The Effect of Protein Kinase C β Inhibition on Renal Hemodynamic Function and Urinary Biomarkers in Humans with Type 1 Diabetes Mellitus: A Pilot Study

doi:10.2337/dc08-1609

The Effect of Protein Kinase C β Inhibition on Renal Hemodynamic Function and Urinary Biomarkers in Humans with Type 1 Diabetes Mellitus: A Pilot Study

David Z.I. Cherney, MD CM, PhD (david.cherney{at}utoronto.ca)¹,
Ana Konvalinka, MD¹,
Bernard Zinman, MD²,
Eleftherios P. Diamandis, MD, PhD³,
Anton Soosaipillai, BSc³,
Heather Reich, MD CM, PhD¹,
Joanne Lorraine, MD⁴,
Vesta Lai, RN¹,
James W. Scholey, MD¹ and
Judith A. Miller, MD, MSc, MHSc¹

¹ Division of Nephrology, Toronto General Hospital, University of Toronto
² Leadership Sinai for Diabetes, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Medicine, University of Toronto
³ Mount Sinai Hospital and Department of Laboratory Medicine and Pathobiology, University of Toronto
⁴ Eli Lilly Canada, Ontario, Canada

Abstract

Objective: The aim of this study was to examine the effect of protein kinase Cβ (PKCβ) inhibition with ruboxistaurin (RBX) on renal hemodynamic function and the urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1], epidermal growth factor [EGF]) in RAS blockade-treated type 1 DM subjects.

Research Design and Methods: Albuminuric subjects were randomized (2:1) to RBX (32 mg daily, n=13) or a placebo (n=7) for 8 weeks. Renal hemodynamic function was measured during clamped euglycemia and hyperglycemia, before and after RBX or placebo.

Results: RBX was not associated with between-group differences during clamped euglycemia or hyperglycemia. In a post-hoc analysis comparing hyperfilterers (HF) vs. normofilterers (NF) during euglycemia, GFR and MCP-1 decreased, while the EGF/MCP-1 ratio increased in HF vs. NF subjects (all p<0.05).

Conclusions: The effect of RBX is modest, and dependent, at least in part, on the level of ambient glycemia and baseline GFR.