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

• Published in: Canadian journal of physiology and pharmacology Vol. 90; no. 1; pp. 113 - 121
• Main Authors: Cherney, David Z.I., Reich, Heather N., Scholey, James W., Lai, Vesta, Slorach, Cameron, Zinman, Bernard, Bradley, Timothy J.
• Format: Journal Article
• Language: English
• Published: Plattsburgh, NY NRC Research Press 01.01.2012; National Research Council of Canada
• Subjects: Adult; Analysis; angiotensin II; Angiotensin II - administration & dosage; Angiotensin II - pharmacology; angiotensine II; Antihypertensive Agents - therapeutic use; Biological and medical sciences; Blood Glucose - metabolism; Care and treatment; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - physiopathology; diabète sucré de type 1; endothelial function; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; fonction endothéliale; Fundamental and applied biological sciences. Psychology; Glucose Clamp Technique - methods; Glucose Clamp Technique - statistics & numerical data; Health aspects; Hemodynamics; Hemodynamics - drug effects; Humans; hyperglycemia; Hyperglycemia - chemically induced; Hyperglycemia - drug therapy; Hyperglycemia - physiopathology; hyperglycémie; Indoles - pharmacology; Indoles - therapeutic use; Infusions, Intravenous; inhibition de la PKCβ; Male; Maleimides - pharmacology; Maleimides - therapeutic use; Physiological aspects; Pilot Projects; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - physiology; Protein Kinase C beta; protein kinase Cβ inhibition; Protein kinases; Renin-angiotensin system; Renin-Angiotensin System - drug effects; Type 1 diabetes; type 1 diabetes mellitus; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Canada; Endocrinopathy; Human; Immunopathology; Enzyme; Transferases; Non-specific serine/threonine protein kinase; Peptide hormone; Autoimmune disease; Octapeptide; Vertebrata; Hyperglycemia; Renin angiotensin system; Mammalia; Type 1 diabetes; Hemodynamics; Inhibition; Angiotensin II
• ISSN: 0008-4212; 1205-7541; 1205-7541
• DOI: 10.1139/y11-106

The protein kinase Cβ (PKCβ) 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 PKCβ 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 PKCβ may modulate endothelial function in type 1 DM. The lack of effect on Ang II responses suggests that PKCβ inhibition may act through non-RAS pathways in humans with DM.