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HDL and glucose metabolism: current evidence and therapeutic potential.

Siebel AL, Heywood SE, Kingwell BA - Front Pharmacol (2015)

Bottom Line: 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.This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies.

View Article: PubMed Central - PubMed

Affiliation: Metabolic and Vascular Physiology Laboratory, Baker IDI Heart and Diabetes Institute , Melbourne, VIC, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of the pathways activated by HDL in skeletal muscle that modulate glucose metabolism. Both human and rodent studies have demonstrated that HDL can increase glucose uptake through an ABCA1/AMPK-dependent mechanism (Drew et al., 2009). Chronically elevating HDL levels pharmacologically or via genetic approaches in mice increases Akt phosphorylation, suggesting activation of an additional signaling pathway (Lehti et al., 2013). There is also more recent evidence in mouse muscle cells showing that HDL can directly stimulate anaerobic glycolysis and glucose oxidation.
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Figure 1: Schematic diagram of the pathways activated by HDL in skeletal muscle that modulate glucose metabolism. Both human and rodent studies have demonstrated that HDL can increase glucose uptake through an ABCA1/AMPK-dependent mechanism (Drew et al., 2009). Chronically elevating HDL levels pharmacologically or via genetic approaches in mice increases Akt phosphorylation, suggesting activation of an additional signaling pathway (Lehti et al., 2013). There is also more recent evidence in mouse muscle cells showing that HDL can directly stimulate anaerobic glycolysis and glucose oxidation.

Mentions: We have previously shown that acute rHDL infusion can reduce blood glucose in individuals with T2DM (Drew et al., 2009). This reduction in glucose preceded an increase in plasma insulin, supporting the hypothesis that HDL may also mediate insulin-independent glucose uptake within skeletal muscle (Drew et al., 2009). This has been further investigated in primary human skeletal muscle cells and adipocytes where both HDL and ApoA-I promoted glucose uptake independently of insulin stimulation (Han et al., 2007; Drew et al., 2009; Zhang et al., 2011; Dalla-Riva et al., 2013). Figure 1 depicts the intracellular signaling pathways activated by HDL in skeletal muscle. HDL-associated ApoA-I binds to ABCA1 inducing intracellular Ca2+ influx and activation of calcium/calmodulin activated protein kinase kinase (CaMKK) (Drew et al., 2009). Subsequent activation and phosphorylation of AMP-activated protein kinase (AMPK) increases translocation of glucose transporter 4 (GLUT4) to the plasma membrane (Dalla-Riva et al., 2013) and facilitates glucose uptake.


HDL and glucose metabolism: current evidence and therapeutic potential.

Siebel AL, Heywood SE, Kingwell BA - Front Pharmacol (2015)

Schematic diagram of the pathways activated by HDL in skeletal muscle that modulate glucose metabolism. Both human and rodent studies have demonstrated that HDL can increase glucose uptake through an ABCA1/AMPK-dependent mechanism (Drew et al., 2009). Chronically elevating HDL levels pharmacologically or via genetic approaches in mice increases Akt phosphorylation, suggesting activation of an additional signaling pathway (Lehti et al., 2013). There is also more recent evidence in mouse muscle cells showing that HDL can directly stimulate anaerobic glycolysis and glucose oxidation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4628107&req=5

Figure 1: Schematic diagram of the pathways activated by HDL in skeletal muscle that modulate glucose metabolism. Both human and rodent studies have demonstrated that HDL can increase glucose uptake through an ABCA1/AMPK-dependent mechanism (Drew et al., 2009). Chronically elevating HDL levels pharmacologically or via genetic approaches in mice increases Akt phosphorylation, suggesting activation of an additional signaling pathway (Lehti et al., 2013). There is also more recent evidence in mouse muscle cells showing that HDL can directly stimulate anaerobic glycolysis and glucose oxidation.
Mentions: We have previously shown that acute rHDL infusion can reduce blood glucose in individuals with T2DM (Drew et al., 2009). This reduction in glucose preceded an increase in plasma insulin, supporting the hypothesis that HDL may also mediate insulin-independent glucose uptake within skeletal muscle (Drew et al., 2009). This has been further investigated in primary human skeletal muscle cells and adipocytes where both HDL and ApoA-I promoted glucose uptake independently of insulin stimulation (Han et al., 2007; Drew et al., 2009; Zhang et al., 2011; Dalla-Riva et al., 2013). Figure 1 depicts the intracellular signaling pathways activated by HDL in skeletal muscle. HDL-associated ApoA-I binds to ABCA1 inducing intracellular Ca2+ influx and activation of calcium/calmodulin activated protein kinase kinase (CaMKK) (Drew et al., 2009). Subsequent activation and phosphorylation of AMP-activated protein kinase (AMPK) increases translocation of glucose transporter 4 (GLUT4) to the plasma membrane (Dalla-Riva et al., 2013) and facilitates glucose uptake.

Bottom Line: 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.This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies.

View Article: PubMed Central - PubMed

Affiliation: Metabolic and Vascular Physiology Laboratory, Baker IDI Heart and Diabetes Institute , Melbourne, VIC, Australia.

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.

No MeSH data available.


Related in: MedlinePlus