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

被引:146
作者
Nasteska, Daniela [1 ]
Harada, Norio [1 ]
Suzuki, Kazuyo [1 ]
Yamane, Shunsuke [1 ]
Hamasaki, Akihiro [1 ]
Joo, Erina [1 ]
Iwasaki, Kanako [1 ]
Shibue, Kimitaka [1 ]
Harada, Takanari [1 ]
Inagaki, Nobuya [1 ]
机构
[1] Kyoto Univ, Dept Diabet Endocrinol & Nutr, Grad Sch Med, Kyoto, Japan
关键词
GASTRIC-INHIBITORY-POLYPEPTIDE; RECEPTOR KNOCKOUT MICE; PANCREATIC BETA-CELLS; RAT ADIPOSE-TISSUE; GLUCOSE-INTOLERANCE; LIPOPROTEIN-LIPASE; PEPTIDE SECRETION; JAPANESE SUBJECTS; STIMULATION; EXPRESSION;
D O I
10.2337/db13-1563
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Gastric inhibitory polypeptide (GIP) exhibits potent insulinotropic effects on beta-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 [GIP(gfp/+)]) exhibited reduced GIP secretion; in the homozygous state (GIP-lacking mice [GIP(gfp/gfp)]), GIP secretion was undetectable. When fed standard chow, GIP(gfp/+) and GIP(gfp/gfp) mice showed mild glucose intolerance with decreased insulin levels; bone volume was decreased in GIP(gfp/gfp) mice and preserved in GIP(gfp/+) mice. Under an HFD, glucose levels during an oral glucose tolerance test were similar in wild-type, GIP(gfp/+), and GIP(gfp/gfp) mice, while insulin secretion remained lower. GIP(gfp/+) and GIP(gfp/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.
引用
收藏
页码:2332 / 2343
页数:12
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