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Acyl Ghrelin Induces Insulin Resistance Independently of GH, Cortisol, and Free Fatty Acids.

ABSTRACT: Ghrelin produced in the gut stimulates GH and ACTH secretion from the pituitary and also stimulates appetite and gastric emptying. We have shown that ghrelin also induces insulin resistance via GH-independent mechanisms, but it is unknown if this effect depends on ambient fatty acid (FFA) levels. We investigated the impact of ghrelin and pharmacological antilipolysis (acipimox) on insulin sensitivity and substrate metabolism in 8 adult hypopituitary patients on stable replacement with GH and hydrocortisone using a 2?×?2 factorial design: Ghrelin infusion, saline infusion, ghrelin plus short-term acipimox, and acipimox alone. Peripheral and hepatic insulin sensitivity was determined with a hyperinsulinemic euglycemic clamp in combination with a glucose tracer infusion. Insulin signaling was assayed in muscle biopsies. Peripheral insulin sensitivity was reduced by ghrelin independently of ambient FFA concentrations and was increased by acipimox independently of ghrelin. Hepatic insulin sensitivity was increased by acipimox. Insulin signaling pathways in skeletal muscle were not consistently regulated by ghrelin. Our data demonstrate that ghrelin induces peripheral insulin resistance independently of GH, cortisol, and FFA. The molecular mechanisms remain elusive, but we speculate that ghrelin is a hitherto unrecognized direct regulator of substrate metabolism. We also suggest that acipimox per se improves hepatic insulin sensitivity.

SUBMITTER: Vestergaard ET

PROVIDER: S-EPMC5309923 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Acyl Ghrelin Induces Insulin Resistance Independently of GH, Cortisol, and Free Fatty Acids.

Vestergaard Esben T ET Jessen Niels N Møller Niels N Jørgensen Jens Otto Lunde JO

Scientific reports 20170215

Ghrelin produced in the gut stimulates GH and ACTH secretion from the pituitary and also stimulates appetite and gastric emptying. We have shown that ghrelin also induces insulin resistance via GH-independent mechanisms, but it is unknown if this effect depends on ambient fatty acid (FFA) levels. We investigated the impact of ghrelin and pharmacological antilipolysis (acipimox) on insulin sensitivity and substrate metabolism in 8 adult hypopituitary patients on stable replacement with GH and hyd ...[more]

PMID: 28198428

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Project description:Background: Perturbation of energy metabolism exacerbates cardiac dysfunction, serving as a potential therapeutic target in congestive heart failure. Although circulating free fatty acids (FFAs) are linked to insulin resistance and risk of coronary heart disease, it still remains unclear whether circulating FFAs are associated with the prognosis of patients with acute heart failure (AHF). Methods: This single-center, observational cohort study enrolled 183 AHF patients (de novo heart failure or decompensated chronic heart failure) in the Second Affiliated Hospital, Zhejiang University School of Medicine. All-cause mortality and heart failure (HF) rehospitalization within 1 year after discharge were investigated. Serum FFAs were modeled as quartiles as well as a continuous variable (per SD of FFAs). The restricted cubic splines and cox proportional hazards models were applied to evaluate the association between the serum FFAs level and all-cause mortality or HF rehospitalization. Results: During a 1-year follow-up, a total of 71 (38.8%) patients had all-cause mortality or HF rehospitalization. The levels of serum FFAs positively contributed to the risk of death or HF rehospitalization, which was not associated with the status of insulin resistance. When modeled with restricted cubic splines, the serum FFAs increased linearly for the incidence of death or HF rehospitalization. In a multivariable analysis adjusting for sex, age, body-mass index, coronary artery disease, diabetes mellitus, hypertension, left ventricular ejection fraction and N-terminal pro-brain natriuretic peptid, each SD (303.07 μmol/L) higher FFAs were associated with 26% higher risk of death or HF rehospitalization (95% confidence interval, 2-55%). Each increasing quartile of FFAs was associated with differentially elevated hazard ratios for death or HF rehospitalization of 1 (reference), 1.71 (95% confidence interval, [0.81, 3.62]), 1.41 (95% confidence interval, [0.64, 3.09]), and 3.18 (95% confidence interval, [1.53, 6.63]), respectively. Conclusion: Serum FFA levels at admission among patients with AHF were associated with an increased risk of adverse outcomes. Additional studies are needed to determine the causal-effect relationship between FFAs and acute cardiac dysfunction and whether FFAs could be a potential target for AHF management.

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

Acyl Ghrelin Induces Insulin Resistance Independently of GH, Cortisol, and Free Fatty Acids.

Publications

Acyl Ghrelin Induces Insulin Resistance Independently of GH, Cortisol, and Free Fatty Acids.

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