Effects of free fatty acids (FFA) on glucose metabolism: Significance for insulin resistance and type 2 diabetes

Most obese individuals have elevated plasma levels of free fatty acids (FFA) which are known to cause peripheral (muscle) insulin resistance. They do this by inhibiting insulin-stimulated glucose uptake and glycogen synthesis. The mechanism involves intra-myocellular accumulation of diacylglycerol and activation of protein kinase C. HAS also cause hepatic insulin resistance. They do this by inhibiting insulin-mediated suppression of glycogenolysis. On the other hand, HAS support between 30 and 50%of lbasal insulin secretion and potentiate glucose-stimulated insulin secretion. The insulin stimulatory action of HAS is responsible for the fact that the vast majority (similar to80%) of obese insulin resistant people do not develop type 2 diabetes. They are able to compensate for their FFA mediated insulin resistance with increased FFA mediated insulin secretion. Individuals who are unable to do this (probably for genetic reasons) eventually develop type 2 diabetes. FFAs have recently been shown to activate the IkappaB/NFkappaB pathway which is involved in many inflammatory processes. Thus, elevated plasma levels of HAS are not only a major cause Or of insulin resistance in skeletal muscle and liver but may, in addition, play a role in the pathogenesis of coronary artery disease.