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

V. Pathak, V. A. Gault, P. R. Flatt, N. Irwin

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

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-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[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-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[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-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[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-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[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-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[Pal] for the treatment of obesity-related diabetes.

Original languageEnglish
Pages (from-to)120-129
JournalMolecular and Cellular Endocrinology
Volume401
Early online date06 Nov 2014
DOIs
Publication statusPublished - 05 Feb 2015

Keywords

  • Administration, Oral
  • Animals
  • Anti-Obesity Agents
  • Blood Glucose
  • Body Weight
  • Diet, High-Fat
  • Drug Administration Schedule
  • Gastric Inhibitory Polypeptide
  • Glucose Tolerance Test
  • Injections, Intraperitoneal
  • Insulin
  • Lipoylation
  • Mice
  • Obesity
  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.

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