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

• Published in: Diabetologia 2007-08, Vol.50 (8), p.1752-1762
• Main Authors: Gault, V. A, McClean, P. L, Cassidy, R. S, Irwin, N, Flatt, P. R
• Format: Article
• Language: English
• Subjects: (Pro³)GIP; Adiponectin - blood; Animals; Biological and medical sciences; Blood Glucose - metabolism; Body fat; Body Weight - drug effects; Carbohydrates; Corticosterone - blood; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Diet-induced obesity; Dietary Fats - administration & dosage; Dietary Fats - pharmacology; Eating - drug effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; gastric inhibitory polypeptide; Gastric Inhibitory Polypeptide - administration & dosage; Gastric Inhibitory Polypeptide - chemistry; Gastric Inhibitory Polypeptide - pharmacology; Gastric inhibitory polypeptide antagonist; Glucagon; Glucagon - blood; Glucose; Glucose Intolerance - prevention & control; Glycated Hemoglobin A - metabolism; Insulin - blood; Insulin Resistance; Lipids - blood; Locomotion - drug effects; Male; Medical sciences; Metabolic diseases; Metabolism; Mice; Mice, Obese; Nutrition research; Obesity; Obesity - blood; Obesity - physiopathology; Obesity - prevention & control; Obesity-related diabetes; Polypeptides; Proteins; Receptors, Gastrointestinal Hormone - antagonists & inhibitors
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-007-0710-4

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.