Apolipoprotein M and Sphingosine-1-Phosphate: A Potentially Antidiabetic Tandem Carried by HDL.

Abstract

The frequent finding of low HDL cholesterol in patients with type 2 diabetes (T2D) or at increased risk for T2D has been traditionally interpreted as the consequence of hypertriglyceridemia and hyperacylemia, which are caused by insulin resistance and hyperinsulinemia (1). However, several observations also point to antidiabetic actions of HDL (1,2). Post hoc analyses of randomized controlled trials showed that inhibitors of cholesteryl ester transfer protein, which increase HDL cholesterol by 25 to 100%, improve the glycemic control of subjects with diabetes and lower the incidence of diabetes in patients who are treated with statins (3). Infusion of artificial reconstituted HDL led to acute decreases in glucose levels and improved insulin sensitivity in subjects with diabetes (4). Mendelian randomization studies generated controversial data, with one study supporting and another disproving genetic causality of HDL for T2D (5,6). Data from genetic mouse models indicate that HDL secures both insulin production in pancreatic β-cells and insulin action in the periphery (2). The clinical exploitation of HDL in the prevention and management of diabetes—for example, the development of drugs that stimulate or mimic the antidiabetic effects of HDL or biomarkers that improve risk prediction—is hampered by the presence of hundreds of different proteins and lipid species in HDL, several of which show antidiabetic properties (7). In this issue of Diabetes , Kurano et al. (8) provide evidence that at least a part of HDL’s antidiabetic action involves apolipoprotein M (apoM) and its lipid ligand sphingosine-1-phosphate (S1P), two quantitatively minor components of HDL. S1P is the …