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      Effect of Oral Glucose Administration on Rebound Growth Hormone Release in Normal and Obese Women: The Role of Adiposity, Insulin Sensitivity and Ghrelin

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          Abstract

          Context

          Metabolic substrates and nutritional status play a major role in growth hormone (GH) secretion. Uncovering the mechanisms involved in GH secretion following oral glucose (OG) administration in normal and obese patients is a pending issue.

          Objective

          The aim of this study was to investigate GH after OG in relation with adiposity, insulin secretion and action, and ghrelin secretion in obese and healthy women, to further elucidate the mechanism of GH secretion after OG and the altered GH secretion in obesity.

          Participants and Methods

          We included 64 healthy and obese women. After an overnight fast, 75 g of OG were administered; GH, glucose, insulin and ghrelin were obtained during 300 minutes. Insulin secretion and action indices and the area under the curve (AUC) were calculated for GH, glucose, insulin and ghrelin. Univariate and multivariate linear regression analyses were employed.

          Results

          The AUC of GH (μg/L•min) was lower in obese (249.8±41.8) than in healthy women (490.4±74.6), P=0.001. The AUC of total ghrelin (pg/mL•min) was lower in obese (240995.5±11094.2) than in healthy women (340797.5±37757.5), P=0.042. There were significant correlations between GH secretion and the different adiposity, insulin secretion and action, and ghrelin secretion indices. After multivariate analysis only ghrelin AUC remained a significant predictor for fasting and peak GH.

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          Most cited references39

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          Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice.

          Ghrelin O-acyltransferase (GOAT) attaches octanoate to proghrelin, which is processed to ghrelin, an octanoylated peptide hormone that stimulates release of growth hormone (GH) from pituitary cells. Elimination of the gene encoding ghrelin or its receptor produces only mild phenotypes in mice. Thus, the essential function of ghrelin is obscure. Here, we eliminate the Goat gene in mice, thereby eliminating all octanoylated ghrelin from blood. On normal or high fat diets, Goat(-/-) mice grew and maintained the same weights as wild-type (WT) littermates. When subjected to 60% calorie restriction, WT and Goat(-/-) mice both lost 30% of body weight and 75% of body fat within 4 days. In both lines, fasting blood glucose initially declined equally. After 4 days, glucose stabilized in WT mice at 58-76 mg/dL. In Goat(-/-) mice, glucose continued to decline, reaching 12-36 mg/dL on day 7. At this point, WT mice showed normal physical activity, whereas Goat(-/-) mice were moribund. GH rose progressively in calorie-restricted WT mice and less in Goat(-/-) mice. Infusion of either ghrelin or GH normalized blood glucose in Goat(-/-) mice and prevented death. Thus, an essential function of ghrelin in mice is elevation of GH levels during severe calorie restriction, thereby preserving blood glucose and preventing death.
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            The GH/IGF-1 axis in obesity: pathophysiology and therapeutic considerations.

            Obesity has become one of the most common medical problems in developed countries, and this disorder is associated with high incidences of hypertension, dyslipidaemia, cardiovascular disease, type 2 diabetes mellitus and specific cancers. Growth hormone (GH) stimulates the production of insulin-like growth factor 1 in most tissues, and together GH and insulin-like growth factor 1 exert powerful collective actions on fat, protein and glucose metabolism. Clinical trials assessing the effects of GH treatment in patients with obesity have shown consistent reductions in total adipose tissue mass, in particular abdominal and visceral adipose tissue depots. Moreover, studies in patients with abdominal obesity demonstrate a marked effect of GH therapy on body composition and on lipid and glucose homeostasis. Therefore, administration of recombinant human GH or activation of endogenous GH production has great potential to influence the onset and metabolic consequences of obesity. However, the clinical use of GH is not without controversy, given conflicting results regarding its effects on glucose metabolism. This Review provides an introduction to the role of GH in obesity and summarizes clinical and preclinical data that describe how GH can influence the obese state.
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              The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men.

              To elucidate the role of leptin in regulating neuroendocrine and metabolic function during an acute fast, six to eight healthy, lean men were studied under four separate conditions: a baseline fed state and three 72-hour fasting studies with administration of either placebo, low-dose recombinant-methionyl human leptin (r-metHuLeptin), or replacement-dose r-metHuLeptin designed to maintain serum leptin at levels similar to those in the fed state. Replacement-dose r-metHuLeptin administered during fasting prevents the starvation-induced changes in the hypothalamic-pituitary-gonadal axis and, in part, the hypothalamic-pituitary-thyroid axis and IGF-1 binding capacity in serum. Thus, in normal men, the fall in leptin with fasting may be both necessary and sufficient for the physiologic adaptations of these axes, which require leptin levels above a certain threshold for activation. In contrast to findings in mice, fasting-induced changes in the hypothalamic-pituitary-adrenal, renin-aldosterone, and growth hormone-IGF-1 axes as well as fuel utilization may be independent of leptin in humans. The role of leptin in normalizing several starvation-induced neuroendocrine changes may have important implications for the pathophysiology and treatment of eating disorders and obesity.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 March 2015
                2015
                : 10
                : 3
                : e0121087
                Affiliations
                [1 ]Department of Medicine, Faculty of Health Sciences, University of A Coruña, A Coruña, Spain
                [2 ]Instituto de Investigación Biomedica (INIBIC), University Hospital A Coruña, A Coruña, Spain
                [3 ]Clinical Epidemiology and Biostatistics Unit, University Hospital A Coruña, A Coruña, Spain
                [4 ]Department of Endocrinology, University Hospital A Coruña, A Coruña, Spain
                [5 ]Department of Physiology (CIMUS), School of Medicine-Instituto de Investigaciones Sanitarias (IDIS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain, and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
                Complexo Hospitalario Universitario de Santiago, SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LPB SPD EOB JGB CD FC. Performed the experiments: LPB EOB FC. Analyzed the data: LPB SPD EOB JGB ST SSA CD FC. Contributed reagents/materials/analysis tools: SPD JGB ST SSA CD FC. Wrote the paper: LPB SPD EOB ST SSA CD FC.

                Article
                PONE-D-14-55382
                10.1371/journal.pone.0121087
                4363632
                25782001
                c6b43814-8fb4-46e6-a44a-29dde8a12731
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 17 December 2014
                : 30 January 2015
                Page count
                Figures: 3, Tables: 3, Pages: 13
                Funding
                This work was supported in part by Fondo de Investigación Sanitaria del Instituto de Salud Carlos III PI10/00088, PI13/00322 (FEDER from E.U.) and Xunta de Galicia IN845B-2010/187, 10CSA916014PR to FC and CN2012/312 to SSA, Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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