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. Agreater fall in plasma glucose from baseline occurred during rHDL than during placebo (at 4 hours rHDL = -2.6±0.4; placebo = -2.1±0.3mmol/L; P = 0.018). rHDL increased plasma insulin (at 4 hours rHDL = 3.4±10.0; placebo = -19.2±7.4 pmol/L; P = 0.034) and also the homeostasis model assessment β-cell function index (at 4 hours rHDL = 18.9±5.9; placebo = 8.6±4.4%; P = 0.025). Acetyl-CoA carboxylase β phosphorylation in skeletal muscle biopsies was increased by 1.7±0.3-fold after rHDL, indicating activation of the AMP-activated protein kinase pathway. Both HDL and apolipoprotein AI increased glucose uptake (by 177±12% and 144±18%, respectively; P < 0.05 for both) in primary human skeletal muscle cell cultures established from patients with type 2 diabetes mellitus (n = 5). 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 and activating AMP-activated protein kinase in skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus.