ENPP1 gene, insulin resistance and related clinical outcomes

Purpose of review Insulin resitance plays a significant role in both morbidity and mortality of the general population. Understanding the molecular mechanisms of insulin resistance would help the identification of at-risk individuals in the presymptomatic stage, and the discovery of novel and more effective treatments. The transmemebrane glycoprotein ectonucleotide pyrophosphates phosphodiesterse 1 (ENPP1) inhibits insulin receptor signalling and has recently emerged as a key player in the development of insulin resistance. This review will summarize data available on the relationship between ENPP1 and insulin resistance. Recent findings Overexpression of ENPP1 in insulin target tissues is an early, intrinsic defect observed in human insulin resitance. A missense ENPP1 single nucleotide polymorphism, K121Q, has been recently described with the Q121 variant being a stronger inhibitor than K121 of insulin receptor function. In addition, the Q121 variant has been repeatedly associated with insulin resitance and related abnormalities including body weight changes, type 2 diabetes and macrovascular complications, thus suggesting a pleiotropic role of the ENPP1 gene on several metabolic abnormalities. Summary A deep undestanding of ENPP1 mode of action and the mechanisms regulating its expression and function are likely to provide new tools for early identification and treatments of patients at risk for the devastating clinical outcomes related to insulin resistance.