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Effects of chemical ablation of the GIP and GLP-1 receptors on metabolic aspects of obesity-diabetes were investigated using the stable receptor antagonists (Pro 3 )GIP and exendin(9–39)amide.  Ob/ob  mice received a daily i.p. injection of saline vehicle, (Pro 3 )GIP, exendin(9–39)amide or a combination of both peptides over a 14-day period. Non-fasting plasma glucose levels were significantly ( p &lt;0.05) lower in (Pro 3 )GIP-treated mice compared to control mice after just 9 days of treatment. (Pro 3 )GIP-treated mice also displayed significantly lower plasma glucose concentrations in response to feeding and intraperitoneal administration of either glucose or insulin ( p &lt;0.05 to  p &lt;0.001). The (Pro 3 )GIP-treated group also exhibited significantly ( p &lt;0.05) reduced pancreatic insulin content. Acute administration of exendin(9–39)amide immediately prior to re-feeding completely annulled the beneficial effects of sub-chronic (Pro 3 )GIP treatment, but non-fasting concentrations of active GLP-1 were unchanged. Combined sub-chronic administration of (Pro 3 GIP) with exendin(9–39)amide revealed no beneficial effects. Similarly, daily administration of exendin(9–39)amide alone had no significant effects on any of the metabolic parameters measured. These studies highlight an important role for GIP in obesity-related forms of diabetes, suggesting the possible involvement of GLP-1 in the beneficial actions of GIP receptor antagonism.

biological chemistry

Metabolic effects of sub-chronic ablation of the incretin receptors by daily administration of (Pro 3 )GIP and exendin(9–39)amide in obese diabetic ( ob/ob ) mice