta Ser(9) phosphorylation was reduced in muscles only. A novel finding was that glycogen synthase (GS) Ser(7) phosphorylation was higher in both muscles from dexamethasone-treated rats. GS expression decreased (by 50%) in adipocytes only. Basal and insulin-stimulated GS Ser(641) and GS Ser(645,649,653,657) phosphorylation was elevated in epitrochlearis and soleus muscles and GS fractional activity was reduced correspondingly. In conclusion, dexamethasone treatment (1) decreases PKB expression and insulin-stimulated phosphorylation in both muscles and adipocytes, and (2) increases GS phosphorylation (reduces GS fractional activity) in muscles and decreases GS expression in adipocytes. We suggest PKB and GS as major targets for dexamethasone-induced insulin resistance.

mTOR inhibition with rapamycin causes impaired insulin signalling and glucose uptake in human subcutaneous and omental adipocytes

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

Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes.

Aims  This study compared the effects of 52 weeks’ treatment with pioglitazone, a thiazolidinedione that reduces insulin resistance, and glibenclamide, on insulin sensitivity, glycaemic control, and lipids in patients with Type 2 diabetes.

Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds

Differentiation between Type 1 and Type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as Type 1 diabetes.

Postprandial regulation of blood lipids and adipose tissue lipoprotein lipase in type 2 diabetes patients and healthy control subjects

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.

Effects of decavanadate and insulin enhancing vanadium compounds on glucose uptake in isolated rat adipocytes.

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

Soluble CD36 (sCD36) Clusters with Markers of Insulin Resistance, and High sCD36 Is Associated with Increased Type 2 Diabetes Risk

CONTEXT AND OBJECTIVE Soluble CD36 (sCD36) may be an early marker of insulin resistance and atherosclerosis. The objective of this prospective study was to evaluate sCD36 as a predictor of type 2 diabetes and to study its relationship with components of the metabolic syndrome (MetSy). DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES: We conducted a case-referent study nested within a population-based health survey. Baseline variables included sCD36, body mass index, blood pressure, blood lipids, adipokines, inflammatory markers, and beta-cell function. A total of 173 initially nondiabetic cohort members who developed type 2 diabetes during 10 yr of follow-up were matched (1:2) with referents. Exploratory factor analysis was applied to hypothesize affiliation of sCD36 to the MetSy components. RESULTS Doubling of baseline sCD36 increases the odds ratio for diabetes development by 1.24 in the general study population and by 1.45 in the female population (P < 0.025). Comparing upper sCD36 quartiles with lower, odds ratio for diabetes was 4.6 in women (P = 0.001), 3.15 in men (P = 0.011), and 2.6 in obese individuals (P < 0.025). Multivariate analysis shows that sCD36 does not predict diabetes independent of fasting plasma glucose and insulin. Factor analysis of 15 variables generates a six-factor model explaining 66-69% of total variance, where sCD36, body mass index, insulin, proinsulin, and leptin were assigned to the obesity/insulin resistance cluster. CONCLUSIONS Upper quartile sCD36 is associated with elevated diabetes risk independent of age, gender, and obesity. Baseline sCD36 does not, however, predict diabetes independent of fasting glucose and insulin. sCD36 clusters with important markers of insulin resistance and MetSy that are key predictors of type 2 diabetes.