Chemical Ablation of Gastric Inhibitory Polypeptide Receptor Action by Daily (Pro3)GIP Administration Improves Glucose Tolerance and Ameliorates Insulin Resistance and Abnormalities of Islet Structure in Obesity-Related Diabetes

Abstract

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R)action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro 3 )GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro 3 )GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P < 0.05) in (Pro 3 )GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P < 0.05) and insulin (1.5-fold; P < 0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P < 0.05) insulin sensitivity in the (Pro 3 )GIP-treated group. Daily injection of (Pro 3 )GIP reduced pancreatic insulin content (1.3-fold; P < 0.05) and partially corrected the obesityrelated islet hypertrophy and ␤-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro 3 )GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes. Diabetes 54:2436 -2446, 2005 G lucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is a 42-amino acid peptide hormone secreted by enteroendocrine K-cells after nutrient absorption (1). In the pancreas, GIP stimulates glucose-dependent insulin secretion through interaction with specific heterotrimeric G-protein-coupled GIP receptors (GIP-Rs) on pancreatic ␤-cells (2). Evidence suggests that GIP also stimulates proinsulin gene transcription and translation (3) and acts as a ␤-cell growth factor (4,5) and antiapoptotic agent (6,7). Receptors for GIP have been demonstrated at a number of extrapancreatic sites (8,9), suggesting a range of additional effects on nutrient metabolism. Key among these is the ability of GIP to inhibit gastric acid secretion (10), attenuate glucagon-stimulated hepatic glucose production (11), stimulate glucose uptake in muscle (12), and increase both fatty acid synthesis and lipoprotein lipase activity in adipocytes (13,14). This action profile is reminiscent, but not identical, to that displayed by glucagon-like peptide 1 (GLP-1) (15). Together, GIP and GLP-1 constitute two major physiological incretin hormones of the enteroinsular axis (16).Much recent attention has been devoted to enhancement of incretin action using dipeptidyl peptidase (DPP) IV inhibitors or stable analogs of GLP-1 and GIP for the treatment of type 2 diabetes (17,18). Such an approach is reliant on the possibility that incretin action ...

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

“…As such, the ob/ob model represents an appropriate but strong challenge to potential antihyperglycaemic agents. Consistent with other observations [30,32,34], GIP blockade had no effect on food intake, and mice continued to thrive throughout the study period. Obesity was already well established in the ob/ob mice, which were 5-7 weeks of age at commencement of the study, and body weights increased progressively , obtained in a study that used GIP receptor knockout mice [30], interference of GIP signalling by daily injections of (Pro 3 )GIP did not significantly arrest the development of obesity as assessed by simple body weight or body weight gain measurements.…”

“…glucose tolerance, meal tolerance and insulin sensitivity in ob/ob mice. Similar actions have also been noted with 11 days of (Pro 3 )GIP treatment in adult ob/ob mice [32]. However, more remarkably, GIP receptor blockade prevented the agerelated development of diabetes in the present study, and none of the above mentioned parameters differed significantly between (Pro 3 )GIP-treated ob/ob mice and normal age-matched lean control mice.…”

“…This dose of (Pro 3 ) GIP was chosen on the basis of earlier studies showing blockade of glucoregulatory effects of exogenous and endogenous GIP in ob/ob mice [35,36]. The once daily dosing regimen has also proved effective in longer-term studies [32,34]. Food intake and body weight were recorded daily, whereas plasma glucose and insulin concentrations were monitored at intervals of 3-7 days.…”

“…Experimental evidence in mice also indicates that inhibition of GIP signalling by genetic knockout of the GIP receptor prevents diet-induced obesity through the preferential use of fat as an energy substrate [30]. Furthermore, it has been shown that short-term administration of the specific and stable GIP receptor antagonist (Pro 3 )GIP [31] can reverse many of the established metabolic abnormalities in adult ob/ob mice [32].…”

Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion

“…The findings of Flatt and colleagues [23,25,26] in rodents provide an interesting parallelism with our results in humans. Genetic knockout of the GIP receptor and blockade of GIP action were both associated with a large improvement in insulin resistance and diabetes [25,26].…”