We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Genetic Ablation of GIP Producing K Cells Reduces Diet Induced Obesity (OB) and Insulin Resistance (IR) in Mice.
- Authors
Althage, Matthew C.; Ford, Eric L.; Polonsky, Kenneth S.; Wice, Burton M.
- Abstract
Novel treatments for obesity (OB) and insulin resistance (IR) would have major positive health benefits for millions of people. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is produced by K cells in the proximal small intestine. GIP receptor knockout mice do not develop OB or IR on a high fat diet implicating a GIP sensitive pathway in the pathogenesis of these conditions. The present study was undertaken to test the hypothesis that a reduction in GIP action would ameliorate/prevent OB and/or IR on a high fat (HF) diet. Transgenic mice were generated that express an attenuated Diphtheria Toxin A chain (DT) using regulatory elements from the GIP promoter. The DT mice lack K cells and detectable levels of circulating GIP. DT and wild type (WT) were placed on a HF diet for up to 52 wks. Body weight (25% reduction at 35 weeks, p <0.0001), % body fat (22% reduction at 45 weeks, p <0.01), and plasma leptin levels (77% reduction at 15 weeks, p <0.01), were decreased in DT compared to WT mice. Surprisingly, daily food intake was increased in the DT mice (10% increase when normalized to body weight at 21 weeks, p <0.03). Indirect calorimetry showed that oxygen consumption was similar in WT and DT animals, and DT mice preferentially oxidized carbohydrates and exhibited reduced heat output. Thus, the DT mice may utilize novel mechanisms to regulate energy balance. As expected, oral glucose tolerance was impaired in the DT mice due to reduced incretin effects on insulin release although HbAlc levels were similar in WT and DT mice implying that long-term glucose homeostasis was not perturbed in the DT animals. Intraperitoneal glucose tolerance was similar in both lines of mice. Insulin tolerance tests and insulin/glucose ratios showed the DT mice have improved insulin sensitivity. Thus, reduced insulin release may be an adaptive effect to compensate for improved insulin sensitivity. In conclusion, ablation of GIP-producing K cells reduces the development of OB/IR suggesting that inhibition of GIP production/release/action may he an effective strategy to reduce OB/IR in humans.
- Publication
Diabetes, 2007, Vol 56, pA455
- ISSN
0012-1797
- Publication type
Academic Journal