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

Brian G. Drew, Stephen J. Duffy, Melissa F. Formosa, Alaina K. Natoli, Darren C. Henstridge, Sally A. Penfold, Walter G. Thomas, Nigora Mukhamedova, Barbora de Courten, Josephine M. Forbes, Felicia Y. Yap, David M. Kaye, Gerrit van Hall, Mark A. Febbraio, Bruce E. Kemp, Dmitri Sviridov, Gregory R. Steinberg, Bronwyn A. Kingwell*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

260 Citations (Scopus)

Abstract

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 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 beta-cell function index (at 4 hours rHDL=18.9 +/- 5.9; placebo=8.6 +/- 4.4%; P=0.025). Acetyl-CoA carboxylase beta 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

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. (Circulation. 2009; 119: 2103-2111.)

Original languageEnglish
Pages (from-to)2103-U134
Number of pages18
JournalCirculation
Volume119
Issue number15
DOIs
Publication statusPublished - 21-Apr-2009

Keywords

  • glucose
  • insulin
  • lipoproteins
  • metabolism
  • muscles
  • ACTIVATED PROTEIN-KINASE
  • RANDOMIZED CONTROLLED-TRIAL
  • HUMAN SKELETAL-MUSCLE
  • FATTY-ACID OXIDATION
  • RESTORES ENDOTHELIAL FUNCTION
  • NO SYNTHASE
  • CORONARY ATHEROSCLEROSIS
  • HYPERCHOLESTEROLEMIC MEN
  • INSULIN-RESISTANCE
  • APOLIPOPROTEIN AL

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