The points of potential impact of islet cholesterol levels on insulin secretion are shown. Glucose enters the β cell via a glucose transporter (GLUT-2 in rodents), whereupon it is modified by GK in the rate-limiting step in glucose sensing. The subsequent glucose metabolism pathway results in closing of the ATP-sensitive potassium channel, membrane depolarization, calcium influx into the cell via the L-type calcium channel, and exocytosis of insulin-containing granules. Cholesterol is taken up in islets by the LDL receptor. ABCA1 regulates the efflux of cellular cholesterol, and in the absence of β cell ABCA1, cellular cholesterol content increases. LXR is a major transcriptional activator of ABCA1, and deletion of LXR results in a similar phenotype to that observed in the absence of β cell ABCA1. Elevated β cell cholesterol levels may impair insulin secretion by promoting the dimerization of nNOS, which downregulates GK, thus impairing glucose sensing. It is possible that cholesterol also inhibits distal steps in insulin exocytosis and that ABCA1 has other independent effects on insulin secretion. Cholesterol-lowering drugs such as pravastatin may reduce the incidence of diabetes, potentially by protecting the β cell from cholesterol overload. Rosiglitazone, a member of the thiazolidinediones, requires ABCA1 for part of its beneficial effect on β cell function, suggesting that targeted therapies that activate β cell ABCA1 may have favorable effects on T2D.