Evidence for beneficial effects of compromised gastric inhibitory polypeptide action in obesity-related diabetes and possible therapeutic implications

• Published in: Diabetologia Vol. 52; no. 9; pp. 1724 - 1731
• Main Authors: Irwin, N, Flatt, P. R
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.09.2009; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Adipocytes; Animals; Biological and medical sciences; Diabetes; Diabetes Mellitus - drug therapy; Diabetes Mellitus - physiopathology; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gastric Bypass; Gastric Inhibitory Polypeptide - immunology; Gastric Inhibitory Polypeptide - secretion; Gastric Inhibitory Polypeptide - therapeutic use; Glucagon; Glucose; Heart surgery; Homeostasis; Human Physiology; Humans; Hyperglycemia; Insulin - physiology; Insulin Resistance; Internal Medicine; Lipids; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Knockout; Obesity; Obesity - drug therapy; Obesity - prevention & control; Obesity - surgery; Ovariectomy; Pathophysiology; Physiology; Polypeptides; Receptors, Gastrointestinal Hormone - deficiency; Review; Small intestine; Vaccines - therapeutic use; K-cell; Obesity; GIP receptor; Gastric inhibitory polypeptide (GIP); Insulin resistance; Bypass surgery; Review; Endocrinopathy; Stomach; Digestive system; Diabetes mellitus; Nutrition disorder; Metabolic diseases; K -cell; Target tissue resistance; Gastrointestinal hormone; Bypass; Polypeptide; Surgery; Gastric inhibitory peptide; Nutritional status; Biological receptor
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-009-1422-8

Gastric inhibitory polypeptide (GIP) is a physiological gut peptide secreted from the intestinal K-cells with well documented insulin-releasing actions. However, the GIP receptor is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex and brain, suggesting that it may have other functions. The presence of functional GIP receptors on adipocytes and the key role played by GIP in lipid metabolism and fat deposition suggest a possible beneficial effect of compromised GIP action in obesity and insulin resistance. Several key observations in animal models of obesity-related diabetes with chemically or genetically mediated biological GIP deficiency support this concept. Thus, obese diabetic animals with compromised GIP action due to peptide-based GIP receptor antagonists, small molecular weight GIP receptor antagonists, vaccination against GIP, genetic knockout of GIP receptor or targeted K-cell destruction are protected against obesity and associated metabolic disturbances. In addition, by causing preferential oxidation of fat, blockade of GIP signalling clears triacylglycerol deposits from liver and muscle, thereby restoring mechanisms for suppression of hepatic glucose output and improving insulin sensitivity. Emerging evidence also suggests that rapid cure of diabetes in grossly obese patients undergoing bypass surgery is mediated, in part, by surgical removal of GIP-secreting K-cells in the upper small intestine.