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Thyrotropin (TSH) levels display a positive association with body mass index (BMI), and the prevalence of isolated hyperthyrotropinemia is higher in obese adolescents compared to their normal weight controls. However, the metabolic significance of the higher TSH in obese adolescents is less clear. The objective of this study was to determine the relationship between TSH concentrations and insulin sensitivity, lipids, and adipokines in euthyroid, non-diabetic, obese adolescents.Thirty-six euthyroid, non-diabetic, obese adolescents between the ages of 12 and 18 years underwent a 75 g oral glucose tolerance test. Insulin sensitivity (Si) and pancreatic β-cell function as assessed by disposition index (DI) were measured using the oral glucose minimal model approach. Cholesterol (total, low-density lipoprotein [LDL-C], and high-density lipoprotein [HDL-C]), triglycerides (TG), interleukin-6 (IL-6), total and high molecular weight (HMW) adiponectin, and retinol binding protein-4 (RBP4) were also determined. Associations between measures of thyroid function and Si, DI, lipids, and adipokines were computed using Pearson's correlation coefficient and multiple regression analysis.The mean age of the subjects was 14.3±1.88 years, and the mean BMI was 32.5±4.65 kg/m2; 97% were non-Hispanic white and 47% were male. The mean TSH was 2.7±1.2 mIU/L. Increasing serum TSH was correlated with decreasing Si (log Si) in the entire cohort (p=0.03), but this relationship persisted only in males (p=0.02). The correlation between TSH and Si in males remained significant after adjusting for BMI (p=0.02). There was no correlation between TSH and pancreatic β-cell function as assessed by DI (p=0.48). TSH correlated positively with LDL-C (p=0.04) and IL-6 (p=0.03), but these associations vanished or weakened after adjusting for BMI (LDL-C p-value=0.44; IL-6 p-value=0.07).This study suggests a sex-specific association between TSH and insulin sensitivity in euthyroid, non-diabetic, obese adolescent males. Prospective studies are warranted to explore further this sexual dimorphism in the relationship between thyroid function and insulin sensitivity and to determine if obese adolescents with insulin resistance receiving thyroid supplements for hypothyroidism would benefit from targeting TSH levels in the lower half of normal range.

Background: There is increasing interest in the extraskeletal effects of vitamin D, particularly in the obese state with regard to the development of insulin resistance and diabetes. Objective: The objective of the study was to determine the effect of 2 doses of cholecalciferol (vitamin D(3)) supplementation on insulin action (S(i)) and pancreatic β-cell function in obese adolescents. Methods: We performed a 12-wk double-blind, randomized comparison of the effect of vitamin D(3) supplementation on S(i) and β-cell function in obese Caucasian adolescents (body mass index > 95(th) percentile). The subjects were randomly assigned to receive either 400 IU/d (n = 25) or 2000 IU/d (n = 26) of vitamin D(3). Each subject underwent a 7-sample 75 g oral glucose tolerance test, with glucose, insulin, and C-peptide measurements, to calculate S(i) and β-cell function as assessed by the disposition index (DI), with use of the oral minimal model before and after supplementation. A total of 51 subjects aged 15.0 ± 1.9 y were enrolled. Included for analysis at follow-up were a total of 46 subjects (20 male and 26 female adolescents), 23 in each group. Results: Initial serum 25-hydroxyvitamin D [25(OH)D] was 24.0 ± 8.1 μg/L. There was no correlation between 25(OH)D concentrations and S(i) or DI. There was a modest but significant increase in 25(OH)D concentration in the 2000 IU/d group (3.1 ± 6.5 μg/L, P = 0.04) but not in the 400 IU/d group (P = 0.39). There was no change in S(i) or DI following vitamin D(3) supplementation in either of the treatment groups (all P > 0.10). Conclusions: The current study shows no effect from vitamin D(3) supplementation, irrespective of its dose, on β-cell function or insulin action in obese nondiabetic adolescents with relatively good vitamin D status. Whether obese adolescents with vitamin D deficiency and impaired glucose metabolism would respond differently to vitamin D(3) supplementation remains unclear and warrants further studies. This trial was registered at clinicaltrials.gov as NCT00858247.

