Role of High‐Density Lipoproteins in Cholesterol Homeostasis and Glycemic Control

N umerous human epidemiological studies have established unequivocally that a high plasma high-density lipoprotein cholesterol (HDL-C) level is inversely associated with the risk of developing atherosclerotic cardiovascular disease. This has led to the hypothesis that increasing HDL-C levels may reduce the risk of having a cardiovascular event. However, most therapies that increase plasma HDL-C levels have not reduced cardiovascular events when tested in largescale clinical outcome trials. Despite these discouraging results, there has been an upside suggesting that interventions that increase HDL-C levels are associated with significantly improved glycemic control in people with type 2 diabetes mellitus (T2DM). When this association is considered in light of outcomes from preclinical studies and small randomized clinical trials in which HDL-C levels were increased in patients with T2DM, as well as in vitro studies that have provided an insight into the molecular basis of the clinical findings, it follows that modulating the individual constituents of HDLs, which may or may not include increasing HDL-C levels, may be a potential therapeutic target for improving glycemic control in patients with diabetes mellitus. This review outlines what is known about the antidiabetic properties of HDLs and the main HDL apolipoprotein, apoA-I. Insights into the mechanistic basis of these properties, and how they are regulated by intracellular and plasma cholesterol levels, is also discussed in the context of the 2 main forms of diabetes mellitus: T2DM, in which insulin resistance leads to pancreatic b-cell compensation and increased insulin secretion that eventually culminates in b-cell exhaustion and complete loss of function; and type 1 diabetes mellitus (T1DM), which is characterized by selective autoimmune bcell destruction.