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GH Receptor Deficiency in Ecuadorian Adults Is Associated With Obesity and Enhanced Insulin Sensitivity
Jaime Guevara-Aguirre1, Arlan L Rosenbloom1, Priya Balasubramanian1
1Universidad San Francisco de Quito (J.G.-A., E.T.), Quito, Ecuador; Instituto de Endocrinologia, Metabolismo y Repróduccion (J.G.-A., A.L.R., M.G.-A., C.G., P.P., L.N., J.S.), Quito Ecuador; University of Florida College of Medicine (A.L.R.), Gainesville, Florida 32608; Davis School of Gerontology (P.B., S.D.B., V.D.L.), University of Southern California, Los Angeles, California 90089; Experimental Gerontology Section (I.A., R.D.C.), Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224; and Longevity Institute (V.D.L.), University of Southern California, Los Angeles, California 90089.
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:
Although GHRD subjects had greater mean percentage body fat than controls, their fasting insulin, 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 in GHRD (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, their mean glucose concentrations were lower, with mean insulin 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:
Without GH counter-regulation, GHRD is associated with insulin efficiency and obesity. Lower leptin levels, despite higher percentage body fat, suggest that obesity-associated leptin resistance is GH dependent. Elevated adiponectin levels not correlated with percentage body fat indicate that GH signaling is necessary for their typical suppression with obesity.
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