Blockade of gastric inhibitory polypeptide (GIP) action as a novel means of countering insulin resistance in the treatment of obesity-diabetes

Gastric inhibitory polypeptide (GIP) is a 42 amino acid hormone secreted from intestinal K-cells in response to nutrient ingestion. Despite a recognised physiological role for GIP as an insulin secretagogue to control postprandial blood glucose levels, growing evidence reveals important actions of GIP on adipocytes and promotion of fat deposition in tissues. As such, blockade of GIP receptor (GIPR) action has been proposed as a means to counter insulin resistance, and improve metabolic status in obesity and related diabetes. In agreement with this, numerous independent observations in animal models support important therapeutic applications of GIPR antagonists in obesity-diabetes. Sustained administration of peptide-based GIPR inhibitors, low molecular weight GIPR antagonists, GIPR neutralising antibodies as well as genetic knockout of GIPR's or vaccination against GIP all demonstrate amelioration of insulin resistance and reduced body weight gain in response to high fat feeding. These observations were consistently associated with decreased accumulation of lipids in peripheral tissues, thereby alleviating insulin resistance. Although the impact of prolonged GIPR inhibition on bone turnover still needs to be determined, evidence to date indicates that GIPR antagonists represent an exciting novel treatment option for obesity-diabetes.