期刊
METABOLISM-CLINICAL AND EXPERIMENTAL
卷 65, 期 6, 页码 904-914出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/j.metabol.2016.03.002
关键词
Clinical trial; Glucose metabolism; Type 2 diabetes; High-density lipoprotein; Prediabetes
资金
- Resverlogix Corp.
- National Health & Medical Research Council (NHMRC) of Australia [APP1065462]
- Victorian Government's Operational Infrastructure Support (OIS) Program
- NHMRC Research Fellowships
Aims. High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) can modulate glucose metabolism through multiple mechanisms. This study determined the effects of a novel bromodomain and extra-terminal (BET) inhibitor (RVX-208) and putative apoA-I inducer on lipid species contained within HDL (HDL lipidome) and glucose metabolism. Materials and methods. Twenty unmedicated males with prediabetes received 100 mg b.i.d. RVX-208 and placebo for 29-33 days separated by a wash-out period in a randomized, cross-over design trial. Plasma HDL-cholesterol and apoA-I were assessed as well as lipoprotein particle size and distribution using NMR spectroscopy. An oral glucose tolerance test (OGTT) protocol with oral and infused stable isotope tracers was employed to assess postprandial plasma glucose, indices of insulin secretion and insulin sensitivity, glucose kinetics and lipolysis. Whole plasma and HDL lipid profiles were measured using mass spectrometry. Results. RVX-208 treatment for 4 weeks increased 6 sphingolipid and 4 phospholipid classes in the HDL lipidome (p <= 0.05 versus placebo), but did not change conventional clinical lipid measures. The concentration of medium-sized HDL particles increased by 11% (P = 0.01) and small-sized HDL particles decreased by 10% (P = 0.04) after RVX-208 treatment. In response to a glucose load, after RVX-208 treatment, plasma glucose peaked at a similar level to placebo, but 30 min later with a more sustained elevation (treatment effect, P = 0.003). There was a reduction and delay in total (P = 0.001) and oral (P = 0.003) glucose rates of appearance in plasma and suppression of endogenous glucose production (P = 0.014) after RVX-208 treatment. The rate of glucose disappearance was also lower following RVX-208 (P = 0.016), with no effect on glucose oxidation or total glucose disposal. Conclusions. RVX-208 increased 10 lipid classes in the plasma HDL fraction, without altering the concentrations of either apoA-I or HDL-cholesterol (HDL-C). RVX-208 delayed and reduced oral glucose absorption and endogenous glucose production, with plasma glucose maintained via reduced peripheral glucose disposal. If sustained, these effects may protect against the development of type 2 diabetes. (C) 2016 Elsevier Inc. All rights reserved.
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