High-Density Lipoprotein Modulates Glucose Metabolism in Patients With Type 2 Diabetes Mellitus

Background—Low plasma high-density lipoprotein (HDL) is associated with elevated cardiovascular risk and aspects of the metabolic syndrome. We hypothesized that HDL modulates glucose metabolism via elevation of plasma insulin and through activation of the key metabolic regulatory enzyme, AMP-activated protein kinase, in skeletal muscle. Methods and Results—Thirteen patients with type 2 diabetes mellitus received both intravenous reconstituted HDL (rHDL: 80 mg/kg over 4 hours) and placebo on separate days in a double-blind, placebo-controlled crossover study. A greater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDL2.60.4; placebo2.10.3mmol/L; P0.018). rHDL increased plasma insulin (at 4 hours rHDL3.410.0; placebo 19.27.4 pmol/L; P0.034) and also the homeostasis model assessment -cell function index (at 4 hours rHDL18.95.9; placebo8.64.4%; P0.025). Acetyl-CoA carboxylase phosphorylation in skeletal muscle biopsies was increased by 1.70.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 17712 % and 14418%, respectively; P0.05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (n5). The mechanism is demonstrated to include stimulation of the ATP-binding cassette transporter A1 with subsequent activation of the calcium/calmodulin-dependent protein kinase kinase and the AMP-activated protein kinase pathway. Conclusions—rHDL reduced plasma glucose in patients with type 2 diabetes mellitus by increasing plasma insulin an