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© 2020 the American Physiological Society. Dynamic glucose disposal is driven by reduced endogenous glucose production in response to voluntary wheel running: A stable isotope approach. Am J Physiol Endocrinol Metab 319: E2-E10, 2020. First published April 28, 2020; doi:10.1152/ajpendo.00450.2019.-To resolve both the systems level and molecular mechanisms responsible for exerciseinduced improvements in glucose tolerance, we sought to test the effect of voluntary wheel running exercise on postprandial glucose dynamics. We utilized a stable isotope-labeled oral glucose tolerance test (SI-OGTT) incorporating complementary deuterium glucose tracers at a 1:1 ratio (2-2H-glucose and 6-6 2H-glucose; 2g/kg lean body mass) to distinguish between endogenous glucose production (EGP) and whole-body glucose disposal. SI-OGTT was performed in C57BL/6J mice after 8 wk on a high-fat diet (HFD; 45% fat). Mice were then randomized to either a wheel-running cage (n = 13, HFD Ex) or a normal cage (n = 13, HFD Sed) while maintaining the HFD for 4 wk before performing a SI-OGTT. HFD Ex mice demonstrated improvements in whole blood glucose total area under the curve (AUC) that was attributed primarily to a reduction in EGP AUC. Serum insulin levels measured at 0 and 15 min post-glucose gavage were significantly elevated in the HFD Sed mice, whereas HFD Ex mice demonstrated the expected reduction in insulin at both time points. Overall, exercise improved hepatic insulin sensitivity by reducing postprandial EGP, but also increased whole-body glucose disposal. Finally, these results demonstrate the benefits of exercise on hepatic insulin sensitivity by combining a more physiological route of glucose administration (oral glucose) with the resolution of stable isotope tracers. These novel observations clearly demonstrate that SI-OGTT is a sensitive and cost-effective method to measure exercise adaptations in obese mice with as little as 2 μl of tail blood.

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American Journal of Physiology - Endocrinology and Metabolism

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