Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes mellitus

Abstract

Objectives: The development of microvascular complications in diabetes is a complex process in which endothelial dysfunction is important. Emerging evidence suggests that arginase is a key mediator of endothelial dysfunction in type 2 diabetes mellitus by reciprocally regulating nitric oxide bioavailability. The aim of this prospective intervention study was to test the hypothesis that arginase activity is increased and that arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes and microvascular dysfunction. Design: Microvascular endothelium-dependent and-independent dilatation was determined in patients with type 2 diabetes (n=12) and healthy age-matched control subjects (n=12) with laser Doppler flowmetry during iontophoretic application of acetylcholine and sodium nitroprusside, respectively, before and after administration of the arginase inhibitor N-hydroxy-nor-L-ar-inine (120 min). Plasma ratios of amino acids involved in arginase and nitric oxide synthase activities were determined. The laser Doppler flowmetry data were the primary outcome variable. Results: Microvascular endothelium-dependent dilatation was impaired in subjects with type 2 diabetes (P < .05), suggesting increased arginase activity. Conclusion: Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes and microvascular dysfunction. Arginase inhibition may represent a novel therapeutic strategy to improve microvascular endothelial function in patients with type 2 diabetes. (J Clin Endocrinol Metab 101: 3952-3958, 2016).