Insulin resistance is a state whereby the insulin receptor become insensitive to the effects of insulin. As a result blood glucose levels remain elevated even in the fasted state. The presence of glucose in the blood postprandially, when normally levels would fall, results in the pancreas releasing more insulin and this causes elevations in fasting insulin. The higher than normal levels of insulin in turn cause metabolic dysfunction, particularly the accumulation of body fat. The exact cause of insulin resistance is not known, but several hypotheses have been suggested to account for the dysfunction of the insulin receptor that may characterise declines in insulin sensitivity. One hypothesis that is supported by a large body of evidence is the oxidative stress theory of insulin resistance. This theory suggests that free radical generation, in the absence of adequate antioxidant defences, leads to conformational changes in the insulin receptor and its signal pathway proteins and this then leads to a failure of the normal signal transduction route.
Free radicals are generated as a natural consequence of metabolic activity in all living organisms. However, cells are protected from the damaging effects of free radals by antioxidants. Many antioxidants are endogenously synthesised enzymes such as superoxide dismutase and glutathione peroxidase. Generally endogenously synthesised antioxidants require mineral cofactors to function. In the case of superoxide dismutate this can be manganese or zinc and copper, and in the case of glutathione peroxidase, selenium. Some vitamins such as vitamin C and vitamin E also act as antioxidants. Many exogenous substances, usually components of the diet also provide antioxidant defences. Antioxidants from plants are particularly well studies and include polyphenols such as terpenes, stilbenes, chalcones and flavonoids. Carotenoids are a separate group of plant antioxidants. Oxidative stress only develops if the rate of generation of free radicals overwhelms the antioxidant defences made up from these groups of antioxidants.
Oxidative stress is implicated as a causative factor in a number of diseases including cardiovascular disease, cancer and obesity. The observation that antioxidants are able to improve insulin sensitivity supports the contention that oxidative stress is a causative factor in the development of the insulin resistant state. One of the complications of studying the effects of free radicals on insulin signalling is that some free radicals may act as important signal molecules in cells. Hydrogen peroxide for example, is known to mimic insulin and can cause cellular changes normally associated with insulin binding to its receptor. That the activity of insulin is perpetuated through the generation of free radicals such as hydrogen peroxide acting as intracellular signal molecules has been suggested. The possibility arises therefore that excessive generation of intracellular free radical signal molecules, such as hydrogen peroxide, may negatively feedback to inhibit, rather than to stimulate the action of insulin.
If oxidative stress is implicated in the aetiology of metabolic syndrome, then low quality diets may play a considerable role in modulating insulin sensitivity. As mentioned the endogenous antioxidant enzymes superoxide dismutase and glutathione peroxidase are both reliant on inorganic minerals, that must come from the diet, for their function. Further free radicals can form as a direct result of inflammation and so diets that induce inflammation, such as those with an imbalance of omega-3 and omega-6 fats, may be a cause of insulin resistance. Plant foods are abundant in antioxidant chemicals and diets high in plant foods are protective of disease, perhaps for this reason. In contrast, traditional diets such as the Mediterranean diet are high in plant foods containing antioxidants, with olive oil being particularly well researched in this regard. Such traditional diets are associated with improved insulin sensitivity in those that regularly consume them and this explains their protective effects against obesity.
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