title: Reconstituted high-density lipoprotein infusion modulates fatty acid metabolism in patients with type 2 diabetes mellitus.
abstract: We recently demonstrated that reconstituted high-density lipoprotein (rHDL) modulates glucose metabolism in humans via both AMP-activated protein kinase (AMPK) in muscle and by increasing plasma insulin. Given the key roles of both AMPK and insulin in fatty acid metabolism, the current study investigated the effect of rHDL infusion on fatty acid oxidation and lipolysis. Thirteen patients with type 2 diabetes received separate infusions of rHDL and placebo in a randomized, cross-over study. Fatty acid metabolism was assessed using steady-state tracer methodology, and plasma lipids were measured by mass spectrometry (lipidomics). In vitro studies were undertaken in 3T3-L1 adipocytes. rHDL infusion inhibited fasting-induced lipolysis (P = 0.03), fatty acid oxidation (P < 0.01), and circulating glycerol (P = 0.04). In vitro, HDL inhibited adipocyte lipolysis in part via activation of AMPK, providing a possible mechanistic link for the apparent reductions in lipolysis observed in vivo. In contrast, circulating NEFA increased after rHDL infusion (P < 0.01). Lipidomic analyses implicated phospholipase hydrolysis of rHDL-associated phosphatidylcholine as the cause, rather than lipolysis of endogenous fat stores. rHDL infusion inhibits fasting-induced lipolysis and oxidation in patients with type 2 diabetes, potentially through both AMPK activation in adipose tissue and elevation of plasma insulin. The phospholipid component of rHDL also has the potentially undesirable effect of increasing circulating NEFA.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. bdrew@mednet.ucla.edu
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Carey
authors.forename: Alaina K
authors.initials: AK
authors.lastname: Natoli
authors.forename: Melissa F
authors.initials: MF
authors.lastname: Formosa
authors.forename: Donna
authors.initials: D
authors.lastname: Vizi
authors.forename: Medini
authors.initials: M
authors.lastname: Reddy-Luthmoodoo
authors.forename: Jacquelyn M
authors.initials: JM
authors.lastname: Weir
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Barlow
authors.forename: Gerrit
authors.initials: G
authors.lastname: van Hall
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Duffy
authors.forename: Bronwyn A
authors.initials: BA
authors.lastname: Kingwell
mesh_terms: D041721:3T3-L1 Cells; D000263:Adenylate Kinase / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D008066:Lipolysis / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D008075:Lipoproteins, HDL; D000263:Adenylate Kinase