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Obesity is characterized by insulin-resistance (IR), enhanced lipolysis, and ectopic, inflamed fat. We related the histology of subcutaneous (SAT), visceral fat (VAT), and skeletal muscle to the metabolic abnormalities, and tested their mutual changes after bariatric surgery in type 2 diabetic (T2D) and weight-matched non-diabetic (ND) patients. We measured IR (insulin clamp), lipolysis ( 2 H 5 -glycerol infusion), ß-cell glucose-sensitivity (ß-GS, mathematical modeling), and VAT, SAT, and rectus abdominis histology (light and electron microscopy). Presurgery, SAT and VAT showed signs of fibrosis/necrosis, small mitochondria, free interstitial lipids, thickened capillary basement membrane. Compared to ND, T2D had impaired ß-GS, intracapillary neutrophils and higher intramyocellular fat, adipocyte area in VAT, crown-like structures (CLS) in VAT and SAT with rare structures (cyst-like) ~10-fold larger than CLS. Fat expansion was associated with enhanced lipolysis and IR. VAT histology and intramyocellular fat were related to impaired ß-GS. Postsurgery, IR and lipolysis improved in all, ß-GS improved in T2D. Muscle fat infiltration was reduced, adipocytes were smaller and richer in mitochondria, and CLS density in SAT was reduced. In conclusion, IR improves proportionally to weight loss but remains subnormal, whilst SAT and muscle changes disappear. In T2D postsurgery, some VAT pathology persists and beta-cell dysfunction improves but is not normalized.

Objective: To assess the impact of obesity and insulin sensitivity on resting (REE) and glucose-induced thermogenesis (GIT)., Design: Data from 322 studies carried out in non-diabetic subjects of either gender, covering a wide range of age (18-80y) and body mass index (BMI, 18-50 kg/m2)., Measurements: Insulin sensitivity and thermogenesis were measured by combining the euglycaemic insulin clamp technique with indirect calorimetry., Results: REE was inversely related to age (P = 0.001) and the respiratory quotient (P = 0.03), and positively related to BMI, lean body mass (LBM), fat mass, and percentage fat mass (all P<0.0001). In a multiple regression model, LBM-adjusted REE was estimated to decline by 9% between 18 and 80 y, independently of obesity and insulin sensitivity. In contrast, GIT was strongly associated with insulin sensitivity (P<0.0001) but not with gender, age or BMI. By multiple regression analysis, GIT was linearly related to insulin sensitivity after controlling for gender, age, BMI and steady-state plasma insulin levels. Furthermore, both of the main components of insulin-mediated glucose disposal (glucose oxidation and glycogen synthesis) correlated with GIT independently of one another. In the subset of subjects (n = 89) in whom waist-to-hip ratio (WHR) measurements were available, GIT was inversely associated with WHR (P<0.001 after adjustment by gender, age, BMI, insulin sensitivity and steady-state plasma insulin concentration). In this model, a significant interaction between WHR and gender indicated a stronger adverse effect on GIT of a high WHR in women than in men., Conclusions: In healthy humans, age, lean mass and respiratory quotient are the main independent determinants of resting thermogenesis. In contrast, insulin sensitivity and, to a lesser extent, abdominal obesity are the principal factors controlling glucose-induced thermogenesis.

Objective: To investigate whether duration of obesity has an independent impact on insulin resistance., Design: Case-control study., Subjects: 30 non-diabetic obese subjects (age, 34+/-12 y, body mass index (BMI), 33.5+/-0.8 kg x m[-2]) with a range (1-35 y) of self-reported duration of obesity, and 12 age- and gender-matched non-obese controls (BMI, 22.1+/-0.6 kg x m[-2])., Measurements: Oral glucose tolerance (40 g x m[-2]), insulin sensitivity (by the euglycaemic insulin clamp technique), and insulin secretion (as the product of post-hepatic insulin clearance and plasma insulin concentration)., Results: The obese group presented hyperinsulinaemia in the basal state and after glucose loading (insulin area = 58+/-5 vs 33+/-3 nmol x I[-1] x 2 h, P = 0.005), insulin resistance (M value = 37.4+/-4.8 vs 50.6+/-2.6 micromol x min[-1] x kg FFM[-1], P = 0.002), and insulin hypersecretion (61.9+/-6.0 vs 33.9 +/- 4.0 nmol x 2 h, P = 0.007); endogenous glucose production was similar in the two groups. In the whole dataset, insulin resistance was directly related to BMI, the waist-to-hip ratio (WHR), endogenous glucose production, insulin secretion, and fasting serum triglycerides and uric acid concentrations. When the obese subjects were stratified by duration of obesity, insulin resistance was progressively lower with longer obesity duration (P = 0.04). When simultaneously adjusting by age, gender and BMI, obesity duration was independently associated with greater insulin sensitivity (P = 0.003), lower plasma insulin response to oral glucose (P = 0.001), and lower fasting and glucose-stimulated insulin release (P = 0.01 for both)., Conclusions: In obese subjects with preserved glucose tolerance, duration of obesity is associated with better insulin sensitivity irrespective of the degree of overweight.