Insulin resistance is thought to be a primary contributory factor in the development of obesity. Evidence supports the contention that increased accumulation of free fatty acids in tissues, as typified by elevated blood levels, are a significant contributory cause of insulin resistance. Acute elevations of free fatty acids in experimental animals and humans causes a reduction in the uptake of glucose. The development of reduced insulin sensitivity occurs roughly 2 hours following elevations of free fatty acids in the blood and insulin sensitivity improves approximately 4 hours following lowering of free fatty acids in the blood. The effects is dose dependent, and the insulin resistance occurs mainly in skeletal muscle, the main target tissue for insulin stimulated glucose uptake. Those with elevated levels of free fatty acids therefore have decreased glucose disposal in their skeletal muscle, and this also raises levels of glucose. The insulin desensitising effects of fatty acid may however be a natural feedback mechanism.
Biochemically that elevated levels of free fatty acids inhibit glucose uptake to the cell is to be expected. As levels of free fatty acids rise they can become a useful source of energy that decreases the requirement for glucose as a substrate. Randle originally proposed that the free fatty acids levels decreased glucose uptake through inhibition of the oxidation rates of carbohydrate in muscle, in preference for the free fatty acids. However, it is now thought that elevated levels of free fatty acids inhibit the uptake of glucose at the level of the transport into the cell through inhibition of the glucose transporter or the insulin signal cascade. Current evidence suggests that it is an interference with the insulin signal cascade that decreases glucose uptake in the presence of elevated levels of free fatty acids. This hypothesis is based on the finding that elevated levels of free fatty acids increase intracellular lipid accumulation and increase fatty acid reesterification metabolites which may interfere with insulin signalling.
When free fatty acids are re-esterified to form triglycerides in cells, levels of diacylglycerol (DAG) increase. In turn DAG is able to activate an intracellular signal molecule called protein kinase C. Protein kinase C can decrease insulin sensitivity because it inhibits the phosphorylation of the insulin receptor, which is required for the correct function of the receptor. This may be a normal feedback mechanism to prevent excess glucose uptake to the cell in the presence of high levels of free fatty acids. The lowering of free fatty acids may therefore explain the insulin sensitising effects of exercise. Exercise is able to lower plasma levels of free fatty acids as increased lipid oxidation rates consuming the fatty acids as a substrate for energy production, thus lowering cellular levels of DAG. That levels of free fatty acids are permanently elevated in obese individuals may explain the low insulin sensitivities observed in such cases, and the free fatty acid lowering effects of certain glucose sensitising pharmaceuticals are well reported.
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