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(Pro(3))GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy.

ABSTRACT: 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.

SUBMITTER: McClean PL

PROVIDER: S-EPMC2584927 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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(Pro(3))GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy.

McClean P L PL Irwin N N Hunter K K Gault V A VA Flatt P R PR

British journal of pharmacology 20080811 5

<h4>Background and purpose</h4>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 int ...[more]

PMID: 18695644

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Project description:ContextIn healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP's insulinotropic effect is impaired and effects on bone may be reduced.ObjectiveTo investigate GIP's effect on bone biomarkers in patients with T2D.DesignRandomized, double-blinded, crossover study investigating 6 interventions.PatientsTwelve male patients with T2D.InterventionsA primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with "insulin-induced hypoglycemia" (PG lowered to 3 mmol/L), "fasting hyperglycemia" (mean PG ~8 mmol/L), or "aggravated hyperglycemia" (mean PG ~12 mmol/L).Main outcome measuresBone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH.ResultsOn days with insulin-induced hypoglycemia, CTX was suppressed by up to 40 ± 15% during GIP administration compared with 12 ± 11% during placebo infusion (P < 0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36 ± 15% during GIP administration, compared with 0 ± 9% during placebo infusion (P < 0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47 ± 23% during GIP administration compared with 10 ± 9% during placebo infusion (P = 0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes.ConclusionsShort-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients.PrécisShort-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.

Dataset Information

(Pro(3))GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy.

Publications

(Pro(3))GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy.

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