Is Oxidative Stress The Maid Driver of Insulin Resistance?

Obesity, cardiovascular disease and type 2 diabetes are all aetiologically linked through the metabolic syndrome. The observation that all three diseases are associated with oxidative stress, has lead some to speculate that oxidative stress is the causative factor in metabolic syndrome. In fact evidence suggests that free radicals and oxidative stress are indeed a causative factor in insulin resistance and the development of insulin resistance then causes the development of secondary diseases characterised by the metabolic syndrome including cardiovascular disease, obesity and type 2 diabetes. Since Denham Harman first postulated about the role of oxidative stress in ageing and disease, many studies have confirmed the link between high levels of oxidative stress and disease and the aging process. It is not known what causes the generation of the oxidative stress that leads to the development of insulin resistance, but stress, poor diet, recreational drugs both legal and illegal as well as pollution may play a role.

However, adipocytes may generate free radicals through exposure to excessive energy. As energy, particularly in the form of free fatty acids and glucose, accumulates in the adipocytes, the energy pathways of the cell overproduce acetyl CoA and this in turn increases production of energy donors such as reduced NAD (NADH). As the electron donors accumulate, they increase the hydrogen ion membrane potential in the mitochondria, and this inhibits the flux of electrons down the electron transport chain. Inhibition of complex III of the electron transport chain increases the half life of the free radical intermediates of coenzyme Q and this results in superoxide generation. As superoxide accumulates it leads to the formation of oxidative stress. Over time, the generation of superoxide radicals would deplete the body of cellular antioxidants, which may explain the association between obesity and low antioxidant status. This theory also explains nicely why animals on reduced energy intakes have longer lifespans.

Accumulation of free fatty acids in adipocytes may also reduce the translocation of glucose transporters (GLUT4) to the cell membrane surface and this may inhibits the efficient uptake of glucose to the cells, causing insulin resistance. This process may be a reaction by the cell to prevent further uptake of energy in order to limit the production of free radicals. Insulin resistance can therefore be thought of, if this theory is correct, as a compensatory mechanism to prevent the cellular generation of oxidative stress. Refined carbohydrates and fructose may therefore be a source of free radical generation as they cause an overload of energy in the blood following consumption. Whole grains prevent this as the fibre content slows the absorption of the glucose and other sugars. Further, beta cells of the pancreas may be particularly susceptible to oxidative stress as they have low levels of endogenous antioxidants such as catalase, superoxide dismutase and glutathione peroxidase.

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