OBJECTIVE Glucagon-like peptide (GLP)-1 receptor is encoded by GLP1R. The effect of genetic variation at this locus on the response to GLP-1 is unknown. This study assessed the effect of GLP1R polymorphisms on insulin secretion in response to hyperglycemia and to infused GLP-1 in nondiabetic subjects. RESEARCH DESIGN AND METHODS Eighty-eight healthy individuals (aged 26.3 ± 0.6 years, fasting glucose 4.83 ± 0.04 mmol/l) were studied using a hyperglycemic clamp. GLP-1 was infused for the last 2 h of the study (0.75 pmol/kg/min over 121–180 min, 1.5 pmol/kg/min over 181–240 min). β-Cell responsivity (ΦTotal) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on ΦTotal was examined. RESULTS Two SNPs (rs6923761 and rs3765467) were nominally associated with altered β-cell responsivity in response to GLP-1 infusion. CONCLUSIONS Variation in GLP1R may alter insulin secretion in response to exogenous GLP-1. Future studies will determine whether such variation accounts for interindividual differences in response to GLP-1–based therapy.

Genetic variation in transcription factor 7-like 2 (TCF7L2), a regulator of proglucagon processing, is reproducibly associated with type 2 diabetes. GLP-1 alters gastric function and increases satiation.Genetic variation in TCF7L2 is associated with satiation, gastric motor function, and GLP-1 concentrations.In 62 adults, a single nucleotide polymorphism (SNP) of TCF7L2 (rs7903146) was genotyped and associations with gastric emptying (GE) of solids and liquids, gastric volume (GV), and satiation (maximum tolerated volume and symptoms after nutrient drink test) were explored using a dominant genetic model, with gender and BMI as covariates. In 50 of the participants, we also measured plasma GLP-1 during fasting and after ingestion of a nutrient drink.Presence of the T allele compared to CC genotype in rs7903146 SNP of the TCF7L2 gene was associated with reduced fasting GV (246.3 ± 11.4 mL for CC group, compared to 215.7 ± 11.4 mL for CT/TT group, p= 0.05) and accelerated GE t(1/2) of liquids (26.3 ± 2.0 minutes for CC compared to 17.7 ± 1.4 for CT/TT, p0.005). There was no significant association of rs7903146 SNP with GE of solids, gastric accommodation, satiation, fasting, or postprandial GLP-1.Our data suggest TCF7L2 is associated with altered gastric functions that may predispose to obesity.

Impaired fasting glucose (IFG) confers a high risk of progression to diabetes [1]. Its pathogenesis has been an area of active investigation, with defects in insulin and glucagon secretion as well as insulin action likely to play a role [2]. Several studies have suggested that the prediabetic [3] and diabetic [4] state are associated with alterations in circulating incretin concentrations. More recently, a large study of non-diabetic individuals demonstrated decreased GLP-1 concentrations after a glucose challenge in individuals with prediabetes but concluded that defects in GLP-1 secretion were unrelated to insulin secretion [5]. In impaired glucose tolerance (IGT), defects in incretin-induced insulin secretion coexist with defects in glucose induced insulin secretion [6]. Worsening degrees of glucose tolerance are associated with decreased insulin secretion for the prevailing insulin action. Moreover early glucagon suppression is impaired in IGT [2]. Since GLP-1 is an insulin secretagogue and suppresses glucagon, it is conceivable that defects in GLP-1 secretion could contribute to the pathogenesis of pre-diabetes. Inhibition of Dipeptidyl Peptidase-4 (DPP-4), an enzyme which rapidly degrades the incretin hormones, has been shown to be a useful therapeutic strategy in type 2 diabetes [7]. DPP-4 inhibitors increase (model-calculated) insulin secretion and decrease glucagon concentrations resulting in a lowering of fasting (and postprandial) glucose concentrations in people with type 2 diabetes [8]. Their effects in people with IFG are less certain [9, 10]. However, DPP-4 inhibitors provide an opportunity to directly examine the contribution of abnormal incretin concentrations to the pathogenesis of IFG, by raising concentrations of endogenous incretin hormones. The current experiments tested this hypothesis by measuring insulin secretion and action and fasting and postprandial glucose turnover before and after 8 weeks of therapy with a DPP-4 inhibitor.

