Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Oxidative/Nitrosative Stress and Disease Potential mechanisms for reduced delivery of nitric oxide to peripheral tissues in diabetes mellitus Thomas Stabler, Aarti Kenjale, Katherine Ham, Nicole Jelesoff, and Jason Allen Duke University School of Medicine, Durham, North Carolina Address for correspondence: Jason Allen David, Assistant Professor, Duke University School of Medicine DUMC 3022, Durham, NC 27710. j.d.allen@duke.edu Nitric oxide (NO) bioavailability is crucial for normal vascular endothelial function and health. Recent studies have demonstrated an endocrine role for NO equivalents that may be transported in the blood to peripheral tissue beds, where under hypoxic conditions they can liberate NO and cause vasodilation. Exercise training improves endothelial function but its effect on NO bioavailability in peripheral tissues during acute exercise stress in CVD is unclear. This paper will present evidence and discuss possible mechanisms by which NO delivery to peripheral tissues may be dysfunctional in diabetic subjects. Keywords: nitric oxide; diabetes mellitus; vascular Introduction Diabetes mellitus is a major cause of morbidity in the Western world. 1 Recent increases in sedentary lifestyle and obesity are antecedents to the rising prevalence of type 2 diabetes becoming more com- mon in younger adults. 2,3 Both macrovascular dis- ease (resulting in myocardial infarction, stroke, and claudication) and microvascular disease (resulting in diabetic nephropathy and retinopathy) are more prevalent in diabetic than in nondiabetic popula- tions and contribute importantly to the morbidity associated with this disease. 4–6 Currently, despite medical treatment diabetics die approximately 5– 10 years earlier than nondiabetics, primarily from vascular disease. Nitric oxide (NO) bioavailability plays an im- portant role in several antiatherogenic mechanisms including the regulation of arterial tone, and the in- hibition of platelet aggregation, leukocyte adhesion and smooth muscle proliferation. 7,8 Disruptions in NO production and signaling have been implicated in the pathogenesis of atherosclerosis. It has been suggested that atherosclerosis maybe a result of en- dothelial dysfunction in large- and medium-sized arteries whereas, type 2 diabetes maybe induced by dysfunction in the capillary and arteriolar endothe- lium, with a vast surface area in intimate contact with metabolically active, insulin-sensitive tissues such as skeletal muscle. 9 Impaired NO-mediated va- sodilatation may cause inadequate insulin delivery to these tissues, resulting in peripheral insulin resis- tance and reduced glucose uptake. Until recently, NO bioactivity was considered to be limited both temporally and spatially to the proximity of the vascular endothelium where it was produced, as it is readily inactivated in the vasculature. 10 This suggests site specific reductions in NO production would be responsible for local dysfunction. This concept has been challenged by studies of inhaled and intravenously applied NO which indicate protected transport mechanisms in the blood, taking NO from areas of high pro- duction to be released at critical areas of the cir- culation, where it can influence macro- and mi- crovascular tone and possibly vasculopathy. 11–13 It appears that in vivo NO bioavailability may be reg- ulated by formation of NO-containing compounds in the blood 14,15 (S-nitrosothiols, 16 N-nitroso pro- teins, and iron-nitrosyl complexes, 17 as well as ni- trite 18,19 and potentially nitrated-lipids 20 ) and may be transported throughout the vasculature in both the plasma 13 and red blood cells (RBC). 21 Un- der normal conditions, this endocrine-like role is doi: 10.1111/j.1749-6632.2010.05599.x Ann. N.Y. Acad. Sci. 1203 (2010) 101–106 c  2010 New York Academy of Sciences. 101