Insulin action in the double incretin receptor knockout mouse

OBJECTIVE-The incretins glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide have been postulated to play a role in regulating insulin action, although the mechanisms behind this relationship remain obscure. We used the hyperinsulinemic-euglycemic clamp to determine sites where insulin action may be modulated in double incretin receptor knockout (DIRKO) mice, which lack endogenous incretin action. RESEARCH DESIGN AND METHODS-DIRKO and wild-type mice were fed regular chow or high-fat diet for 4 months. Clamps were performed on 5-h-fasted, conscious, unrestrained mice using an arterial catheter for sampling. RESULTS-Compared with wild-type mice, chow and high fat-fed DIRKO mice exhibited decreased fat and muscle mass associated with increased energy expenditure and ambulatory activity. Clamp rates of glucose infusion (GIR), endogenous glucose production (endoR(a)), and disappearance (R-d) were not different in chow-fed wild-type and DIRKO mice, although insulin levels were lower in DIRKO mice. Liver Akt expression was decreased but Akt activation was increased in chow-fed DIRKO compared with wild-type mice. High-fat feeding resulted in fasting hyperinsulinemia and hyperglycemia in wild-type but not in DIRKO mice. GIR, suppression of endoRa, and stimulation of R-d were inhibited in high fat-fed wild-type mice but not in DIRKO mice. High-fat feeding resulted in impaired tissue glucose uptake (R-g) in skeletal muscle of wild-type mice but not of DIRKO mice. Liver and muscle Akt activation was enhanced in high fat-fed DIRKO compared with wild-type mice. CONCLUSIONS-ln summary, DIRKO mice exhibit enhanced insulin action compared with wild-type mice when fed a regular chow diet and are protected from high-fat diet-induced obesity and insulin resistance.