Can Oxidative Stress Cause Insulin Resistance

The question of precedence between hyperinsulinemia and oxidative stress into the subsequent development of diabetes remains unanswered (64). The studies mentioned above suggest that at least the secondary hyperinsulinemia could plausibly precede or cause increased free radical production and the resulting oxidative stress. Further studies are necessary to address whether oxidative stress, as a result of hyperinsulinemia-mediated increased free radical production, could precede insulin resistance and lead to the onset of diabetes. To date there is no evidence that primary insulin resistance is linked to oxidative effects. The following sections analyze two emerging lines of study in this direction.

1. Oxidative Stress, Antioxidants, and Insulin Resistance In Vivo There is little evidence for a role of antioxidant therapy in the prevention of insulin resistance and type 2 diabetes. Serum of individuals with type 2 diabe tes have a lower vitamin E level and a higher GSH/GSSG ratio compared with control subjects (88). Individuals with type 2 diabetes who received vitamin E supplementation had improved metabolic control, as indicated by the significant drop in circulating levels of glycosylated hemoglobin (89). In a small randomized trial with humans with or without type 2 diabetes, vitamin E supplementation reduced oxidative stress and improved insulin action (64,88), verifying an important role for antioxidant therapy in diabetes. This study involved the use of a euglycemic hyperinsulinemic clamp to study the effects of vitamin E supplementation on insulin sensitivity (90). The results showed a significant gain in insulin-mediated nonoxidative glucose disposal after supplementation of 900 mg vitamin E (90). In addition, the vitamin E supplementation significantly increased plasma vitamin E levels and significantly reduced GSH/GSSG ratios in all subjects (90). It was proposed that the mechanism by which vitamin E improves insulin responsiveness in individuals with and without diabetes was related to its role as an antioxidant (88). The hypothesis was put forward that increased lipid peroxidation, as a result of increased free radical-induced oxidative stress or a reduction in the antioxidant capacity of the cell, could cause changes in the fluidity of the membrane; this in turn would puiportedly lower glucose uptake (91). The ability of an antioxidant to quench free radicals and reduce lipid peroxidation could presumably provide protection from changes to membrane fluidity and restore normal glucose transporter function.

The first prospective population study undertaken to address the role of free radical stress and antioxidants in relation to the incidence of diabetes examined whether low vitamin E concentrations are a risk factor for the incidence of type 2 diabetes (92). The authors computed the levels of plasma vitamin E and the incidence of developing diabetes over a 4-year period in 944 men aged 42-60 who were determined not to have diabetes at baseline examination (92). Type 2 diabetes was defined by either a fasting blood glucose concentration of S:6.7 mM, a blood glucose concentration > 10.0 mM 2 h after a glucose load, or by a clinical diagnosis of diabetes with either dietary, oral, or insulin treatments. Forty-five men developed diabetes over the 4-year follow-up period (92). However, these 45 men also had a raised baseline body mass index, elevated blood glucose and serum fructosamine concentrations, a higher ratio of saturated fatty acids to the sum of monounsa-turated and polyunsaturated fatty acids, and a higher serum triglyceride concentration (92). From the multivariate logistic regression model used in this study, it was found that the baseline body mass index was the strongest predictor of diabetes. Other factors with significant associations to an excess risk of diabetes included low plasma vitamin E concentrations, a high ratio of saturated to other fatty acids in serum, and a high socioeconomic status (92).

From this multivariate logistic regression model, a 3.9-fold risk of developing diabetes was associated with a low lipid standardized plasma vitamin E concentration (below median) (92). In addition, another model was used whereby lipid standardized vitamin E concentrations were replaced by unstandardized vitamin E concentrations when other risk factors such as serum low-density-lipoprotein cholesterol and triglyceride concentrations were taken as the strongest predictors of diabetes. From this model, a decrease of 1 |imol/L of uncategorized vitamin E concentration was associated with an increment of 22% in the risk of developing diabetes (92). Hence, a significant relationship was proposed to exist between low vitamin E concentrations and an increased risk of diabetes. Clinical trials are needed to support the effect of antioxidants in the prevention of diabetes. It has been suggested that these trials should address the need for a "free radical initiative" (93) to understand how free radicals could affect the intrinsic mechanisms of diabetes (65). Also, trials are necessary to confirm a role of vitamin E, or other antioxidants, in the prevention of type 2 diabetes (92).

2. Oxidative Stress and Insulin Resistance In Vitro

In vitro, insulin resistance can be induced by prolonged insulin treatment, exposure of cells to high glucose concentrations, or by the preexposure of cells to glucosamine (Fig. 5). Insulin resistance at the level of glucose transport can result from various signaling defects as previously mentioned, including alterations in insulin receptor function, depletion of the GLUT4 transporter pool, and alterations in the postreceptor signaling pathway (94).

Prolonged insulin treatment of 3T3-L1 adipocytes induced an insulin-resistant state as a result of changes in the insulin signal transduction cascade (95). Treatment of 3T3-L1 adipocytes with 500 nM insulin for 24 h increased basal glucose transport and led to an insulin-resistant state for this transport (5,96,97). This treatment did not modify the insulin receptor or levels of GLUT4; however, it prevented GLUT4 translocation in response to acute insulin stimulation (95). Prolonged insulin treatment also induced a decrease in the level of IRS-1 expression and phosphorylation and a reduced ability of insulin to stimulate PI 3-kinase and MAP kinase (98). Thus, insulin resistance induced by prolonged insulin treatment of 3T3-L1 adipocytes is associated with multiple signaling defects, including defects at the level of IRS-1, PI 3-kinase, MAP kinase, and impaired GLUT4 translocation (98). These defects are similar to those observed in the hyperinsulinemic states of obese humans and rodents (98), validating this insulin-resistant model as an effective approach to study alterations of the insulin signaling pathway and insulin resistance.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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