Relation of the degree of obesity in childhood to adipose tissue insulin resistance.

AIMS: In this study, we investigated whether adipose tissue insulin resistance (IR) is affected by the degree of obesity during the fasting and post-prandial state, independent of glucose tolerance among obese children and adolescents. We also tested whether systemic subclinical inflammation is associated with adipose tissue IR. METHODS: Subjects were recruited to the Yale Pathophysiology of Type 2 Diabetes in Youth Study (NCT01967849). An oral glucose-tolerance test was performed to establish glucose-tolerance status and blood samples were drawn for measurement of free fatty acids (FFAs), to calculate the area under the curve (AUC) of FFA. Adipose tissue insulin resistance was calculated as the product of insulin and FFA concentrations. RESULTS: In total, 671 children and adolescents (58.6% females) were included with a mean age of 13.3(2.7) years and BMI Z score of 2.45(0.31). The degree of obesity emerged as an independent predictor of both fasting and post-prandial adipose IR, p < 0.0001. Higher degree of obesity was associated with greater AUC FFA (lower suppression) compared to lower degree of obesity, p = 0.01. Furthermore, higher levels of IL-6 were positively associated with post-prandial adipose tissue IR, p = 0.02. CONCLUSIONS: The degree of obesity in childhood and adolescence is strongly associated with adipose tissue IR independent of glucose tolerance. This is reflected not only in calculated indices of adipose IR but also in lower suppression of FFAs during the OGTT regardless of glucose tolerance or fasting adipose tissue IR. Furthermore, markers of subclinical inflammation such as IL-6 are associated with adipose tissue IR, independent of other factors.

Adipose Insulin Resistance in Obese Adolescents Across the Spectrum of Glucose Tolerance.

CONTEXT: Adipocytes represent an important insulin-responsive tissue taking an active part in glucose metabolism. OBJECTIVE: This study sought to assess adipose tissue insulin resistance (IR) across the spectrum of glucose tolerance and to test its relation with free fatty acid (FFA) suppression during an oral glucose tolerance test (OGTT). DESIGN AND SETTING: A cross-sectional analysis of a pediatric clinic-derived cohort of obese adolescents. PATIENTS OR OTHER PARTICIPANTS: Participants age 7-20 y with a body mass index that exceeded the 95th percentile for their age and sex. INTERVENTION(S): A standard oral glucose tolerance test. MAIN OUTCOME MEASURES: The adipose tissue insulin resistance index (calculated as the product of fasting insulin and FFA concentrations) (Adipose IR) and the area under curve of FFAs during the OGTT were compared between glucose tolerance categories. RESULTS: A total of 962 obese children and adolescents participated in this study. Adipose IR significantly increased across glucose tolerance categories (P for trend < .001). Within the normal glucose tolerance participants, an increase in adipose IR was observed related to an increase in 2-hr glucose levels. In a subsample of participants who underwent abdominal imaging for determination of lipid partitioning (n = 115), a tight relation of visceral fat (r = 0.34; P < .001) and the visceral/sc fat ratio (r = 0.55; P < .001) with the Adipose IR index was evident. Greater area under the curve FFAs (lower FFA suppression) during the OGTT was evident with worsening glucose tolerance (P for trend < .001). Glucose tolerance category, degree of obesity (body mass index-z score), IL-6, and low adiponectin emerged as significant predictors of the Adipose IR. CONCLUSIONS: Adipose IR is associated with reduced suppression of FFAs during the OGTT and with an altered adipocytokine profile. The negative relation with insulin secretion deserves further longitudinal investigation in the context of deteriorating glucose tolerance.

Glucose effectiveness in obese children: relation to degree of obesity and dysglycemia.

OBJECTIVE: Impaired glucose effectiveness (GE) plays a role in the deterioration of glucose metabolism. Our aim was to validate a surrogate of GE derived from an oral glucose tolerance test (OGTT) and to assess the impact of degrees of obesity and of glucose tolerance on it. RESEARCH DESIGN AND METHODS: The OGTT-derived surrogate of GE (oGE) was validated in obese adolescents who underwent an OGTT and an intravenous glucose tolerance test (IVGTT). We then evaluated anthropometric determinants of the oGE and its impact on the dynamics of glucose tolerance in a cohort of children with varying degrees of obesity. RESULTS: The correlation of oGE and IVGTT-derived GE in 98 obese adolescents was r = 0.35 (P < 0.001) as a whole and r = 0.51 (P < 0.001) in subjects with normal glucose tolerance. In a cohort of 1,418 children, the adjusted GE was associated with increasing obesity (P < 0.001 for each category of obesity). Quartiles of oGE and the oral disposition index were associated with 2-h glucose levels (P < 0.001 for both). Among 421 nondiabetic obese subjects (276 subjects with normal glucose tolerance/145 subjects with impaired glucose tolerance who repeated their OGTT after a mean time of 28 ± 16 months), oGE changes were tightly associated with weight (r = 0.83, P < 0.001) and waist circumference changes (r = 0.67, P < 0.001). Baseline oGE and changes in oGE over time emerged as significant predictors of the change in 2-h glucose levels (standardized B = -0.76 and B = -0.98 respectively, P < 0.001 for both). CONCLUSIONS: The oGE is associated with the degree of and changes in weight and waist circumference and is an independent predictor of glucose tolerance dynamics.

