Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions

• Published in: Diabetes (New York, N.Y.) Vol. 63; no. 7; pp. 2332 - 2343
• Main Authors: Nasteska, Daniela, Harada, Norio, Suzuki, Kazuyo, Yamane, Shunsuke, Hamasaki, Akihiro, Joo, Erina, Iwasaki, Kanako, Shibue, Kimitaka, Harada, Takanari, Inagaki, Nobuya
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.07.2014
• Subjects: Animals; Biological and medical sciences; Body Weight - genetics; Diabetes. Impaired glucose tolerance; Diet, High-Fat; Down-Regulation - genetics; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gastric Inhibitory Polypeptide - genetics; Gastric Inhibitory Polypeptide - secretion; Gene Knock-In Techniques; Genotype & phenotype; Glucose; Glucose - metabolism; Homeostasis; Insulin resistance; Insulin Resistance - genetics; Insulin-Secreting Cells - metabolism; Male; Medical sciences; Metabolic diseases; Mice; Mice, Transgenic; Obesity; Obesity - metabolism; Obesity - therapy; Polypeptides; Receptors, Gastrointestinal Hormone - genetics; Receptors, Gastrointestinal Hormone - metabolism; Rodents; Endocrinopathy; Obesity; Secretion; Diabetes mellitus; Nutrition disorder; Metabolic diseases; Feeding; Target tissue resistance; Chronic; Gastrointestinal hormone; Diet; Insulin resistance; Gastric inhibitory peptide; Nutritional status
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db13-1563

Gastric inhibitory polypeptide (GIP) exhibits potent insulinotropic effects on β-cells and anabolic effects on bone formation and fat accumulation. We explored the impact of reduced GIP levels in vivo on glucose homeostasis, bone formation, and fat accumulation in a novel GIP-GFP knock-in (KI) mouse. We generated GIP-GFP KI mice with a truncated prepro-GIP gene. The phenotype was assessed in heterozygous and homozygous states in mice on a control fat diet and a high-fat diet (HFD) in vivo and in vitro. Heterozygous GIP-GFP KI mice (GIP-reduced mice [GIPgfp/+]) exhibited reduced GIP secretion; in the homozygous state (GIP-lacking mice [GIPgfp/gfp]), GIP secretion was undetectable. When fed standard chow, GIPgfp/+ and GIPgfp/gfp mice showed mild glucose intolerance with decreased insulin levels; bone volume was decreased in GIPgfp/gfp mice and preserved in GIPgfp/+ mice. Under an HFD, glucose levels during an oral glucose tolerance test were similar in wild-type, GIPgfp/+, and GIPgfp/gfp mice, while insulin secretion remained lower. GIPgfp/+ and GIPgfp/gfp mice showed reduced obesity and reduced insulin resistance, accompanied by higher fat oxidation and energy expenditure. GIP-reduced mice demonstrate that partial reduction of GIP does not extensively alter glucose tolerance, but it alleviates obesity and lessens the degree of insulin resistance under HFD conditions, suggesting a potential therapeutic value.