Reconstituted HDL: A Therapy for Atherosclerosis and Beyond

Andrew J Murphy; Jaye Chin-Dusting; Dmitri Sviridov

Disclosures

Clin Lipidology. 2009;4(6):731-739. 

In This Article

rHDL Therapy for the Treatment of Type 2 Diabetes

It has been previously described that HDL can become dysfunctional in the setting of Type 2 diabetes,[40] thus correcting this dysfunction may have beneficial effects. Indeed, administration of rHDL has proven to be not only cardioprotective, but also improve the metabolic profile of patients suffering from Type 2 diabetes. In a recent paper by Drew et al., it was discovered that HDL can modulate glucose metabolism in patients with Type 2 diabetes.[38] A single high-dose infusion of rHDL significantly reduced plasma glucose levels over the 4-h infusion period. Glucose reduction was accompanied by a dramatic increase in plasma insulin levels. An increase in β-cell function, as measured by homeostasis model function of β-cells, was also reported.[38] It was suggested that the reduction in glucose levels observed after only 30 min into the infusion may be attributed to activation of skeletal muscle AMPK by rHDL as plasma insulin levels did not begin to rise until 2.5 h into the infusion period. The increased β-cell function correlating to increased insulin levels appears to be a direct effect of the rHDL on β-cells based on in vitro data.[38,41]

Drew and colleagues also examined the anti-inflammatory effects of rHDL infusion in Type 2 diabetics.[42] It was found that rHDL enhanced the anti-inflammatory properties of plasma HDL. The authors purified plasma HDL at 0, 4 and 72 h postinfusion and assessed the ability of the HDL particles to inhibit human coronary endothelial cell ICAM-1 and VCAM-1 expression in vitro. As previously reported, HDL isolated from diabetics was dysfunctional and in this study was unable to significantly inhibit ICAM-1 or VCAM-1 expression.[40,42] However, HDL isolated after the infusion period resulted in a significant reduction in the expression of these adhesion molecules, which was still evident after 72 h. The inhibition of both ICAM-1 and VCAM-1 correlated to the amount of HDL present in the plasma. When cholesterol efflux to plasma was assessed, a significant improvement was observed after rHDL infusion compared with placebo. In light of a recent study by McGillicuddy et al. describing that RCT is inhibited by inflammation in vivo, the data may suggest that overall inflammation is reduced by HDL.[43] Indeed, this may be the case as neutrophils isolated from healthy donors incubated with plasma from patients receiving either placebo or rHDL showed significantly less adhesion after rHDL infusion. Further ex vivo measurement of monocyte activation showed that rHDL infusion significantly reduced monocyte activation compared with placebo. Levels of soluble(s) ICAM-1 and VCAM-1 were also measured and while sVCAM-1 levels were reduced, there was no change in sICAM-1. In a separate study in Type 2 diabetics, rHDL was shown to increase circulating endothelial progenitor cells.[44] Interestingly, this was only evident at 7 days postinfusion, suggesting that infusion of rHDL also has delayed and sustained effects in agreement with the PVD study.[36,44] Thus, one of the critical questions that requires follow-up is whether rHDL can correct the imbalance of lipids to restore normal function, thus allowing the body to take over and fight disease. If so, single infusions may be more beneficial than initially anticipated.

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