Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion.

Abstract

The role of nitric oxide (NO) and free radicals in the development of microvascular disease in type 1 diabetes remains unclear. We have measured NO and isoprostane (a stable marker of in vivo lipid peroxidation) production in 13 type 1 diabetic subjects with normal urinary albumin excretion and 13 healthy volunteers. Whole-body NO synthesis was quantified by measuring the urinary excretion of 15 N-nitrate after the intravenous administration of L-[15 N] 2 -arginine. The urinary excretion of the major urinary metabolite of 15-F 2t -isoprostane (8-iso-prostaglandin-F 2␣ ), 2,3-dinor-5,6-dihydro-F 2t -IsoP, was quantified as a marker of in vivo lipid peroxidation. Whole-body NO synthesis was significantly higher in diabetic subjects compared with control subjects (342 vs. 216 nmol 15 N-nitrate/mmol creatinine [95% CI of the difference 45-207], P = 0.005). This increase was not explained by a difference in renal function between the 2 groups. There was no difference in 2,3-dinor-5,6-dihydro-F 2t -IsoP excretion between diabetic subjects and control subjects (44.8 ± 7.8 vs. 41.4 ± 10.0 ng/mmol creatinine, mean ± 95% CI). However, there was an inverse correlation between NO synthesis and free radical activity in subjects with diabetes (r = -0.62, P = 0.012) that was not observed in control subjects (r = 0.37, P = 0.107). We conclude that whole-body NO synthesis is higher in type 1 diabetic subjects with normal urinary albumin excretion than in control subjects. The inverse correlation between isoprostane production and NO synthesis in diabetic subjects is consistent with the hypothesis that NO is being inactivated by reactive oxygen species. Diabetes 49:857-862, 2000 T he Diabetes Control and Complications Trial has confirmed that tight blood glucose control significantly delays the onset and slows the progression of microvascular complications in type 1 diabetes (1). However, despite optimum blood glucose control, a substantial proportion of diabetic subjects in this study developed serious microvascular complications. In contrast, in the Wisconsin Epidemiological Study, a significant proportion (30%) of subjects with type 1 diabetes did not manifest severe microvascular complications after 10 years of follow-up, although they had chronic poorly controlled diabetes (2). It would be useful if we could understand this discrepancy underlying the development of microvascular disease so that those at risk could be identified. The benefit/risk ratio of maintaining tight blood glucose control could be increased if targeted toward individuals at greatest risk of complications due to hyperglycemia.The complex issues involved in both the pathogenesis of and individual susceptibility to the angiopathy associated with type 1 diabetes have been well documented (3-5). The endothelium and, in particular, the production of nitric oxide (NO) have been the subject of considerable research in recent years. NO maintains basal vasodilator tone, is a potent platelet anti-aggregant, reduces the ability of monocytes to adhere to endothelial...

A Noninvasive, Sensitive, Specific, and Reliable Approach to Assess Whole-Body Nitric Oxide Synthesis in Children

“…However, there was no correlation between renal creatinine clearance and 24-h urinary [ 15 N]nitrate excretion. Interestingly, we observed that whole-body NO synthesis was significantly higher in girls than in boys, which agrees with our previous observations of an enhanced NO biosynthesis in premenopausal healthy women (29,31). However, multiple regression analysis showed age as the only predictor variable of whole-body NO synthesis, suggesting that normal aging modulates NO homeostasis in children.…”

Hyperfiltration and effect of nitric oxide inhibition on renal and endothelial function in humans with uncomplicated type 1 diabetes mellitus

“…While we cannot precisely anatomically localize differences in segmental resistance in human studies, the exaggerated rise in FF with L-NMMA suggests that intraglomerular pressure increases to mitigate the renal vasoconstriction and resulting fall in ERPF associated with NOS inhibition. Studies in normoalbuminuric patients with type 1 DM measuring urinary 15 N nitrate excretion after an intravenous injection of radiolabeled L-arginine demonstrate increased whole body NO synthesis compared with healthy controls (45). Urinary 15 N nitrate excretion has also been positively associated with creatinine clearance, suggesting a role for NO bioactivity in the pathogenesis of glomerular hyperfiltration (45).…”

Impact of Renin Angiotensin System Modulation on the Hyperfiltration State in Type 1 Diabetes

“…For example, nitric oxide is thought to counteract RAS action, preventing RAS-mediated decreases in GFR (28). Nitric oxide upregulation has been associated with microalbuminuria (3) and with hyperfiltration in humans with type 1 diabetes without microalbuminuria (30). Vasodilatory prostaglandins (PG) such as PGI 2 also are thought to be important vasodilators in diabetes (4,31).…”