Baseline abdominal lipid partitioning is associated with the metabolic response to bariatric surgery.

BACKGROUND: The purpose of this study was to compare the effects of two bariatric procedures on abdominal lipid partitioning and metabolic response. METHODS: Fifty-one patients (RYGB 31(11 M/20 F); (SG) 20(8 M/12 F)) who met the criteria of metabolic syndrome before the operation were followed following Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Visceral and subcutaneous abdominal fat depots were assessed by CT before, 6 months, and 12 months following the operation. RESULTS: Patients undergoing both procedures did not differ in baseline body mass index (BMI) (42.84 ± 4.65 vs. 41.70 ± 4.68 kg/m(2)) or abdominal lipid depots. BMI at 12 months post-op was similar (29.44 ± 3.35 vs 30.86 ± 4.31 kg/m(2) for RYGB and SG, respectively). Both procedures led to a significant reduction in visceral and subcutaneous fat at 6 months (p < 0.001 for both). The visceral-to-subcutaneous fat ratio was comparable at 6 months vs. baseline yet was lower at 12 months vs. baseline for both procedures (p < 0.01). In patients who lost the diagnosis of metabolic syndrome, baseline visceral/subcutaneous fat was the only predictor of recovery (p < 0.005). No difference was detected between procedures in dynamics of abdominal fat depots or remission of cardiovascular risk factors. CONCLUSIONS: RYGB and SG induce a similar effect on abdominal fat mobilization. The metabolic effects in individual patients are mostly determined by their baseline abdominal lipid partitioning.

Roux-en-Y gastric bypass vs sleeve gastrectomy for obese patients with type 2 diabetes: a randomised trial.

AIMS/HYPOTHESIS: Bariatric surgery is gaining acceptance as a 'metabolic surgical intervention' for patients with type 2 diabetes. The optimal form of surgery and the mechanism of action of these procedures are much debated. We compared two bariatric procedures for obese patients with type 2 diabetes and evaluated their effects on HbA1c and glucose tolerance. METHODS: We performed a parallel un-blinded randomised trial of Roux-en-Y gastric bypass (RYGB) vs sleeve gastrectomy (SG) in 41 obese patients with type 2 diabetes, who were bariatric surgery candidates attending the obesity clinic. HbA1c, body composition and glucose tolerance were evaluated at baseline, and at 3 and 12 months. RESULTS: Of the 41 patients, 37 completed the follow-up (19 RYGB, 18 SG). Both groups had similar baseline anthropometric and biochemical measures, and showed comparable weight loss and fat:fat-free mass ratio changes at 12 months. A similar normalisation of HbA1c levels was observed as early as 3 months post-surgery (6.37 ± 0.71% vs 6.23 ± 0.69% for RYGB vs SG respectively, p < 0.001 in both groups for baseline vs follow-up). CONCLUSIONS/INTERPRETATION: In this study, RYGB did not have a superior effect in comparison to SG with regard to HbA1c levels or weight loss during 12 months of follow-up. TRIAL REGISTRATION: ClinicalTrials.gov NCT00667706. FUNDING: This work was supported by grant no. 3-000-8480 from the Israel Ministry of Health Chief Scientist, the Stephen Morse Diabetes Research Foundation and by Johnson & Johnson.

Basal alpha-cell up-regulation in obese insulin-resistant adolescents.

CONTEXT: The aim of this analysis was to evaluate glucagon and c-peptide concentrations in two scenarios: euglycemic hyperinsulinemia and hyperglycemic hyperinsulinemia. We postulated that worsening obesity and insulin resistance will be reflected as an up-regulated (less suppressible) islet secretion profile. METHODS: Eighty-two [34 obese with normal glucose tolerance (NGT), 30 obese with impaired glucose tolerance (IGT), and 18 nonobese with NGT] subjects underwent a euglycemic-hyperinsulinemic clamp (EHC) and a hyperglycemic clamp. C-peptide and glucagon were evaluated at basal and steady-state (SS) conditions. RESULTS: Basal glucagon was significantly elevated in obese insulin-resistant and obese IGT subjects as was basal c-peptide. SS glucagon and c-peptide levels during the EHC were lower in the lean and obese insulin-sensitive subjects compared with the obese insulin-resistant subjects with NGT or IGT. Fasting glucagon was the only significant determinant (ß = 0.66, P < 0.001) of SS glucagon during the EHC (R(2) = 0.57). In a longitudinal follow-up of a subsample, those who converted from normal to IGT significantly increased their fasting glucagon concentration in comparison with those who remained with NGT. CONCLUSIONS: Islet up-regulation manifesting as basal elevated glucagon and c-peptide secretion that determines the suppressive effects of hyperinsulinemia appears early in the course of deteriorating glucose tolerance.