PURPOSE:Type-2 diabetes mellitus increases risk of atherosclerotic cardiovascular disease. However, the mechanisms linking hyperglycemia and atherosclerosis remain poorly understood. One proposed mechanism involves endothelial dysfunction via activation of protein kinase C beta (PKC beta). Prior studies demonstrate beneficial effects of PKC beta inhibition on microvascular parameters, but, to date, no study has examined the effect on macrovascular atherosclerotic readouts. METHODS: The goal of this double-masked, placebo-controlled trial in type-2 diabetes was to assess the effect of the PKC beta-specific inhibitor, ruboxistaurin (32 mg/day for 6 weeks) on ultrasound assessed brachial artery flow mediated dilatation (FMD), a surrogate of macro vascular endothelial function, and urinary isoprostanes, indices of oxidant stress. RESULTS: Compared to placebo, ruboxistaurin tended to improve FMD (difference in 6-week change in FMD, mean +/- SD millimeter) at one (0.13 +/- 0.26 mm, p = 0.08) and 5 min (0.12 +/- 0.21 mm, p = 0.02) after cuff deflation, but had no effect on nitroglycerin-mediated dilatation or urinary isoprostanes. CONCLUSIONS: This proof of concept trial is the first to suggest that specific inhibition of PKC beta may improve macro vascular endothelial function in type-2 diabetes. Larger trials including clinical endpoints are warranted to determine the potential efficacy of PKC beta inhibition in reducing atherosclerotic cardiovascular complications in diabetes mellitus.
RCT Entities:
PURPOSE:Type-2 diabetes mellitus increases risk of atherosclerotic cardiovascular disease. However, the mechanisms linking hyperglycemia and atherosclerosis remain poorly understood. One proposed mechanism involves endothelial dysfunction via activation of protein kinase C beta (PKC beta). Prior studies demonstrate beneficial effects of PKC beta inhibition on microvascular parameters, but, to date, no study has examined the effect on macrovascular atherosclerotic readouts. METHODS: The goal of this double-masked, placebo-controlled trial in type-2 diabetes was to assess the effect of the PKC beta-specific inhibitor, ruboxistaurin (32 mg/day for 6 weeks) on ultrasound assessed brachial artery flow mediated dilatation (FMD), a surrogate of macro vascular endothelial function, and urinary isoprostanes, indices of oxidant stress. RESULTS: Compared to placebo, ruboxistaurin tended to improve FMD (difference in 6-week change in FMD, mean +/- SD millimeter) at one (0.13 +/- 0.26 mm, p = 0.08) and 5 min (0.12 +/- 0.21 mm, p = 0.02) after cuff deflation, but had no effect on nitroglycerin-mediated dilatation or urinary isoprostanes. CONCLUSIONS: This proof of concept trial is the first to suggest that specific inhibition of PKC beta may improve macro vascular endothelial function in type-2 diabetes. Larger trials including clinical endpoints are warranted to determine the potential efficacy of PKC beta inhibition in reducing atherosclerotic cardiovascular complications in diabetes mellitus.
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