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.
Highlights
We recently demonstrated that reconstituted high-density lipoprotein modulates glucose metabolism in humans via both AMP-activated protein kinase (AMPK) in muscle and by increasing plasma insulin
Plasma insulin was elevated by reconstituted high-density lipoprotein (rHDL) by 3.4 ± 10.0 pmol/l, while the placebo group fell by 19.2 ± 7.4 pmol/l (P = 0.034, rHDL versus placebo at 4 hr; Table1 and Ref. 7)
Inhibition of lipolysis possibly results from the dual effects of High-density lipoprotein (HDL)-mediated insulin release [7] as well as activation of AMPK in adipose tissue
Summary
The current investigation concerning fatty acid metabolism was performed in parallel with previous studies from our laboratory; patient characteristics and study design have been previously reported [7, 27, 28]. 13 patients with type 2 diabetes mellitus participated in the study and received 80 mg/ kg (lyophilised rHDL is reconstituted with water for injection and is infused based on protein content of the rHDL particle) (CSL Behring AG, Bern, Switzerland) over 4 h and saline placebo on separate occasions separated by at least two weeks in a doubleblind crossover study. The preparation did not contain any other proteins (leptin, insulin, adiponectin) likely to induce a metabolic response (data not shown). Palmitate tracer preparation and infusion Stably 13C-labeled palmitate (U-13C-palmitate) A 2 hr equilibration period was implemented to achieve steady-state tracer concentrations prior to commencement of the rHDL/placebo infusion [30,31,32,33]
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