Free fatty acids and pathogenesis of type 2 diabetes mellitus.
Plasma free fatty acids (FFA) might mediate the insulin resistance and impaired 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 increased. Muscle insulin resistance might result from the 'Randle' mechanism, from downregulation of the insulin signaling pathway, and/or reduced access of insulin to skeletal muscle owing to changes in blood flow or insulin transport across capillary endothelium. TG storage within muscle might interfere 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 engenders an insulin response matched to the degree of insulin resistance, leaving open the question of whether lipotoxicity of islet cells contributes to glucose intolerance and diabetes in humans. Elevated portal FFA might account for overproduction of liver glucose output with visceral adiposity. Additionally, portal FFA might reduce hepatic extraction of insulin, diminishing the necessity of increased beta-cell response to compensate for FFA-driven insulin resistance. Overall, effects of FFA can lead to several components of the insulin resistance syndrome and risk for diabetes. Reduction in FFA might be the appropriate therapy for these disorders.
Bergman
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Diabetes Research Center, Keck School of Medicine, University of Southern California, 1333 San Pablo Street, Los Angeles, CA 90033, USA. rbergman@usc.edu
Ader
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D000818:Animals; D003920:Diabetes Mellitus / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D005230:Fatty Acids, Nonesterified / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000502:physiology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D009765:Obesity
D005230:Fatty Acids, Nonesterified; D007328:Insulin