Laugen, Jeanette M.

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.