Raising HDL: potential beyond atherosclerosis in managing type 2 diabetes?

Raising levels of high-density lipoprotein (HDL) cholesterol may improve glucose tolerance in patients with type 2 diabetes, according to a new study published in Circulation. HDL Forum Editor Professor Kerry-Anne Rye reviews and comments on this study.

 

Drew BG, Duffy SJ, Formosa MF et al. High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus. Circulation 2009;119:2103-11.

 

Low HDL cholesterol is typically associated with insulin resistant conditions such as type 2 diabetes and metabolic syndrome (usually in association with elevated triglycerides). In contrast, physical training promotes elevation of circulating HDL and improves glucose tolerance (1). This suggests a possible link between HDL and glucose metabolism.

 

In previous studies, infusion of reconstituted HDL (rHDL), i.e. synthetic HDL particles assembled with phosphatidylcholine and apolipoprotein A-I, the main apolipoprotein of HDL was shown to have beneficial effects on coronary plaque morphology (2). In addition, there was evidence of benefit on endothelial function in patients with type 2 diabetes (3). In the current study, the authors investigated whether rHDL infusion would also modulate glucose metabolism in type 2 diabetes patients, and if so, whether effects on skeletal muscle AMP-activated protein kinase (AMPK) are implicated. 

 

Thirteen patients with type 2 diabetes were enrolled in this randomized, crossover, double-blind, placebo-controlled study. Six patients were treated with oral sulphonylureas (glicazide, glibenclamide or glimepiride) and seven were not receiving any antidiabetic treatment (Table 1). After an overnight fast, patients received rHDL (80 mg/kg over 4 hours) and saline infusions on separate occasions, separated by at least 4 weeks. Percutaneous muscle biopsy (vastus lateralis muscle) was performed before and after infusion on each occasion.

 

At the end of the 4-hour infusion, plasma glucose levels fell (p=0.018) and plasma insulin levels increased (p=0.034) to a greater extent with rHDL than placebo.  The homeostasis model assessment (HOMA), a measure of beta-cell function, was also increased after rHDL infusion compared with placebo (p=0.05), although there was no effect on HOMA insulin resistance index (Table 2).

 

 

The effects on plasma glucose were especially notable given that there was considerable variation in diabetic control among the patients (fasting plasma glucose ranged between 8 mmol/L and 17 mmol/L at baseline). Findings from in vitro studies provided preliminary evidence that HDL also directly stimulate insulin secretion from a mouse pancreatic beta-cell line. It should be noted that these studies were not carried out under physiologically ideal conditions, as incubation was performed for 3 days at a very low HDL concentration (0.05 mg/ml protein). This observation needs to be confirmed using conditions that take into account the biphasic nature of insulin secretion from pancreatic beta cells and with more physiologically relevant HDL concentrations (~1 mg/ml protein).

 

In vitro studies using the muscle biopsies showed that rHDL infusion did not influence AMPK activity but did increase acetyl Co-A carboxylase b (ACCb) phosphorylation compared with placebo (by 1.7-fold). These data were indicative of AMPK activation by rHDL.

 

Additionally, in skeletal muscle cell cultures established from a further five type 2 diabetes patients, both HDL and apoA-I increased glucose uptake (by 178 ± 12% and 144 ± 18%, respectively, p<0.05 for each analysis). The magnitude of this effect was similar to that produced by insulin. Further studies showed that the increase in HDL activated the AMPK pathway in skeletal muscle, and that this effect was associated with elevated ACCb phosphorylation, as was observed in the muscle biopsy studies. Increases in AMPKa2 activity but not AMPKa1 demonstrated by these in vitro studies is consistent with the pattern of AMPK activation stimulated by moderate cycling (4) or adipokines (5), which lends support to the physiological relevance of this finding. Additional studies using an ATP-binding cassette transporter AI (ABCA1) neutralising antibody also indicated the involvement of ABCA1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and AMPK pathways (Figure 1). These studies should ideally be confirmed by silencing ABCA1 with siRNA. 

 

 

The authors do acknowledge a number of limitations to their findings. Additionally, there is also a need for studies investigating whether long-term elevation of HDL causes sustained metabolic effects. In this context, investigation of the effects of treatment with cholesteryl ester transfer protein (CETP) inhibitors, the most potent type of HDL-raising agents currently available, may be especially relevant.

 

In their conclusions, the authors suggest a potential link between low plasma levels of HDL and metabolic dysregulation, implying that therapeutic approaches aimed at raising HDL cholesterol levels may have implications beyond vascular disease to manage type 2 diabetes.

 

References

1. Kraus WE, Houmard JA, Duscha BD, et al. Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med 2002;347:1483-92.

2. Tardif JC, Gregoire J, L’Allier PL et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized trial. JAMA 2007;297:1675-82.

3. Nieuwdorp M, Vergeer M, Bisoendial RJ et al. Reconstituted HDL infusion restores endothelial function in patients with type 2 diabetes mellitus. Diabetologia 2008;51:1081-4.

4. Fujii N, Hayashi T, Hirshman MF et al. Exercise induces isoform-specific increase in 5’AMP-activated protein kinase activity in human skeletal muscle. Biochem Biophys Res Comm 2000;273:1150-5

5. Chen MB, McAinch AJ, Macaulay SL et al. Impaired activation of AMP-kinase and fatty acid oxidation by globular adiponectin in cultured human skeletal musvle of obese type 2 diabetics. J Clin Endocrinol Metab 2005;90:3665-72.

 


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