Assessing the risk of impaired glucose metabolism in overweight adolescents in a clinical setting.

OBJECTIVE: The study aims were to examine the relationship between adiposity and surrogate indices of pancreatic beta-cell function and insulin sensitivity obtained from an oral glucose tolerance test (OGTT) in overweight adolescents and determine which factors best predict impaired glucose metabolism (IGM). METHODS: In a sample of adolescents (n=209) severity of overweight was determined by relative body mass index (RBMI). Insulin sensitivity (QUICKI, CISI) and beta-cell function (Fasting insulin: FI; Insulinogenic Index: deltaI30/deltaG30). RESULTS: IGM was present in 26.8% (n=56), of which five had type 2 diabetes (T2DM). IGM prevalence was similar among RBMI strata. Once RBMI reached 150%, pronounced deterioration in CISI occurred (approximately 55%) (P<0.0001) while less dramatic reductions were seen in QUICKI (P<0.05), with fasting blood glucose (FBG) and beta-cell indices remaining stable. Compared to those with normal glucose tolerance, the IGM group exhibited higher beta-cell activity (FI, P<0.0001; deltaI30/deltaG30, P=0.004) with reduced insulin sensitivity (CISI, P<0.0001; QUICKI, P<0.0002). CISI was the single predictor of IGM (P<0.0001). Low insulin sensitivity increased adolescents' chance for IGM (CISI: OR=6.49, 95%CI=2.63, 16.05, P<0.0001; QUICKI: OR=3.16, 95%CI=1.61, 6.05, P=0.0006) as did beta-cell deterioration (deltaI30/delta G30: OR=3.18, 95%CI=1.33, 7.59, P=0.0069). Normal FBG occurred in 37.5% of youth with IGM. CONCLUSION: The prevalence of IGM escalates in overweight adolescents, even at lower levels of overweight, and is associated with pronounced deterioration of insulin sensitivity. Current screening recommendations for FBG underestimate the prevalence of IGM in overweight adolescents thus limiting the opportunity for earlier intervention to prevent progression to diabetes.

Obesity, leptin resistance, and the effects of insulin reduction.

Leptin resistance is a hallmark of obesity, but its etiology is unknown, and its clinical measurement is elusive. Leptin-sensitive subjects have normal resting energy expenditure (REE) at a low leptin concentration, while leptin-resistant subjects have a normal REE at a higher leptin concentration; thus, the ratio of REE:Leptin may provide a surrogate index of leptin sensitivity. We examined changes in REE and leptin in a cohort of 17 obese subjects during experimental weight loss therapy with the insulin-suppressive agent octreotide-LAR, 40 mg i.m. q28d for 6 months. Six subjects lost significant weight (>10%) and BMI (>-3 kg/m(2)) with a 34% decline in leptin and a 46% decrease in insulin area under the curve (IAUC) to oral glucose tolerance testing. These subjects maintained their pretreatment REE, and thus exhibited a rise in REE:Leptin, while the other 11 showed minimal changes in each of these parameters. For the entire cohort, the change in IAUC correlated negatively with the change in REE:Leptin. These results suggest that the REE:Leptin ratio, while derivative, may serve as a useful clinical indicator of changes in leptin sensitivity within obese subjects. They also support the possibilities that hyperinsulinemia may be a proximate cause of leptin resistance, and that reduction of insulinemia may promote weight loss by improving leptin sensitivity.

Race affects insulin and GLP-1 secretion and response to a long-acting somatostatin analogue in obese adults.

OBJECTIVE: This study investigated (1) the effect of octreotide-LAR (Sandostatin-LAR Depot; Novartis) on the enteroinsular axis in a biracial cohort of severely obese adults, (2) whether octreotide suppression of insulin secretion occurs by both a direct beta-cell effect and through mediating a glucagon-like peptide 1 (GLP-1) response, and (3) whether differences in GLP-1 concentrations could explain racial differences in insulin concentrations. DESIGN: Prospective, open-label trial using a pre-post test design. SETTING: Single university, clinical research center. SUBJECTS: In all, 42 healthy, severely obese Caucasian and African-American (AA) adults (93% female, 64% Caucasian, age=37.8+/-1.2 y, weight=123+/-4.2 kg, BMI=44.5+/-1 kg/m(2)), recruited through physician referral and newspaper ads, participated in the study. INTERVENTIONS: Indices of beta-cell activity, insulin and GLP-1 response before and during a 75-gm oral glucose tolerance test were determined before and after 24 weeks of octreotide-LAR. RESULTS: AA exhibited higher beta-cell activity, and insulin and GLP-1 concentrations than Caucasians. Octreotide-LAR suppressed the insulin and GLP-1 levels in both groups.

