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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 (endoRa), and disappearance (Rd) 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 Rd were inhibited in high fat–fed wild-type mice but not in DIRKO mice. High-fat feeding resulted in impaired tissue glucose uptake (Rg) 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—In 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.