Giesler, Paula D.

Background: 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. Methods: 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 (S i ) 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 S i , DI, lipids, and adipokines were computed using Pearson's correlation coefficient and multiple regression analysis. Results: The mean age of the subjects was 14.3±1.88 years, and the mean BMI was 32.5±4.65 kg/m 2 ; 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 S i (log S i ) in the entire cohort ( p =0.03), but this relationship persisted only in males ( p =0.02). The correlation between TSH and S i 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). Conclusions: 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.

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.

OBJECTIVE—The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS—We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (SI), glucose effectiveness, and β-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously. RESULTS—Vildagliptin reduced postprandial glucose concentrations (905 ± 94 vs. 1,008 ± 104 mmol/6 h, P = 0.02). Vildagliptin did not alter net SI (7.71 ± 1.28 vs. 6.41 ± 0.84 10−4 dl · kg−1 · min−1 · μU−1 · ml−1, P = 0.13) or glucose effectiveness (0.019 ± 0.002 vs. 0.018 ± 0.002 dl · kg−1 · min−1, P = 0.65). However, the net β-cell responsivity index was increased (35.7 ± 5.2 vs. 28.9 ± 5.2 10−9 min−1, P = 0.03) as was total disposition index (381 ± 48 vs. 261 ± 35 10−14 dl · kg−1 · min−2 · pmol−1 · l−1, P = 0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0 ± 1.1 vs. 29.7 ± 1.5 μg · l−1 · 6 h−1, P = 0.03), especially after administration of exogenous insulin (81.5 ± 6.4 vs. 99.3 ± 5.6 ng/l, P = 0.02). CONCLUSIONS—Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters α-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.

OBJECTIVE— We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations. RESEARCH DESIGN AND METHODS— We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design. RESULTS— Fasting (7.3 ± 0.5 vs. 7.9 ± 0.5 mmol/l) and peak postprandial (14.1 ± 0.6 vs. 15.9 ± 0.9 mmol/l) glucose concentrations were lower (P < 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 ± 1.6 vs. 23.7 ± 1.3 mg/ml per 5 h, P < 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 ± 270 vs. 1,277 ± 312 pmol/l per 5 h, P = 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments. CONCLUSIONS— Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.