Plasma free fatty acids are raised in cases of obesity, and this may occur for a number of reasons. However, the cause and effect are not fully understood, and it is not clear if the raised levels of free fatty acids cause obesity, or are a consequence of it. Larger stores of adipose tissue may cause plasma free fatty acids to rise because there is a larger reservoir for release to the circulation. Another factor to consider is that clearance of free fatty acids may be impaired in cases of obesity, for example via a reduced oxidation of free fatty acids in skeletal muscle. Experiments that have infused free fatty acids into the blood of animals and humans have shown that insulin resistance develops within a short time of around 2 hours, and then disappears after around 4 hours following cessation of infusion. Such effects have been witnesses in healthy nondiabetic individuals. Because insulin causes glucose uptake most readily into skeletal muscle, it follows that free fatty acids induced insulin resistance should be greatest in skeletal muscle.
The raised levels of free fatty acids observed in obese individuals may be able to inhibit the normal suppression of hepatic glucose production. In other words, when insulin resistance occurs due to raised levels of free fatty acids, the normal inhibition of the gluconeogenesis pathway that occurs under conditions of high insulin levels, does not occur. It follows therefore that long term elevations in free fatty acids stimulate gluconeogenesis and this raises hepatic production of glucose from non-glucose sources such as amino acids from skeletal muscle, producing a pronounced catabolic effect in muscle tissue as well as raised blood glucose levels. Artificially lowering free fatty acids in obese individuals causes reduction in insulin resistance that may be between 25 to 50 % in the short term. The insulin sensitising effects of some drugs may be explained by their ability to lower plasma levels of free fatty acids. Thiazolidinediones for example improve insulin sensitivity and concomitantly increase free fatty acid oxidation.
The ability to stimulate the oxidation of free fatty acids also explains the insulin sensitising effects of exercise. Exercise may be potentially beneficial against insulin resistance because it can cause the oxidation of intramyocellular and intrahepatic lipids such as triglycerides, diacylglycerol and long chain acyl CoAs. Evidence suggests that high levels of free fatty acids cause increased accumulation of lipids and lipid metabolites intracellularly in muscle and hepatic tissue, and that these have the potential to interfere with the insulin signal cascade. Diacylglycerol is for example an potent activator of protein kinase C, which may in turn be able to induce insulin resistance through alterations to tyrosine residues on the receptor. By decreasing plasma free fatty acids and also causing the oxidation of intramyocellular and intrahepatic lipids, exercise may increase insulin sensitivity, that is to say it may reverse insulin resistance in hepatic and muscle tissue.
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