Abstract

Objective: The incretins GLP-1 and GIP 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 (WT) mice were fed regular chow or high fat (HF) diet for 4 months. Clamps were performed on 5h-fasted, conscious, unrestrained mice using an arterial catheter for sampling.

Results: Compared to WT mice, chow and HF-fed DIRKO mice exhibited decreased fat and muscle mass associated with increased energy expenditure and ambulatory activity. Clamp rates of glucose infusion (GIR), production (endoR_a), and disappearance (R_d) were not different in chow-fed WT 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 to WT mice. HF feeding resulted in fasting hyperinsulinemia and hyperglycemia in WT but not in DIRKO mice. GIR, suppression of endoR_a, and stimulation of R_d were inhibited in HF-fed WT but not in DIRKO mice. HF feeding resulted in impaired tissue glucose uptake (R_g) in skeletal muscle of WT but not of DIRKO mice. Liver and muscle Akt activation was enhanced in HF-fed DIRKO compared to WT mice.

Conclusions: In summary, DIRKO mice exhibit enhanced insulin action compared to WT mice when fed a regular chow diet and are protected from HF diet-induced obesity and insulin resistance.