Tissue Specific Insulin Resistance Following Voluntary Physical Activity

Abstract

PURPOSE: Physical inactivity and a sedentary lifestyle are risk factors for insulin resistance and the development of type 2 diabetes. However, the systemic impact of voluntary exercise on insulin sensitivity in the liver compared to skeletal muscle has not been adequately explored. METHODS: Subgroups of young, male C57BL/6J mice (SED) were provided voluntary access to running wheels for 8 weeks (RUN). Then, mice were challenged with a physiological dose of insulin (i.p., 0.5 U kg-1) and insulin-dependent signaling mechanisms in the liver and gastrocnemius/plantaris complex were quantified. RESULTS: Mice provided voluntary access to running wheels consistently averaged 6-8km of daily running for the duration of the 8 weeks. Insulin-stimulated Akt phosphorylation modestly increased by 37% in the gastrocnemius/plantaris complex from RUN mice compared to SED controls (p=0.17). In contrast, a significant increase in insulin-stimulated Akt and GSK3β phosphorylations (2.5 and 3-fold, respectively) were evident in livers from RUN mice compared to SED controls. Further, expression of SOCS3, a protein implicated in insulin resistance, was decreased 2-fold in livers from RUN mice (no effect in skeletal muscle). CONCLUSIONS: Here, we identified disparate responses in insulin sensitivity and signaling in the liver and exercising skeletal muscles following 8 weeks of voluntary physical activity. These findings demonstrate that even in otherwise healthy animals, the lack of physical activity leads to significant alterations in insulin-dependent signaling which likely represent the initial pathogenesis of impaired glucose metabolism and type 2 diabetes.