Inhibition of Protein Kinase Cβ Does Not Improve Endothelial Function in Type 2 Diabetes

This is the authors' abstract. We don't add key points for this paper.

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.

No benefit of ruboxistaurin on endothelial function in T2D; challenges PKCβ inhibition as a therapeutic target for vascular complications.