Free fatty acids and pathogenesis of type 2 diabetes mellitus

Plasma free fatty acids (FFA) might mediate the insulin resistance and impa ired glucose tolerance associated with central obesity. Central adipocytes are resistant to insulin, suggesting that FFA delivery to the liver via the portal vein is increased when visceral triglyceride (TG) stores are increa sed. Muscle insulin resistance might result from the 'Randle' mechanism, fr om downregulation of the insulin signaling pathway, and/or reduced access o f insulin to skeletal muscle owing to changes in blood flow or insulin tran sport across capillary endothelium. TG storage within muscle might interfer e with insulin action, but a causal relationship between myocellular lipid and glucose disposal remains to be demonstrated. Basal levels of FFA appear to be permissive for insulin secretion; however elevated FFA have a minor effect on insulin secretion in vivo. In humans, prolonged hyperlipidemia en genders an insulin response matched to the degree of insulin resistance, le aving open the question of whether lipotoxicity of islet cells contributes to glucose intolerance and diabetes in humans. Elevated portal FFA might ac count for overproduction of Liver glucose output with visceral adiposity. A dditionally, portal FFA might reduce hepatic extraction of insulin, diminis hing the necessity of increased beta -cell response to compensate for FFA-d riven insulin resistance. Overall, effects of FFA can lead to several compo nents of the insulin resistance syndrome and risk for diabetes. Reduction i n FFA might be the appropriate therapy for these disorders.