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Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice

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Author: Heijboer, A.C. · Hoek, A.M. van den · Parlevliet, E.T. · Havekes, L.M. · Romijn, J.A. · Pijl, H. · Corssmit, E.P.M.
Type:article
Date:2006
Institution: TNO Kwaliteit van Leven
Source:Diabetologia, 4, 49, 732-738
Identifier: 239214
doi: doi:10.1007/s00125-006-0138-2
Keywords: Biology · Biomedical Research · Animal models · GHRP-6 · Glucose metabolism · Gut hormone · Hyperinsulinaemic- euglycaemic clamp technique · Insulin resistance · Tracer methodology · Deoxyglucose · Desoctanoylghrelin · Ghrelin · Growth hormone secretagogue receptor · Growth hormone secretagogue receptor stimulating agent · Histidyl dextro tryptophylalanyltryptophyl dextro phenylalanyllysinamide · Peptide derivative · Unclassified drug · Adipose tissue · Adolescent · Body weight · Controlled study · Food intake · Glucogenesis · Glucose clamp technique · Glucose metabolism · Hormone action · Hyperinsulinemia · Insulin sensitivity · Isotope dilution assay · Liver metabolism · Mouse · Muscle metabolism · Nonhuman · Animals · Body Weight · Glucose · Hepatocytes · Insulin · Male · Mice · Mice, Inbred C57BL · Peptide Hormones

Abstract

Aims/hypothesis: This study was conducted to evaluate the effects of ghrelin on insulin's capacity to suppress endogenous glucose production and promote glucose disposal in mice. To establish whether the growth hormone secretagogue (GHS) receptor can mediate the putative effect of ghrelin on the action of insulin, we also determined the metabolic effects of growth hormone releasing peptide 6 (GHRP-6), a specific GHS receptor agonist. In addition, we explored the biological significance of des-ghrelin (unacylated ghrelin) in this experimental context. Materials and methods: Vehicle (n=8), ghrelin (n=9), GHRP-6 (n=9), des-ghrelin (n=8) or a combination of des-ghrelin and ghrelin (n=7) were infused i.v. for 3 h. Simultaneously, endogenous glucose production and glucose disposal were measured by 14C-glucose dilution during a hyperinsulinaemic-euglycaemic clamp. Tissue-specific glucose uptake in muscle and adipose tissue was measured using 3H-2-deoxyglucose. Results: During hyperinsulinaemia, glucose disposal was 31% higher in mice treated with ghrelin than in those treated with vehicle (77±16 and 59±8 μmol kg-1 h-1, respectively, p<0.05). This was in accordance with enhanced 2-deoxyglucose uptake in muscle in ghrelin-treated animals. In contrast, endogenous glucose production was less effectively suppressed by insulin during ghrelin infusion (46±22 vs 71±11% in controls, p<0.05). GHRP-6 did not affect insulin action. Des-ghrelin hampered insulin's capacity to inhibit endogenous glucose production, whereas it did not affect glucose disposal. The restraining effects of des-ghrelin and ghrelin on hepatic insulin action were abolished by simultaneous administration of both peptides. Conclusions/interpretation: Ghrelin hampers insulin's capacity to suppress endogenous glucose production, whereas it reinforces the action of insulin on glucose disposal, independently of food intake and body weight. These metabolic effects are unlikely to be mediated by the GHS receptor. Furthermore, simultaneous administration of des-ghrelin abolishes the inhibitory effect of ghrelin on hepatic insulin action. © Springer-Verlag 2006. Chemicals / CAS: deoxyglucose, 154-17-6; ghrelin, 258279-04-8, 304853-26-7; glucose, 50-99-7, 84778-64-3; histidyl dextro tryptophylalanyltryptophyl dextro phenylalanyllysinamide, 87616-84-0; insulin, 9004-10-8; ghrelin; Glucose, 50-99-7; Insulin, 11061-68-0; Peptide Hormones