Aims/hypothesis Ablation of gastric inhibitory polypeptide ( GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro(3)) GIP is able to counter the development of genetic obesity-related diabetes. Materials and methods Young ( 5 - 7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro(3)) GIP (25 nmol kg(-1) day(-1)) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA(1c), circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro(3)) GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose ( p <0.001), HbA(1c) ( p <0.05), glucose tolerance (p <0.001), meal tolerance ( p <0.001) and insulin sensitivity ( p <0.05). Remarkably, (Pro(3)) GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro(3)) GIP, while levels of triacylglycerol, LDL-cholesterol and resistin were decreased ( p <0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro(3)) GIP treatment than in control ob/ob mice ( p <0.01), but plasma insulin levels remained substantially raised ( p <0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.