High-density lipoprotein (HDL) cholesterol levels are both reduced in association with obesity, diabetes and cardiovascular disease and predict adverse outcome. While the principal mechanism linking HDL cholesterol to outcome had been previously associated with the ability of HDL particles to remove cholesterol from the body via reverse cholesterol transport, it is now evident that HDL has multiple functions which may contribute benefit.
HDL and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms.1, 2 The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion1 and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM).3 HDL may mediate effects on glucose metabolism through actions in multiple organs (e.g. pancreas, skeletal muscle, heart, adipose, liver and brain) by three distinct mechanisms:
i) Insulin secretion from pancreatic beta cells
ii) Insulin-independent glucose uptake
iii) Insulin sensitivity
The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia.
This presentation will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies.