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Selective PKC Beta Inhibition with Ruboxistaurin and Endothelial Function in Type-2 Diabetes Mellitus

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Abstract

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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Authors and Affiliations

  1. Cardiovascular Institute, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Blvd., Philadelphia, PA, 19104-6160, USA

    Nehal N. Mehta, Lynn Comiskey, Shirish Amrutia, Nayyar Iqbal, Emile R. Mohler & Muredach P. Reilly

  2. Center for Experimental Therapeutics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Nehal N. Mehta, Lynn Comiskey, Shirish Amrutia, Nayyar Iqbal, Emile R. Mohler & Muredach P. Reilly

  3. Eli Lilly Research Labs, Indianapolis, IN, USA

    Matthew Sheetz & Karen Price

Authors
  1. Nehal N. Mehta
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  2. Matthew Sheetz
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  3. Karen Price
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  4. Lynn Comiskey
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  5. Shirish Amrutia
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  8. Muredach P. Reilly
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Corresponding author

Correspondence to Muredach P. Reilly.

Additional information

This study was supported by an unrestricted grant from Eli Lilly & Co (MPR), NCRR K23 RR15532 (MPR), the PENN General Clinical Research Center (GCRC: NIH M01-RR00040) and a Clinical and Translational Science Award (RFA-RM-06-002) from the NCRR/NIH to the University of Pennsylvania.

Dr. Mehta is the recipient of the American College of Cardiology/Merck Young Investigator Grant in Metabolic Syndrome. MPR is supported by HL RO1-073278, HL P50-083799 (SCCOR) and the W.W. Smith Charitable Trust (#H0204).

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Mehta, N.N., Sheetz, M., Price, K. et al. Selective PKC Beta Inhibition with Ruboxistaurin and Endothelial Function in Type-2 Diabetes Mellitus. Cardiovasc Drugs Ther 23, 17–24 (2009). https://doi.org/10.1007/s10557-008-6144-5

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  • DOI: https://doi.org/10.1007/s10557-008-6144-5

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