MON-437 Enteroendocrine Connections in Congenital Isolated GH Deficiency Due to GHRH Receptor Gene Mutation

Abstract

Introduction: Enteroendocrine connections involve interactions between the alimentary system, energy balance, and several hormones, including insulin, GH, IGF-1, ghrelin, and GLP-1. While insulin and GLP-1 are crucial in the fed state, GH and ghrelin are more relevant during fasting or famine. Ghrelin, mostly produced by the neuroendocrine cells in the gastric mucosa, increases GH secretion, reduces insulin secretion, and stimulates hunger, peaking before meals. GLP-1, secreted by the entero endocrine L-cells in response to nutrient ingestion, potentiates insulin secretion, inhibits glucagon secretion, and contributes to satiety, peaking one hour after meal. Ghrelin enhances GLP-1 secretion in mice and probably in men. Conversely, somatostatin decreases GLP-1 secretion. Whether GH deficiency (GHD) affects the secretion of these hormones is unknown. We have studied this question in a cohort of subjects with isolated GHD (IGHD) due to a mutation in the GHRH receptor gene. These individuals exhibit severe dwarfism, visceral obesity, dyslipidemia, but delayed atherosclerosis, and normal longevity. We have previously shown that during OGTT the area under the curve (AUC) for glucose is higher, with similar AUC for insulin in comparison to controls, suggesting a combination of increased insulin sensitivity and reduced beta cell function. In addition, we have reported that these IGHD subjects eat proportionally more than matched controls. We hypothesized that these subjects may have higher ghrelin levels, resulting in reduced insulin secretion, partially compensated by an increase in GLP-1, contributing to the increased insulin sensitivity. Methods: We measured blood concentrations of glucose, insulin, total ghrelin, and GLP-1 in 20 IGHD adults (11 males, 49.4±13.4 yrs) and 20 gender- and age-matched controls (11 males, 48.9±13.6 yrs), during fasting and 30, 60, 120, 180 min after a standard test meal. HOMAir and HOMA-β were calculated. Sensations of hunger, fullness, and prospective food consumption were measured by a validated visual analogic scale questionnaire at each time point. Results: HOMAir and HOMA-β were lower in IGHD than controls (p=0.002 and p=0.023 respectively). AUC were higher for hunger (p<0.0001), glucose (p=0.0157), ghrelin (p<0.0001) and GLP-1 (p<0.0001), and smaller for fullness (p<0.0001) in IGHD compared to controls. There was no difference in AUC for prospective food consumption or insulin. Conclusions: Severe, untreated IGHD causes increase in ghrelin and GLP-1 secretion. The GLP-1 increase may result from a direct stimulatory effect of ghrelin or from a reduction in the somatostatin tone caused by GHD. These enteroendocrine connections may result into a favorable outcome in terms of environmental adaptation, guaranteeing appropriate food intake, and improving insulin sensitivity.