Chemical gastric inhibitory polypeptide receptor antagonism protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat and cafeteria diets

Aims/hypothesis Gastric inhibitory polypeptide (GIP) receptor antagonism with (Pro³)GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure/function in ob/ob mice. This study examined the ability of (Pro³)GIP to counter the development of obesity, insulin resistance and diabetes in mice fed high-fat and cafeteria diets. Materials and methods Young Swiss TO mice on standard chow or high-fat, cafeteria or high-carbohydrate diets received daily injections of either saline or (Pro³)GIP (25 nmol kg⁻¹day⁻¹) over 16 weeks. Food intake, body weight, and circulating glucose and insulin were measured frequently. At 16 weeks, glucose tolerance, insulin sensitivity, HbA₁c, circulating hormones and plasma lipids were assessed. Adipose tissue, liver and muscle were excised and weighed, and their histology and triacylglycerol content were further examined. Results (Pro³)GIP significantly reduced body weight, enhanced locomotor activity, and improved HbA₁c, glucose tolerance, beta cell responsiveness and insulin sensitivity in mice fed high-fat and cafeteria diets (p < 0.05 to p < 0.01). Similarly, (Pro³)GIP significantly reduced plasma corticosterone and triacylglycerols (p < 0.05 to p < 0.001), while glucagon, resistin and adiponectin were unchanged. (Pro³)GIP decreased adipose tissue mass (p < 0.01) and the triacylglycerol content of liver, muscle and adipose tissue (p < 0.01 to p < 0.001). Adipocyte size and liver morphology were partially normalised. (Pro³)GIP did not significantly affect any of these parameters in mice fed a high-carbohydrate diet. Conclusions/interpretation (Pro³)GIP protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat and cafeteria diets. This highlights chemical GIP receptor antagonism as a new possibility for the treatment of obesity and associated metabolic disturbances.