Inhibition of protein kinase Cbeta does not improve endothelial function in type 2 diabetes

J Clin Endocrinol Metab. 2010 Aug;95(8):3783-7. doi: 10.1210/jc.2010-0286. Epub 2010 May 5.


Context: Antagonism of protein kinase Cbeta (PKCbeta) restores endothelial function in experimental models of diabetes and prevents vascular dysfunction in response to hyperglycemia in healthy humans.

Objective: We tested the hypothesis that PKCbeta antagonism would improve vascular function in subjects with type 2 diabetes compared with healthy control subjects.

Design: The effect of PKCbeta was evaluated in a randomized, placebo-controlled, double-blinded crossover trial.

Setting: The study was performed in the outpatient setting of a university medical center.

Participants: Thirteen subjects with type 2 diabetes without evidence of cardiovascular disease and 15 healthy control subjects were recruited via newspaper advertisement.

Intervention: Subjects underwent a randomized, double-blind, crossover, placebo-controlled trial of the selective PKCbeta antagonist ruboxistaurin mesylate. Subjects received each treatment for 14 d.

Main outcome measure: Endothelium-dependent and endothelium-independent vasodilation of forearm resistance vessels was measured with mercury-in-silastic, strain-gauge plethysmography during intraarterial administration of methacholine chloride and verapamil, respectively. Markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress were measured after each treatment.

Results: Endothelium-dependent vasodilation of forearm resistance vessels was attenuated in diabetic subjects when compared with healthy subjects (P=0.001). Endothelium-independent vasodilation did not differ between groups (P value not significant). Ruboxistaurin did not significantly change endothelium-dependent or endothelium-independent vasodilation or blood-based markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress in either diabetic or healthy subjects.

Conclusion: Endothelial dysfunction of forearm resistance vessels was not improved by 2 wk of selective PKCbeta inhibition in patients with diabetes. These results suggest that PKCbeta does not contribute significantly to vascular dysfunction in otherwise healthy patients with type 2 diabetes.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Analysis of Variance
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Double-Blind Method
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiopathology*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Forearm / blood supply
  • Forearm / physiopathology
  • Humans
  • Indoles / pharmacology*
  • Male
  • Maleimides / pharmacology*
  • Middle Aged
  • Oxidative Stress / drug effects
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C beta
  • Vasodilation / drug effects


  • Enzyme Inhibitors
  • Indoles
  • Maleimides
  • ruboxistaurin
  • Protein Kinase C
  • Protein Kinase C beta