Effects of exercise on lipid -induced insulin resistance.

It is known that excessive systemic lipid availability (as found in obesity) markedly reduces insulin-mediated glucose uptake. This insulin resistance is a primary symptom of type 2 diabetes, and is associated with many other chronic metabolic diseases. This dissertation was designed to determine whether exercise can prevent the insulin resistance caused by elevated systemic lipid availability. We hypothesized that exercise improves insulin sensitivity when lipid availability is high by enhancing oxidation and storage of lipid within muscle. This repartitioning of excessive lipids may reduce activation of pro-inflammatory pathways in skeletal muscle, such as e-Jun N-terminal Kinase (JNK), which impairs insulin signaling. In Study 1, a 16h lipid/heparin infusion after one exercise session did not impair insulin sensitivity the next morning. Maintenance of insulin sensitivity was associated with a ∼30% increase in intramuscular triglycerides (IMTG) concentration, suggesting that partitioning excess lipid toward IMTG may be beneficial. In Study 2, an overnight lipid infusion reduced insulin sensitivity when subjects were sedentary. However, one bout of exercise before the lipid infusion completely prevented this impairment. This protective effect of exercise on lipid-induced insulin resistance (compared with when sedentary) was associated with a 30% increase in lipid oxidation, a 50% increase in IMTG concentration, and a 50% reduction in INK phosphorylation/activation. In Study 3, an endurance exercise training/weight loss program (EX+WL) increased insulin sensitivity, and fatty acid oxidative capacity, while systemic lipid availability was reduced. However, increasing lipid availability after EX+WL to levels found before weight loss (via lipid infusion) completely reversed the improvement in insulin sensitivity. Therefore, enhancing fatty acid oxidative capacity through EX+WL was not sufficient to protect against lipid-induced insulin resistance. Importantly, all measurements in Study 3 were made three days after the last exercise training session to differentiate the effects of exercise training from the effects of one exercise session. In summary, a single session of exercise protects against lipid-induced insulin resistance, but increased fatty acid oxidative capacity after exercise training does not. This protection after acute exercise appears to be mediated by enhanced partitioning of excess fatty acids toward both oxidation and storage, which reduced skeletal muscle pro-inflammatory stress.Ph.D.Health and Environmental SciencesKinesiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125875/2/3224738.pd