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.
Highlights
There is accumulating experimental and clinical evidence that High-density lipoprotein (HDL) particles can control glucose metabolism via a variety of mechanisms (Drew et al, 2012; von Eckardstein and Widmann, 2014)
We have shown that impairment of glucosestimulated insulin secretion induced by oxidized low-density lipoprotein (LDL) can be countered by native HDL (50μg/mL) treatment (Drew et al, 2009)
We have previously shown that acute reconstituted HDL (rHDL) infusion can reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM) (Drew et al, 2009)
Summary
There is accumulating experimental and clinical evidence that HDL particles can control glucose metabolism via a variety of mechanisms (Drew et al, 2012; von Eckardstein and Widmann, 2014). At a mechanistic level HDL particles can alter multiple aspects of glucose metabolism These include insulin secretion from pancreatic beta cells, and both insulin-dependent and insulin-independent glucose uptake and utilization in tissues. A recent Mendelian randomization study showed that genetically reduced HDL cholesterol does not associate with increased risk of T2DM (Haase et al, 2015). While this may reflect that the observational association is due to confounding and/or reverse causation, consideration must be given to the fact that HDL cholesterol, while clinically accessible, does not accurately reflect HDL function and may not be the best instrumental variable to test. Mechanistic and intervention studies are uncovering links between HDL and glucose metabolism, which may have physiological and therapeutic relevance
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