Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice

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Abstract

Compromise of gastric inhibitory polypeptide (GIP) receptor signalling represents a possible therapeutic strategy for the treatment of obesity-related diabetes. This study has characterised and evaluated the C-terminally fatty acid derivatised GIP analogues, GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal], as potential GIP inhibitors. Both GIP analogues lack the two N-terminal amino acids cleaved by DPP-4 and have addition of nine amino acids from the C-terminal of exendin(1-39), Cex. GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] effectively (p <0.01 to p <0.001) inhibited GIP-induced cAMP production and insulin secretion in vitro. In normal mice, GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] displayed a significant (p <0.05 to p <0.001) and prolonged inhibitory effect on GIP-induced glucose-lowering and insulin-releasing actions. When injected once daily for 21 days in obese-diabetic high fat fed mice, both GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] significantly reduced body weight (p <0.01 to p <0.001) and lowered circulating glucose (p <0.001) and insulin (p <0.01 to p <0.001) concentrations. The observed beneficial changes were independent of effects on energy intake, locomotor activity or metabolic rate. Oral and intraperitoneal glucose tolerance were significantly (p <0.05 to p <0.001) improved in both treatment groups at the end of the study, despite reduced glucose-induced plasma insulin concentrations. This improvement of metabolic control was accompanied by enhanced (p <0.05 to p <0.01) insulin sensitivity compared with high fat controls. These data demonstrate the potential offered by GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] for the treatment of obesity-related diabetes.
Original languageEnglish
Pages (from-to)120-129
Number of pages10
JournalMolecular and Cellular Endocrinology
Volume401
Early online date6 Nov 2014
DOIs
Publication statusPublished - 5 Feb 2015

Keywords

  • Body weight
  • Diabetes
  • GIP
  • Glucose homeostasis
  • Insulin secretion
  • Obesity

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