Metabolic Effects ofγ-Linolenic Acid–α-Lipoic Acid Conjugate in Streptozotocin Diabetic Rats

Abstract

Data suggesting the involvement of increased oxidative stress in the pathophysiology of diabetes has raised interest in the potential therapeutic benefit of antioxidants. Although beneficial metabolic effects of antioxidant supplementation have been suggested, an antioxidant mode of action, particularly in skeletal muscle, has not been documented. In the present study, we evaluate the metabolic effects of a gamma-linolenic acid-alpha-lipoic acid conjugate (GLA-LA) in streptozotocin-induced diabetic rats, and assess its potential mode of action by comparing its effects with equimolar administration of LA and GLA alone. Ten days of oral supplementation of 20 mg/kg body weight GLA-LA, but not LA or GLA alone, caused a mild reduction in fasting blood glucose concentration as compared with vehicle-treated diabetic rats (375 +/- 11 vs. 416 +/- 16 mg/dl, p = 0.03), with no change in fasting plasma insulin levels. A peripheral insulin-sensitizing effect could be observed with GLA-LA, LA, and GLA treatments, as demonstrated by a significant (p < 0.04) 23%, 13%, and 10% reduction, respectively, in the area under the glucose curve following an intravenous insulin tolerance test. This effect was associated with a 67% and 50% increase in GLUT4 protein content in the membranes of gastrocnemius muscle of GLA-LA and LA-treated animals, respectively; however, no change was observed with GLA treatment alone. Interestingly, both GLA-LA and LA treatments corrected a diabetes-related decrease in the gastrocnemius muscle low-molecular-weight reduced thiols content. These data demonstrate insulin-sensitizing properties of the GLA-LA conjugate by distinct mechanisms attributable to each of its components, which are associated with antioxidant effects.

Effect of inhibition of glutathione synthesis on insulin action: in vivo and in vitro studies using buthionine sulfoximine

“…Both basal and insulinstimulated glucose uptake values were not significantly different between the two groups. Accordingly, the protein content of the insulin-responsive glucose transporter GLUT4, previously shown to be reduced in gastrocnemius muscle membranes of diabetic rats [38,41], was not affected by BSO treatment (representative blot shown in Figure 3B). …”

“…Recent studies from several groups, including our own, have demonstrated that oxidative stress impairs the normal cellular response to insulin [30,31,33]. Decreased GSH levels were found in both 3T3-L1 adipocytes exposed to a H # O # -generating system [44], and also in blood and tissues of streptozotocin-induced diabetic rats [38], in which impaired peripheral insulin sensitivity was observed. These data established an association between decreased GSH content and impaired insulin response, raising the possibility that decreased GSH is causative in impairing insulin action.…”

“…In skeletal muscle of streptozotocin-induced diabetic rats, GLUT4 protein levels were decreased, which was associated with decreased GSH content [38,41]. Moreover, multiple regression analysis demonstrated skeletal muscle GSH content as an independent predictor for GLUT4 protein levels [38]. Furthermore, when skeletal muscle GSH content was increased by treating diabetic rats with lipoic acid, GLUT4 protein content was increased [38,41].…”

“…3T3-L1 adipocytes exposed for 18 h to micromolar H # O # concentrations exhibit decreased GLUT4 protein and mRNA expression [30]. In skeletal muscle of streptozotocin-induced diabetic rats, GLUT4 protein levels were decreased, which was associated with decreased GSH content [38,41]. Moreover, multiple regression analysis demonstrated skeletal muscle GSH content as an independent predictor for GLUT4 protein levels [38].…”

“…Whole blood, liver and muscle LMRTs were measured spectrophotometrically according to Ellman 's method [37], as previously described [38]. Liver GSH and GSSG were measured spectrophotometrically by the glutathione reductase recycling assay, following a method described by Anderson [39].…”