Racial differences in glucagon-like peptide-1 (GLP-1) concentrations and insulin dynamics during oral glucose tolerance test in obese subjects.

Obese African-American (AA) subjects have higher resting and stimulated insulin concentrations than obese Caucasians (C), which could not be explained by the severity of obesity or the degree of insulin sensitivity. We investigated whether differences in glucagon-like peptide-1 (GLP-1), the most potent incretin that regulates insulin secretion, might explain racial differences in insulin response. Accordingly, we measured fasting and stimulated glucose, insulin, and GLP-1 levels during a 3-h oral glucose tolerance test (OGTT) in 26 obese C (age 38+/-2 y, body mass index 44+/-1 kg/m(2)) and 16 obese AA (age 36+/-2 y, BMI 46+/-2 kg/m(2)) subjects. Corrected insulin response (CIR(30)), a measure of beta-cell activity, whole body insulin sensitivity index (WBISI), and area under the curve (AUC) for insulin, GLP-1, and C-peptide/insulin ratio were computed from the OGTT. Glucose levels, fasting and during the OGTT, were similar between racial groups; 32% of the C and 31% of the AA subjects had impaired glucose tolerance. With a similar WBISI, AAs had significantly higher CIR(30) (2.3+/-0.4 vs 1.01+/-0.1), insulin response (IAUC: 23 974+/-4828 vs 14 478+/-1463), and lower insulin clearance (0.07+/-0.01 vs 0.11+/-0.01) than C (all, P<0.01). Obese AAs also had higher fasting GLP-1 (6.7+/-2.5 vs 4.5+/-1.1) and GLP-1AUC (1174.7+/-412 vs 822.4+/-191) than C (both, P<0.02). Our results indicate that obese AAs had higher concentrations of GLP-1 both at fasting and during the OGTT than obese C. The increased GLP-1 concentration could explain the greater insulin concentration and the increased prevalence of hyperinsulinemia-associated disorders including obesity and type 2 diabetes in AAs.

Suppression of insulin secretion is associated with weight loss and altered macronutrient intake and preference in a subset of obese adults.

PURPOSE: Hyperinsulinemia is a common feature of many obesity syndromes. We investigated whether suppression of insulin secretion, without dietary or exercise intervention, could promote weight loss and alter food intake and preference in obese adults. METHODS: Suppression of insulin secretion was achieved using octreotide-LAR 40 mg IM q28d for 24 weeks in 44 severely obese adults (89% female, 39% minority). Oral glucose tolerance testing was performed before and after treatment, indices of beta-cell activity (CIRgp), insulin sensitivity (CISI), and clearance (CP/I AUC) were computed, and leptin levels, 3-day food records and carbohydrate-craving measurements were obtained. DEXA evaluations were performed pre- and post-therapy in an evaluable subgroup. RESULTS: For the entire cohort, significant insulin suppression was achieved with simultaneous improvements in insulin sensitivity, weight loss, and body mass index (BMI). Leptin, fat mass, total caloric intake, and carbohydrate craving significantly decreased. When grouped by BMI response, high responders (HR; DeltaBMI<-3 kg/m(2)) and low responders (LR; DeltaBMI between -3 and -0.5) exhibited higher suppression of CIRgp and IAUC than nonresponders (NR; DeltaBMI-0.5). CISI improved and significant declines in leptin and fat mass occurred only in HR and LR. Conversely, both leptin and fat mass increased in NR. Carbohydrate intake was markedly suppressed in HR only, while carbohydrate-craving scores decreased in HR and LR. For the entire cohort, DeltaBMI correlated with DeltaCISI, Deltafat mass, and Deltaleptin. DeltaFat mass also correlated with DeltaIAUC and DeltaCISI. CONCLUSIONS: In a subcohort of obese adults, suppression of insulin secretion was associated with loss of body weight and fat mass and with concomitant modulation of caloric intake and macronutrient preference.