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Inhibition of protein kinase Cbeta does not improve endothelial function in type 2 diabetes
Joshua A Beckman1, Allison B Goldfine, Alison Goldin
1Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA. jbeckman@partners.org
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.
Insights
Protein kinase Cbeta (PKCbeta) antagonism did not improve vascular function in type 2 diabetes patients. This suggests PKCbeta may not significantly contribute to vascular dysfunction in this population.
Area of Science:
- Cardiovascular Research
- Endocrinology
- Pharmacology
Background:
- Protein kinase Cbeta (PKCbeta) antagonism shows promise in restoring endothelial function in diabetes models.
- Previous studies indicate PKCbeta antagonism can prevent vascular dysfunction caused by hyperglycemia in healthy individuals.
Purpose of the Study:
- To test if PKCbeta antagonism improves vascular function in type 2 diabetes patients compared to healthy controls.
- To evaluate the efficacy of ruboxistaurin mesylate in improving endothelial function in diabetic subjects.
Main Methods:
- A randomized, placebo-controlled, double-blinded crossover trial was conducted.
- Participants included 13 type 2 diabetes patients and 15 healthy controls.
- Forearm resistance vessel vasodilation was measured, along with markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress.
Main Results:
- Diabetic subjects exhibited attenuated endothelium-dependent vasodilation compared to healthy subjects (P=0.001).
- Ruboxistaurin treatment did not significantly alter vasodilation or blood markers in either group.
- No significant differences were observed in endothelium-independent vasodilation between groups.
Conclusions:
- Two weeks of selective PKCbeta inhibition did not improve endothelial dysfunction in type 2 diabetes patients.
- PKCbeta may not be a significant contributor to vascular dysfunction in otherwise healthy type 2 diabetes patients.
- Further research may be needed to explore other therapeutic targets for diabetic vascular complications.
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