Streptozotocin Diabetic

There is ample evidence that markers of oxidative stress are increased in the most widely accepted rodent model of type 1 diabetes, the streptozotocin-diabetic rat. For example, plasma and liver lipid peroxides, as measured by the thiobarbituric acid reactive substances assay, are elevated in the streptozo-tocin-diabetic rat (35). In addition, recent evidence indicates that in this model of type 1 diabetes, sciatic nerve levels of reduced glutathione (GSH) are lower and the ratio of oxidized to reduced glutathione (GSSG/GSH) is elevated compared with tissue from normoglycemic control animals (36). Chronic treatment with the antioxidant lipoic acid brings about a nearly complete normalization of the GSH and GSSG/GSH profiles in sciatic nerve from the streptozotocin-diabetic rats and also significantly improves nerve blood flow and conduction velocity (36).

Plasma glucose is markedly elevated and insulin action on skeletal muscle glucose transport activity is substantially reduced in the streptozotocin-diabetic rat, possibly as a result of reduced muscle GLUT4 protein levels (25). Acutely, lipoic acid can cause a marked lowering of plasma glucose in these diabetic animals (25). Chronically, a 10-day treatment period of these diabetic animals with lipoic acid also results in a significant lowering of plasma glucose levels and causes profound increases in both skeletal muscle GLUT4 protein levels and insulin-stimulated glucose transport activity (25). Collectively, these results provide evidence that the beneficial metabolic effects of lipoic acid in this severely hyperglycemic diabetic animal model may be associated with an improvement in the oxidant/antioxidant status of the animal.

B. Obese Zucker Rat

Much less information regarding the oxidant/antioxidant status is presently available for the obese Zucker rat. It should be stressed that this animal model displays only mild fasting hyperglycemia, with more severe abnormalities observed when the animal is presented with a glucose load (27,37,38). Nevertheless, Nourooz-Zadeh (39) reported that the isoprostane 8-cpi-PGF2„, a marker of oxidative stress, is elevated in the plasma of the diabetic Zucker rat compared with lean controls. Interestingly, these elevated levels of oxidative stress are significantly reduced with antioxidant treatment, such as a-tocopherol (39). These results concerning oxidative stress in the diabetic Zucker rat are consistent with observations of human type 2 diabetes. During a euglycemic hyperinsulinemic clamp, a significant inverse relationship has been observed between insulin action on nonoxidative glucose disposal and plasma superoxide ion, and a significant positive relationship has been seen between insulin action on nonoxidative glucose disposal and plasma GSH/GSSG ratio in type 2 diabetic patients (40). Patients with impaired glucose tolerance (a prediabetic state) or overt type 2 diabetes have significantly reduced erythrocyte levels of the antioxidant enzymes catalase and superoxide dismutase and diminished plasma GSH (41). Decreased serum vitamin E content, a marker of impaired oxidant/antioxidant status, was recently reported to be associated with increased risk of developing type 2 diabetes in a Finnish population (42), and type 2 diabetic patients themselves display significantly reduced plasma vitamin E levels (43). Finally, plasma hydroperoxides, another marker of oxidative stress, are higher in subjects with type 2 diabetes compared with healthy control subjects and are significantly inversely con-elated with the degree of metabolic control (43).

The effectiveness of antioxidant interventions, particularly chronic treatment with lipoic acid, in ameliorating the metabolic abnormalities present in the obese Zucker rat has been demonstrated in a series of studies from our laboratory. The results of these studies are summarized below. In these studies, the obese Zucker rats were treated intraperitoneally with a racemic mixture (50% R- and 50% S-enantiomers) of lipoic acid for 10-12 days and were investigated after an overnight fast (food restricted to 4 g at 5 p.m. of the previous evening). As shown in Figure 1, the obese Zucker rat displays only mild hyperglycemia, and this slight elevation in plasma glucose is completely reversed with chronic lipoic acid treatment (30 mg/kg) (44,45). More striking is the marked hyperinsulinemia and dyslipidemia of the obese Zucker rat compared with the lean Zucker rat (44,45). Chronic lipoic acid treatment leads to significant reductions in both plasma insulin (—20%) and free fatty acids (—15%) (Fig. 1). It should be noted that these alterations due to the racemic mixture of lipoic acid are entirely due to the R-enantiomer, as treatment with the S-enantiomer actually exacerbates the hyperinsulinemia and has no significant effect in lowering plasma free fatty acids (45).

More recently, we have shown that glucose tolerance after a 1 -g/kg oral glucose feeding is improved by lipoic acid in a dose-dependent fashion (Fig.

Lean Control I I Obese Control MM Obese Lipoic Acid

Figure 1 Effect of chronic treatment of obese Zucker rats with lipoate on plasma glucose, insulin, and free fatty acids. Values are means ± SE. *p < 0.05 vs. obese vehicle-treated control; Hp < 0.05 vs. lean control. (From Ref. 44.)

Lean Control I I Obese Control MM Obese Lipoic Acid

Figure 1 Effect of chronic treatment of obese Zucker rats with lipoate on plasma glucose, insulin, and free fatty acids. Values are means ± SE. *p < 0.05 vs. obese vehicle-treated control; Hp < 0.05 vs. lean control. (From Ref. 44.)

Figure 2 Effect of chronic treatment of obese Zucker rats with lipoate on glucose and insulin responses to a 1 -g/kg oral glucose tolerance test. Values are means ± SE. *p < 0.05 vs. obese vehicle-treated control.

Time (min)

Figure 2 Effect of chronic treatment of obese Zucker rats with lipoate on glucose and insulin responses to a 1 -g/kg oral glucose tolerance test. Values are means ± SE. *p < 0.05 vs. obese vehicle-treated control.

2), with a significantly smaller area under the curve (AUC) of the glucose response in a group of obese animals treated for 10 days with 30 mg/kg lipoic acid compared with control (Fig. 3, left). Moreover, this improved glucose response was seen in the face of a reduced insulin response during the test (Fig. 2) and a smaller insulin AUC (Fig. 3, middle). The glucose-insulin index, the product of the glucose and insulin AUCs and an indirect index of in vivo insulin action, was significantly lower in the 30 mg/kg lipoic acid-treated obese group compared with the obese control group, implying that peripheral insulin action was enhanced by lipoic acid. Consistent with this finding was our observation that insulin-mediated glucose transport activity in both fast glycolytic muscle (m. epitrochlearis, Fig. 4) and slow oxidative muscle (m. soleus, Fig. 5) was improved in the 30 mg/kg lipoic acid-treated obese group compared with the obese control group.

To determine the functional relevance of this improvement of insulinmediated glucose transport, we assessed the correlation between insulin-mediated glucose transport activity in either the epitrochlearis or the soleus and the glucose-insulin index in obese animals treated with either vehicle, 10 mg/ kg lipoic acid, or 30 mg/kg lipoic acid (Fig. 6). The correlation coefficients between the glucose-insulin index and insulin action on glucose transport in the epitrochlearis (r = —0.598, p < 0.05) and in the soleus (/- = —0.654, p < 0.05) were statistically significant, indicating that the improved insulin action on muscle glucose transport was, at least in part, responsible for the improvement in whole-body glucose tolerance observed after lipoic acid treatment.

Because the whole homogenate level of GLUT4 protein in skeletal muscle from lipoic acid-treated obese Zucker rats is not significantly elevated compared with obese controls (44), this would imply that lipoic acid enhances the ability of insulin to activate translocation of intracellular GLUT4 protein into the sarcolemmal membrane, a process that is defective in obese Zucker rats (8,31). This hypothesis, however, remains to be tested experimentally.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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