HDL and glucose metabolism: current evidence and therapeutic potential

Abstract

High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs (e.g., pancreas, skeletal muscle, heart, adipose, liver, 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 review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies.

Low apoA-I is associated with insulin resistance in patients with impaired glucose tolerance: a cross-sectional study

“…Increased insulin sensitivity that is mediated through high apoA-I levels favours the transport of glucose from the circulation into tissues and has potential clinical relevance in terms of reducing cardiovascular complications by removing excess glucose from the circulation and in providing adequate glucose to tissues for energy production, particularly in the context of cardiovascular events [50]. …”

FADS Gene Polymorphisms, Fatty Acid Desaturase Activities, and HDL-C in Type 2 Diabetes

“…Recent studies have implicated a role of raising HDL-C for the prevention and management of diabetes [2,3]. Adults with diabetes have heart disease-related mortality rates that are two to four times higher than those without diabetes [4].…”

Scavenging dicarbonyls with 5’-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance

“…Short term administration of reconstituted HDL into patients with T2D reduced fast glucose levels and improved glucose metabolism. In addition, HDL via its cholesterol efflux function reduces the fat deposition in the liver suggesting that the PPM effects on cholesterol efflux contributed to the improved insulin sensitivity [8,9]. Furthermore, studies have shown that apoAI promotes activation of AMPK in skeletal muscle and liver which increases fatty acid β-oxidation and glucose uptake [9,56].…”