Mechanisms for Exercise, High-Fat Diet, and Muscle Fiber-Type Effects on Insulin-Stimulated Glucose Uptake in Skeletal Muscle

Abstract

Insulin resistance of skeletal muscle, a tissue which accounts for up to 85% of insulin-mediated glucose disposal, is a primary and essential precursor that leads to type 2 diabetes. A single bout of exercise can subsequently enhance insulin-stimulated glucose uptake (ISGU) in insulin-resistant skeletal muscle. Although much work has been performed in healthy muscle, the mechanisms which lead to increased post-exercise insulin sensitivity in insulin-resistant muscle are far less understood. Therefore, the main objective of this dissertation was to provide insights into the mechanisms for enhanced post-exercise ISGU in muscle from insulin-resistant rats. Further complicating our understanding of post-exercise insulin sensitivity is the fact that skeletal muscle is a heterogeneous tissue composed of multiple fiber types with varied metabolic properties. Therefore, research in this thesis exploited the metabolic heterogeneity of different fiber types to investigate potential mechanisms for enhanced post-exercise ISGU in insulin-resistant muscle at a cellular level. Study 1 revealed that a 2-week high-fat diet (HFD), which causes whole muscle insulin resistance, results in fiber type-specific decrements in ISGU. Study 2 uncovered that acute exercise by HFD-fed rats results in increased ISGU of all type II fiber types (including IIB, IIBX, IIX, IIAX, and IIA), but ISGU was unaltered post-exercise in type I fibers, the only fiber type to maintain normal insulin sensitivity on a HFD. The striking fiber type-specific results of both a HFD and of acute exercise on ISGU revealed a need to better understand mechanisms for enhanced post-exercise ISGU at a cellular level. Studies 3 and 4 assessed key post-exercise signaling events in whole muscle and different fiber types, respectively, from HFD-fed rats. The results from insulin-resistant whole muscle tissue support the concept that increased γ3-AMPK activity is an important post-exercise event which eventually leads to enhanced insulin-stimulated AS160 phosphorylation. Further, the results revealed that fiber type-specific insulin-stimulated AS160 phosphorylation was site-specific. The fiber type-specific AS160 phosphorylation in Study 4 roughly corresponded with the observed fiber type-specific ISGU in Study 2. Therefore, these results support the idea, at least in some fiber types from insulin-resistant muscle, that AS160 plays a key role in mediating enhanced post-exercise ISGU. Further studies are warranted to assess the direct effect of site-specific AS160 phosphorylation and γ3-AMPK activity on post-exercise ISGU. A better understanding of the mechanisms for enhanced ISGU following exercise in insulin-resistant skeletal muscle will facilitate the development and implementation of novel therapies and interventions to mitigate the deleterious effects of insulin resistance.