Arginase Inhibition Improves Microvascular Endothelial Function in Patients With Type 2 Diabetes Mellitus

J Clin Endocrinol Metab. 2016 Nov;101(11):3952-3958. doi: 10.1210/jc.2016-2007. Epub 2016 Jul 11.

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 Nω-hydroxy-nor-L-arginine (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). After administration of Nω-hydroxy-nor-L-arginine, microvascular endothelial function improved significantly in patients with type 2 diabetes to the level observed in healthy controls. Endothelium-independent vasodilatation did not change significantly. Subjects with type 2 diabetes had higher levels of ornithine and higher ratios of ornithine/citrulline and ornithine/arginine (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.

Publication types

  • Controlled Clinical Trial

MeSH terms

  • Acetylcholine / pharmacology
  • Aged
  • Arginase / antagonists & inhibitors*
  • Arginase / metabolism
  • Arginine / adverse effects
  • Arginine / analogs & derivatives
  • Arginine / therapeutic use
  • Cardiovascular Agents / adverse effects
  • Cardiovascular Agents / therapeutic use*
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetic Angiopathies / blood
  • Diabetic Angiopathies / drug therapy*
  • Diabetic Angiopathies / metabolism
  • Diabetic Angiopathies / physiopathology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiopathology
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Humans
  • Laser-Doppler Flowmetry
  • Male
  • Microvessels / drug effects
  • Microvessels / physiopathology
  • Middle Aged
  • Nitroprusside / pharmacology
  • Ornithine / blood
  • Peripheral Vascular Diseases / complications
  • Peripheral Vascular Diseases / drug therapy*
  • Peripheral Vascular Diseases / metabolism
  • Peripheral Vascular Diseases / physiopathology
  • Severity of Illness Index
  • Vascular Resistance / drug effects
  • Vasodilation / drug effects
  • Vasodilator Agents / pharmacology

Substances

  • Cardiovascular Agents
  • Enzyme Inhibitors
  • N(omega)-hydroxynorarginine
  • Vasodilator Agents
  • Nitroprusside
  • Arginine
  • Ornithine
  • Arginase
  • Acetylcholine