1. Oxidative Stress in Skeletal Muscle Diabetes This study was initiated to more rigorously examine insulin actions in the context of heightened state of oxidative stress in skeletal muscle of Goto-Kakizaki (GK) diabetic rats. Insulin-stimulated glucose utilization index in muscles of animals receiving vehicle or χ-lipoic acid Abbreviations: WG, white gastrocnemius; RG, red gastrocnemius; SO, soleus; EDL, extensor digitorum longus; χ-LA, χ-lipoic acid; GK, Cont, Control; Goto–Kakizaki; GK-χ-LA, Goto–Kakizaki treated with χ-lipoic acid. * Significantly different from corresponding control values at P b0.05. ** Significantly different from corresponding vehicle-treated diabetic values at P ‹0.05. In the following four graphs: Animals were subjected to daily treatment of χ-lipoic acid at a dose of (100 mg/kg bw, i.p.). 30 days later, a ventral midline neck incision of the experimental animals was made with concomitant catheterization of the left carotid artery and right jugular vein for blood sampling and infusion, respectively. Three to five days after surgery, circulating metabolites were studied under basal and euglycemic-hyperinsulinemic clamp conditions. Values obtained during the last thirty minutes of the euglycemic clamp are expressed as the mean ± S.E.M. of at least 6 animals/group. Treatment with χ-LA for 30 days effectively reduced circulating concentrations of these metabolites Data suggests: 1)Insulin resistance in GK rats occurs at the hepatic and skeletal muscle levels 2) Muscle cell glucose transport exhibited a blunted response to insulin and it is associated with a major defect in key molecules of both GLUT-4 trafficking and insulin signaling pathways 3) Skeletal muscle insulin resistance in GK rats appears to be of genetic origin and not merely related to a paracrine or autocrine effect, since this is also observed in cultured myoblasts over several passages and finally heightened state of oxidative stress may mediate the development of insulin resistance during diabetes. Reference: Bitar, et al., (2005). Oxidative stress- mediated alterations in glucose dynamics in a genetic animal model of type II diabetes. Life Sciences, 77(20), pp.2552-2573. [ 3 H]-2-DG up take in cultured myoblasts derived from control and diabetic rats Wistar Control Rats; GK Diabetic Rats *Significantly different from corresponding control values at P‹0.005 Serum starved myoblast were washed three times with Krebs-Ringer HEPES buffer, followed by 30 min incubation with the indicated concentrations of insulin. Each point represents the mean of triplicate determinations and is corrected for the non-specific association of [ 3 H]-2-DG uptake with the cells. Data from a representative experiment are shown, expressed as a fold increase relative to basel. The experiment was repeated four times with a similar result. The data revealed that insulin-mediated glucose uptake was impaired in myoblasts of GK rats when compared with corresponding Wistar control values Insulin resistance, characterized by an inexorable decline in skeletal muscle glucose utilization and/or an excessive hepatic glucose production, constitutes a major pathogenic importance in a cluster of clinical disorders including diabetes mellitus, hypertension, dyslipidemia, central obesity and coronary artery disease.” * Significantly different from corresponding control values at P‹0.05 ** Significantly different from corresponding vehicle-treated diabetic values at P‹0.05 Effects of χ-lipoic acid on circulating metabolites under basal and euglycemic- hyperinsulinemic clamp condition with Glucose (mg/100 ml) treatment *Significantly different from corresponding control values at P‹0.05 ** Significantly different from corresponding vehicle-treated diabeteic values at P‹0.05 * Significantly different from corresponding control values at P‹0.05 ** Significantly different from corresponding vehicle-treated diabeteic values at P‹0.05 † Significantly different from basal values at P‹0.05 FFA clamp level was significantly reduced from baseline in response to insulin in control ↓ 36% but not in GK rats Effects of χ-lipoic acid on circulating metabolites under basal and euglycemic- hyperinsulinemic clamp conditions with FFA (mmol/l) treatment Insulin-Stimulated glucose transport was reduced in RG, SOL, EDL and to a lesser extent in WG muscle of GK-diabetic rats. An institution of χ-LA treatment partially prevented the diabetes-induced decrease in insulin-mediated glucose utilization in all of the investigated muscle. Mean Glucose (mg/100 ml) Mean Insulin (µU/ml) Mean FFA (mmol/l) Mean Glucose Utilization (ng/mg/min)