Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance.

The two major elements in the pathogenesis of type 2 diabetes are insulin resistance and β-cell failure. The biochemical mechanisms underlying these two phenomena are incompletely understood. The plasma FFA level is commonly elevated in type 2 diabetes patients (1). Furthermore, previous studies have presented evidence suggesting that FFA released from visceral fat is one of the primary culprits in the pathogenesis of insulin resistance, which is a prerequisite for the development of type 2 diabetes (2). In addition to insulin resistance, relative insulin deficiency is necessary for the development of type 2 diabetes. In this step of β-cell failure, FFA has also been reported to play an important role as a potential effector of pancreatic β-cell dysfunction or death (lipotoxicity) (3, 4). Thus, chronically elevated FFA may contribute to both essential steps in the development of type 2 diabetes, and it represents one of the fundamental etiological mechanisms underlying the complicated and diverse manifestations of type 2 diabetes, obesity, and metabolic syndrome. Despite strong epidemiological and in vivo data suggesting a relationship between FFA and type 2 diabetes, a detailed molecular and cellular mechanism underlying insulin resistance has not been clearly elucidated. Recent studies have dissected the metabolic pathway to unravel the intracellular mechanism of insulin resistance by FFA. The results of such studies have implicated diacylglycerol (DAG), ceramide, triglyceride (TG), or other metabolites arising from incomplete β-oxidation of fatty acids as the final effector molecules inducing insulin resistance or lipotoxicity (5–8). However, it remains controversial which metabolites produced from FFA are directly responsible for the insulin resistance or β-cell failure by FFA. We have studied the mechanism of lipoapoptosis using various pharmacological inhibitors (9). In this investigation, we employed the same pharmacological strategy to determine the mechanism of insulin resistance by FFA, and we found evidence favoring the role of LPC produced from FFA in insulin resistance in vitro and in vivo.