Oxidative stress may be a causative factor in the development of insulin resistance. Insulin resistance is detrimental because it is associated with Western lifestyle diseases including obesity. Obesity is associated with low levels of circulating antioxidants which has lead some nutritionists to speculate that oxidative stress depletes the body of antioxidants and this in turn causes cellular changes to the insulin receptor that induces insulin resistance. The source of the oxidative stress may be excessive production of free fatty acids, a likely product of the de novo lipogenesis pathway that can be activated by fructose in the liver. The increase oxidation of fatty acids in skeletal muscle and peripheral tissue, as well as the liver, may increase the production of superoxide radicals through overstimulation of the electron transport chain. As a result of this excessive production of superoxide radicals, the cell reduces the sensitivity of the insulin receptors to prevent further uptake of energy to the cell in order to limit oxidative stress.
If oxidative stress is a causative factor in the development of insulin resistance, it might be expected that supplementation with antioxidant nutrients would be effective at reversing this effect. And this is generally what has been shown in the nutritional literature. Vitamin E is one such antioxidant that has been investigated for its ability to improve insulin sensitivity and improve oxidative stress. For example, in one study1, diabetic subjects were administered 800 iu per day of D-alpha tocopherol or a placebo for 3 months. Plasma lipid peroxides decreased by 27 % in the treatment group when compared to the placebo group, which was correlated with the vitamin E plasma levels. Fasting glucose, and fasting insulin concentrations also decrease relative to the placebo. The vitamin E was also able to decrease the levels of plasma alanine transferase (ALT), an enzyme associated with the poor liver function that might result from non-alcoholic fatty liver, one of the metabolic conditions associated with insulin resistance.
Vitamin E therefore appears able to improve insulin sensitivity in diabetic human subjects. And this is associated with a reduction in oxidative stress and reductions in markers for liver damage. Interestingly after 3 months of this study, the authors increased the vitamin E dose to 1200 iu per day and this attenuated the insulin sensitising effects such that no improvements over baseline were seen. This suggests either that the beneficial effects of vitamin E are transient, or that the very high 1200 iu per day dose may have actually had pro-oxidant effects. The fact that lipid peroxidation levels remained low and close to their 3 month levels (27 % of baseline at 3 months and 29 % of baseline at 6 months), however argues against a pro-oxidant effect for the vitamin E. It is therefore unclear as to why the benefits of vitamin E diminished after the 3 month period. However, despite the increase in vitamin E concentration in the final three months, circulating levels did not increase, suggesting that saturation of tissues had occurred.
Tocopherol does have other non-antioxidant roles that may explain also its effects on the insulin system, For example, vitamin E is a known inhibitor of protein kinase C, an intracellular signal molecule. Protein kinase C when activated experimentally, for example by phorbol esters, desensitises the insulin receptor to insulin by phosphorylating serine or threonine residues on the receptor and thus changing its conformity. This process decreases the phosphorylation of tyrosine residues in the receptor which is required for its signal transduction effects. By inhibiting protein kinase C, tocopherols may therefore reduce this inhibitory effect. The mechanism by which this occurs is not fully understood but tocopherols accelerate diacylglycerol kinase activity, and this enzyme is able to degrade diacylglycerol, itself an allosteric activator of protein kinase C. Tocopherols in the cell membrane may also be able to change the curvature of the membrane and this may decrease the activity of protein kinase C and diacylglycerol.
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