Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial
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Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes : A randomized controlled trial. / Siebel, Andrew L; Trinh, Si Khiang; Formosa, Melissa F; Mundra, Piyushkumar A; Natoli, Alaina K; Reddy-Luthmoodoo, Medini; Huynh, Kevin; Khan, Anmar A; Carey, Andrew L; van Hall, Gerrit; Cobelli, Claudio; Dalla-Man, Chiara; Otvos, Jim D; Rye, Kerry-Anne; Johansson, Jan; Gordon, Allan; Wong, Norman C W; Sviridov, Dmitri; Barter, Philip; Duffy, Stephen J; Meikle, Peter J; Kingwell, Bronwyn A.
I: Metabolism, Bind 65, Nr. 6, 06.2016, s. 904-914.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes
T2 - A randomized controlled trial
AU - Siebel, Andrew L
AU - Trinh, Si Khiang
AU - Formosa, Melissa F
AU - Mundra, Piyushkumar A
AU - Natoli, Alaina K
AU - Reddy-Luthmoodoo, Medini
AU - Huynh, Kevin
AU - Khan, Anmar A
AU - Carey, Andrew L
AU - van Hall, Gerrit
AU - Cobelli, Claudio
AU - Dalla-Man, Chiara
AU - Otvos, Jim D
AU - Rye, Kerry-Anne
AU - Johansson, Jan
AU - Gordon, Allan
AU - Wong, Norman C W
AU - Sviridov, Dmitri
AU - Barter, Philip
AU - Duffy, Stephen J
AU - Meikle, Peter J
AU - Kingwell, Bronwyn A
N1 - Copyright © 2016 Elsevier Inc. All rights reserved.
PY - 2016/6
Y1 - 2016/6
N2 - 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 100mg b.i.d. RVX-208 and placebo for 29-33days 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 4weeks 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 30min 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.
AB - 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 100mg b.i.d. RVX-208 and placebo for 29-33days 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 4weeks 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 30min 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.
U2 - 10.1016/j.metabol.2016.03.002
DO - 10.1016/j.metabol.2016.03.002
M3 - Journal article
C2 - 27173469
VL - 65
SP - 904
EP - 914
JO - Metabolism
JF - Metabolism
SN - 0026-0495
IS - 6
ER -
ID: 167804325