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Systemic hemodynamic function in humans with type 1 diabetes treated with protein kinase Cβ inhibition and

David Z I Cherney1, Heather N Reich, James W Scholey

  • 1Division of Nephrology, Toronto General Hospital, University of Toronto, 585 University Ave, 8N-845, Toronto, ON M5G 2N2, Canada. david.cherney@uhn.on.ca

Canadian Journal of Physiology and Pharmacology
|December 23, 2011
PubMed

Insights

Protein kinase Cβ (PKCβ) inhibition with ruboxistaurin improved endothelial function in type 1 diabetes by blunting hyperglycemia's negative effects. This suggests PKCβ modulates vascular responses in diabetic patients.

Area of Science:

  • Endocrinology
  • Cardiovascular Science
  • Pharmacology

Background:

  • The protein kinase Cβ (PKCβ) system is linked to vascular damage in diabetes models.
  • Its role in human diabetic vascular responses remains unclear.
  • Angiotensin II (Ang II) and hyperglycemia are implicated in diabetic vascular dysfunction.

Purpose of the Study:

  • To investigate the role of PKCβ in human type 1 diabetes (DM).
  • To determine if PKCβ inhibition affects endothelial function and blood pressure responses in type 1 DM patients.
  • To explore the impact of ruboxistaurin (RBX) on flow-mediated dilation (FMD) during hyperglycemia.

Main Methods:

  • A randomized, placebo-controlled trial in type 1 DM patients on renin-angiotensin system (RAS) blockade.
  • Measured FMD during clamped euglycemia and hyperglycemia before and after 8 weeks of RBX or placebo.
  • Assessed blood pressure response to infused Ang II.

Main Results:

  • Hyperglycemia reduced FMD before RBX treatment.
  • RBX treatment reversed the decline in FMD caused by hyperglycemia (p = 0.009).
  • RBX did not alter the hypertensive response to Ang II infusion.

Conclusions:

  • PKCβ inhibition with RBX blunted the adverse effect of hyperglycemia on endothelial function in type 1 DM.
  • PKCβ may modulate endothelial function in humans with type 1 DM.
  • PKCβ inhibition might act via non-RAS pathways in this context.

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