Food intake and associated behavioral factors are important determinants of weight status (1), and the stomach signals satiation during feeding in response to the volume and calories ingested (2,3). Previous studies in our laboratory showed that the postprandial change in gastric volume is an independent predictor of maximum tolerated volume and satiation (4); in addition, when we applied pharmacological perturbations with i.v. erythromycin and atropine to induce postprandial discomfort including fullness and bloating, we observed in a multivariate analysis that accelerated gastric emptying of solids at 1 hour, and delayed gastric emptying at 4 hours, as well as fasting gastric volume were associated with postprandial symptom scores reflecting satiation (5,6). Postprandial gastric volume and change in gastric volume during fasting were univariately associated, but was not significant if fasting gastric volume was included in the model. The endocannabinoid system, a lipid-derived signaling system, has central and peripheral physiologic functions (7). The endocannabinoids, anandamide and 2-arachidonyl glycerol (2-AG), bind to the cannabinoid (CB) receptor and regulate appetite. The cannabinoid receptor type 1 (CB1) is located centrally in the hypothalamus and nucleus accumbens and in peripheral tissues (8,9). There is evidence that gastric emptying is physiologically regulated in rodents by the endocannabinoid system, which is down regulated following a high fat diet leading to overweight (10). In a pharmacodynamic study in healthy human volunteers, we showed that the non-selective cannabinoid agonist dronabinol retards gastric emptying in females and increases fasting gastric volumes in males (11). The endocannabinoid anandamide is hydrolyzed by the enzyme fatty acid amide hydrolase (FAAH), and the polymorphism rs324420 (FAAH C385A, located on chromosome 1 p35–p34) results in an amino acid change at position 129, P129T. This produces a variant that displays normal catalytic properties but an enhanced sensitivity to proteolytic degradation (12). Both cannabinoid receptor 1 (CNR1, located on 6q14–15) and FAAH play an integral part in the control of the endocannabinoid system and the response to endocannabinoids; these mechanisms also play a role in the development of obesity (12,13). Cannabinoids also modulate motor activity in the gastrointestinal tract; for example, non-selective cannabinoid agonist dronabinol inhibits gastric and colonic motility (11,14,15). In humans, studies using a CB1 receptor antagonist, rimonabant, have shown modest weight reduction and improvement in cardiovascular risk factors in obese subjects (16,17). Common variations in genes controlling cannabinoid function or metabolism have been associated with the development of obesity, diabetes as well as with potential alterations in gastric function. FAAH rs324420 results in a mutant form of FAAH with reduced expression and cellular stability (18). Sipe and colleagues suggested that the FAAH rs324420 polymorphism is associated with overweight and obese individuals (19). Sipe et al. also reported that, in severe obesity (BMI>40kg/m2), significantly increased levels of the endocannabinoid anandamide and related N-acylethanolamines were documented in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls (20). This suggests that FAAH 385 A mutant alleles have a direct effect on elevated plasma endocannabinoid levels which may be biomarkers of risk for severe obesity (20). In addition, there is evidence that this missense mutation influences weight loss in response to a hypocaloric diet (21). Polymorphisms in CNR1 are also associated with obesity. Thus, CNR1 gene variation rs2023239 has been shown to predispose to weight gain in Europeans (22), rs1049353 (G1359A) is associated with fat distribution (23) and abdominal adiposity in men (24), and T allele carriers for the CNR1 polymorphism rs806378 (C4558T) have increased odds ratio of childhood obesity (22) and experience increased antipsychotic-induced weight gain compared to CC carriers (25). rs1049353 is a synonymous change that does not alter the amino acid. The T allele associated with CNR1 polymorphism rs806378 is associated with altered nuclear protein binding in a functional (electron shift mobility) assay, suggesting it is a functional polymorphism (25). Therefore, we focused our study on the CNR1 rs806378 polymorphism and studied its association with gastric function and satiation. The aim of this study was to assess the association of allelic variations in the rs324420 (nearest gene FAAH) and rs806378 (nearest gene CNR1) single nucleotide polymorphisms (SNPs) with gastric motor and sensory functions, and satiation (that could predispose to the development of obesity) in a cohort of overweight and obese human participants.