BACKGROUND AND PURPOSE: Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro(3))GIP) can reverse or prevent many of the metabolic abnormalities associated with diet-induced obesity-diabetes (diabesity). This study has examined the ability of a novel and longer-acting form of (Pro(3))GIP, (Pro(3))GIP mini-polyethylene glycol ((Pro(3))GIP[mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime. EXPERIMENTAL APPROACH: We studied the actions of (Pro(3))GIP[mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity. KEY RESULTS: (Pro(3))GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro(3))GIP[mPEG] inhibited GIP-induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP-induced glucose-lowering action was followed (Pro(3))GIP[mPEG] administration, compared with (Pro(3))GIP. In contrast with (Pro(3))GIP, mice injected once every 3 days for 48 days with (Pro(3))GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high-fat-fed controls. Daily i.p. injection of (Pro(3))GIP, (Pro(3))GIP[mPEG] or (Pro(3))GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high-fat controls. Plasma triglycerides were decreased by (Pro(3))GIP[mPEG] and (Pro(3))GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro(3))GIP[mPEG] was also effective over 16 days treatment of genetically obese-diabetic ob/ob mice. CONCLUSIONS AND IMPLICATIONS: These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro(3))GIP[mPEG] as a long-acting stable GIP receptor antagonist.
BACKGROUND AND PURPOSE: Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro(3))GIP) can reverse or prevent many of the metabolic abnormalities associated with diet-induced obesity-diabetes (diabesity). This study has examined the ability of a novel and longer-acting form of (Pro(3))GIP, (Pro(3))GIP mini-polyethylene glycol ((Pro(3))GIP[mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime. EXPERIMENTAL APPROACH: We studied the actions of (Pro(3))GIP[mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity. KEY RESULTS: (Pro(3))GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro(3))GIP[mPEG] inhibited GIP-induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP-induced glucose-lowering action was followed (Pro(3))GIP[mPEG] administration, compared with (Pro(3))GIP. In contrast with (Pro(3))GIP, mice injected once every 3 days for 48 days with (Pro(3))GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high-fat-fed controls. Daily i.p. injection of (Pro(3))GIP, (Pro(3))GIP[mPEG] or (Pro(3))GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high-fat controls. Plasma triglycerides were decreased by (Pro(3))GIP[mPEG] and (Pro(3))GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro(3))GIP[mPEG] was also effective over 16 days treatment of genetically obese-diabetic ob/ob mice. CONCLUSIONS AND IMPLICATIONS: These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro(3))GIP[mPEG] as a long-acting stable GIP receptor antagonist.
Authors: Juris J Meier; Michael A Nauck; Daniel Kranz; Jens J Holst; Carolyn F Deacon; Dirk Gaeckler; Wolfgang E Schmidt; Baptist Gallwitz Journal: Diabetes Date: 2004-03 Impact factor: 9.461
Authors: G Mingrone; G Nolfe; G Castagneto Gissey; A Iaconelli; L Leccesi; C Guidone; G Nanni; J J Holst Journal: Diabetologia Date: 2009-02-20 Impact factor: 10.122
Authors: M Nagashima; T Watanabe; M Terasaki; M Tomoyasu; K Nohtomi; J Kim-Kaneyama; A Miyazaki; T Hirano Journal: Diabetologia Date: 2011-07-24 Impact factor: 10.122