GH receptor deficiency in ecuadorian adults is associated with obesity and enhanced insulin sensitivity

Abstract

Context: Ecuadorian subjects with GH receptor deficiency (GHRD) have not developed diabetes, despite obesity. Objective: We sought to determine the metabolic associations for this phenomenon. Design: Four studies were carried out: 1) glucose, lipid, adipocytokine concentrations; 2) metabolomics evaluation; 3) metabolic responses to a high-calorie meal; and 4) oral glucose tolerance tests. Setting: Clinical Research Institute in Quito, Ecuador. Subjects: Adults homozygous for the E180 splice mutation of the GH receptor (GHRD) were matched for age, gender, and body mass index with unaffected control relatives (C) as follows: study 1, 27 GHRD and 35 C; study 2, 10 GHRD and 10 C; study 3, seven GHRD and 11 C; and study 4, seven GHRD and seven C. Results:AlthoughGHRDsubjectshadgreatermeanpercentagebodyfatthancontrols,theirfastinginsulin, 2-hour blood glucose, and triglyceride levels were lower. The indicator of insulin sensitivity, homeostasis model of assessment 2%S, was greater (P .0001), and the indicator of insulin resistance, homeostasis model of assessment 2-IR, was lower (P .0025). Metabolomic differences between GHRD and control subjects were consistent with their differing insulin sensitivity, including postprandial decreases of branched-chain amino acids that were more pronounced in controls. High molecular weight and total adiponectin concentrations were greater inGHRD(P .0004 and P .0128, respectively), and leptin levels were lower (P .02). Although approximately 65% the weight of controls, GHRD subjects consumed an identical high-calorie meal; nonetheless, theirmeanglucose concentrationswerelower, withmeaninsulin levels one-third those of controls. Results of the 2-hour oral glucose tolerance test were similar. Main Outcome Measures: Measures of insulin sensitivity, adipocytokines, and energy metabolites. Conclusions:WithoutGHcounter-regulation,GHRDisassociatedwithinsulinefficiencyandobesity.Lower leptin levels, despite higher percentage body fat, suggest that obesity-associated leptin resistance is GH dependent.Elevatedadiponectinlevelsnotcorrelatedwithpercentagebodyfat indicate thatGHsignaling is necessary for their typical suppression with obesity.