Lipotoxicité et insulinorésistance

Abstract

Dysregulation of free fatty acids (FFA) metabolism is a key event responsible for etiology of insulin resistance and type 2 diabetes. According to the glucose-fatty acid cycle described by Randle and coll in the early sixties, preferential oxidation of FFA compared to glucose plays a major role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. However, beside the glucose-fatty acid cycle, other mechanisms are now described to explain molecular basis of insulin resistance. Recent studies have suggested that local accumulation of fat metabolites such as ceramides, diacylglycerol or acyl-CoA, inside skeletal muscle and liver may activate a serine kinase cascade -involving c-Jun N-terminal kinase, nuclear factor-kappaB, protein kinase C- leading to defects in insulin signaling and glucose transport. Inflammation and oxidative stress are also potent mechanisms wich could lead to insulin-resistance state. Finally, modulation of transcription by FFA through their binding to peroxisome proliferators activated receptors could also participate to impaired glucose metabolism.