Insulin signal transduction in skeletal muscle : special consideration for insulin resistance and diabetes

Abstract: This dissertation work is focused on the insulin-signal-transduction pathways to glucose transport in skeletal muscle from animal models of NIDDM. The overall objective is to determine the effectiveness of different pharmacological treatments to improve insulin action in skeletal muscle. Muscle-fiber-type-specific differences in insulin signal transduction was first considered. We noted increased insulin action on insulin signaling events including; IR, IRS- 1, IRS-2, PI 3-kinase, and AKT occur in oxidative soleus muscle versus glycolytic EPI and EDL muscles. The time course for insulin signal transduction was similar between oxidative and glycolytic muscles. We assessed the molecular mechanism underlining insulin resistance in skeletal muscle from diabetic the Goto- Kakizaki (GK) rats, a non-obese model of NIDDM. Impaired insulin signaling and glucose transport occurred in a muscle-fiber-type specific manner in GK rats. For glucose transport, defects in maximal insulin stimulation occurred in oxidative muscle, whereas at submaximal insulin concentrations, defects occurred in glycolytic muscles. Impaired insulinstimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI 3-kinase activity was only observed in oxidative muscle, whereas AKT activity was observed regardless of muscle fiber type. Normalization of hyperglycemia in GK rats by phlorizin treatment improved glucose tolerance. Improved insulin- stimulated glucose transport and AKT activity in both oxidative soleus and glycolytic EDL muscles accompanied the changes in glucose tolerance in GK rats. Phlorizin treatment did not improve insulin action on IRS- I and PI 3-kinase in soleus muscle from GK rats. Exercise training (1-day and 5-day swimming) in Wistar rats increased insulin-stimulated glucose transport, GLUT4 protein expression and glycogen content in skeletal muscle. Changes were also noted for insulin signal transduction. Protein expression of IR, IRS-2 and GLUT4, was increased after 1-day training, whereas, IRS-1 or AKT were not altered. After 5-day swim training IRS-2 protein level was restored to pre-training level. Swim training increased insulin signaling at the level of IR and IRS-1, PI-3 kinase and AKT. Insulin-stimulated IRS-2 associated PI 3-kinase activity was only increased after 1 -day swim training. In diabetic ob/ob mice, acute and chronic treatment with adenosine analog, 5-aminoimidazole-4-carboxamide ribnucleoside (AICAR), lowered blood glucose levels, normalized hyperglycemia, and ameliorated glucose intolerance in ob/ob mice. Despite these improvements, plasma free fatty acid and triglyceride levels were increased in ob/ob mice. Furthermore, insulin-stimulated PI 3-kinase activity and glucose transport in skeletal muscle from were not improved. However, AICAR-treatment increased GLUT4 and Hexokinase II protein expression in skeletal muscle and had a direct (in vitro) effect on glucose transport in isolated muscle from lean and ob/ob mice. In conclusion, oxidative muscle fibers have increased insulin-stimulated phosphorylation and activity of key proteins in the insulin-signaling cascade and this may contribute to fiber-type specific differences in insulin action. Insulin signaling defects in skeletal muscle from diabetic GK rats occur in a fiber-type specific manner. Restoration of glycemia in diabetic GK rats or ob/ob mice animals by either phlorizin or AICAR treatment improves glucose tolerance. However, this is not always accompanied by improved insulin signaling in skeletal muscle. Exercise training effectively increases signal transduction to glucose transport in skeletal muscle from Wistar rats. Finally exercise training is effective in improving glucose tolerance in diabetic animals.