Systemic hemodynamic function in humans with type 1 diabetes treated with protein kinase Cβ inhibition and renin-angiotensin system blockade: a pilot study

The protein kinase C beta (PKC beta) system has been implicated in the deleterious vascular responses to hyperglycemia and angiotensin II (Ang II) in experimental models of diabetes (DM). Whether these interactions are important in humans is unknown. Flow-mediated vasodilatation (FMD) was measured during clamped euglycemia and hyperglycemia, before and after randomization to PKC beta inhibition (ruboxistaurin; RBX, 32 mg daily, n = 13) or a placebo (n = 7) for 8 weeks in renin-angiotensin system (RAS) blockade-treated subjects with type 1 DM. Blood pressure responses to infused Ang II were measured before and after randomization to RBX or a placebo. The RBX and placebo groups displayed similar clinical characteristics. Before RBX, FMD declined in response to hyperglycemia (6.8% +/- 2.8% to 4.9% +/- 1.8%). This effect was reversed after treatment with RBX (5.6% +/- 3.1% to 6.0% +/- 1.6% (within-group change, p = 0.009 (ANOVA)). No changes were observed in the placebo group. Infused Ang II was associated with hypertensive responses in the RBX and placebo groups (p < 0.05 (ANOVA)), and RBX did not influence this effect. In conclusion, RBX blunted the effect of hyperglycemia on FMD, suggesting that PKC beta may modulate endothelial function in type 1 DM. The lack of effect on Ang II responses suggests that PKC beta inhibition may act through non-RAS pathways in humans with DM.