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Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice.

ABSTRACT: A reciprocal relationship between insulin sensitivity and glucose tolerance has been reported in some mouse models and humans with isolated changes in growth hormone (GH) production and signaling. To determine if this could be explained in part by tissue-specific changes in insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed in mice with adult-onset, isolated GH deficiency and in mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin receptors. Our results demonstrate that circulating GH levels are negatively correlated with insulin-mediated glucose uptake in muscle but positively correlated with insulin-mediated suppression of hepatic glucose production. A positive relationship was also observed between GH levels and endpoints of hepatic lipid metabolism known to be regulated by insulin. These results suggest hepatic insulin resistance could represent an early metabolic defect in GH deficiency.

SUBMITTER: Cordoba-Chacon J

PROVIDER: S-EPMC4233257 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice.

Cordoba-Chacon Jose J Gahete Manuel D MD McGuinness Owen P OP Kineman Rhonda D RD

American journal of physiology. Endocrinology and metabolism 20140930 10

A reciprocal relationship between insulin sensitivity and glucose tolerance has been reported in some mouse models and humans with isolated changes in growth hormone (GH) production and signaling. To determine if this could be explained in part by tissue-specific changes in insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed in mice with adult-onset, isolated GH deficiency and in mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin rece ...[more]

PMID: 25269484

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Project description:ContextLow-dose GH (LGH) therapy has been reported to improve insulin sensitivity in GH-deficient adults; however, the mechanism is unclear.HypothesisEffects of LGH therapy on insulin sensitivity are mediated through changes in cortisol metabolism and ectopic fat accumulation.Design and settingThis was a double-blind, placebo-controlled, parallel, 3-month study.Participants and interventionSeventeen GH-deficient adults were randomized to receive either daily LGH or placebo injections. Fasting blood samples were collected at baseline, and months 1 and 3, whereas hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy scans, 24-hour cortisol production rates (CPRs), and sc abdominal fat biopsies were performed at baseline and month 3.Main outcome measuresClamp glucose infusion rate, intramyocellular, extramyocellular, and intrahepatic lipid content, 24-hour CPRs, adipocyte size, and adipocyte 11β-hydroxysteroid dehydrogenase activity in adults with GH deficiency were evaluated.ResultsAt month 1, LGH did not alter fasting levels of glucose, insulin, C-peptide, free fatty acid, adiponectin, total IGF-1, IGF-1 bioactivity, IGF-2, IGF binding protein (IGFBP)-2, or IGF-1 to IGFBP-3 molar ratio. At month 3, LGH increased clamp glucose infusion rates (P < .01) and IGF-1 to IGFBP-3 molar ratio (P < .05), but fasting glucose, insulin, C-peptide, free fatty acid, adiponectin, IGF-1 bioactivity, IGF-2, IGFBP-2, 24-hour CPRs, adipocyte size, adipocyte 11β-hydroxysteroid dehydrogenase activity, intrahepatic lipid, extramyocellular, or intramyocellular were unchanged. In the placebo group, all within-group parameters from months 1 and 3 compared with baseline were unchanged.ConclusionsShort-term LGH therapy improves insulin sensitivity without inducing basal lipolysis and had no effect on cortisol metabolism and ectopic fat accumulation in GH-deficient adults. This may reflect an LGH-induced increase in IGF-1 to IGFBP-3 molar ratio exerting insulin-like effects through the abundant muscle IGF-1 receptors, but this hypothesis requires confirmation with further studies.

Dataset Information

Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice.

Publications

Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice.

Similar Datasets

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