61-LB: Voluntary Wheel-Running Improves Dynamic Glucose Disposal in Diet-Induced Obese Mice: A Stable-Isotope Approach

Methods such as the hyperinsulinemic-euglycemic clamp have demonstrated improved insulin sensitivity in exercise-trained mice, but fail to recapitulate a dynamic physiological route of glucose metabolism. Therefore, we sought to test the effect of exercise (voluntary wheel running; VWR) on postprandial glucose dynamics by using a stable isotope labelled oral glucose tolerance test (SI-OGTT) incorporating complimentary deuterium glucose tracers at 1:1 ratio (2-2H-glucose and 6-6 2H-glucose; 2g/kg lean body mass) to distinguish between endogenous glucose concentrations (index of EGP; tracer less glucose) and meal (load) derived glucose which provides an index of whole-body glucose disposal. SI-OGTT was performed in C57/BL6J mice after 8 weeks on a high fat diet (45% fat). Mice were then randomized to either a wheel running cage (n=13, HFD Ex) or normal cage (n=13, HFD Sed) while maintaining the HFD for 4 weeks before performing a SI-OGTT. HFD Ex mice demonstrated improvements in whole blood glucose total AUC that was attributed primarily to a reduction in the endogenous glucose concentration (tracer less glucose) AUC. HFD Ex mice also demonstrated significantly lower 2-2H-glucose and 6-6 2H-glucose tracer excursions. Serum insulin levels measured at 0 and 15-minutes post glucose gavage were significantly elevated in the HFD Sed mice, whereas HFD Ex mice demonstrated the expected reduction at both time points. Overall, VWR appears to have improved postprandial hepatic insulin sensitivity and increased whole-body glucose disposal. Finally, these results demonstrate the benefits of VWR on hepatic insulin sensitivity by combining a more physiological route of glucose administration (oral glucose) with the resolution of stable isotope tracers. We clearly demonstrate the SI-OGTT to be a sensitive and cost-effective method to measure exercise adaptations in DIO-mice, which only requires as little as 2 µl of tail blood.