Nitric Oxide Synthesis Is Reduced in Subjects With Type 2 Diabetes and Nephropathy

Abstract

OBJECTIVENitric oxide (NO) is a key metabolic and vascular regulator. Its production is stimulated by insulin. A reduced urinary excretion of NO products (NOx) is frequently found in type 2 diabetes, particularly in association with nephropathy. However, whether the decreased NOx excretion in type 2 diabetes is caused by a defective NOx production from arginine in response to hyperinsulinemia has never been studied.RESEARCH DESIGN AND METHODSWe measured NOx fractional (FSR) and absolute (ASR) synthesis rates in type 2 diabetic patients with diabetic nephropathy and in control subjects, after l-[15N2-guanidino]-arginine infusion, and use of precursor–product relationships. The study was conducted both before and after an euglycemic hyperinsulinemic (∼1,000–1,200 pmol/l) clamp.RESULTSIn type 2 diabetes, NOx FSR was reduced both under basal (19.3 ± 3.9% per day, vs. 22.9 ± 4.5% per day in control subjects) and hyperinsulinemic states (24.0 ± 5.6% per day, vs. 37.9 ± 6.4% per day in control subjects; P < 0.03 by ANOVA). Similarly, in type 2 diabetes, NOx ASR was lower than in control subjects under both conditions (basal, 0.32 ± 0.06 vs. 0.89 ± 0.34 mol per day; hyperinsulinemia, 0.35 ± 0.07 vs. 1.15 ± 0.38 mol per day; P = 0.01 by ANOVA). In type 2 diabetes, the ability of insulin to stimulate both the FSR (4.7 ± 3.2% per day) and the ASR (0.03 ± 0.04 mol per day) of NOx was several-fold lower than that in control subjects (15.0 ± 2.9% per day and 0.25 ± 0.07 mol per day, P < 0.03 and P < 0.02, respectively). Also the fraction of arginine flux converted to NOx (basal, 0.22 ± 0.05% vs. 0.65 ± 0.25%; hyperinsulinemia, 0.32 ± 0.06% vs. 1.03 ± 0.33%) was sharply reduced in the patients (P < 0.01 by ANOVA).CONCLUSIONSIn type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states. This defect extends the concept of insulin resistance to NO metabolism.

Reduction of circulating superoxide dismutase activity in type 2 diabetic patients with microalbuminuria and its modulation by telmisartan therapy

“…A recent clinical study reported that blood NO levels were decreased in type 2 diabetic patients with overt DN, compared with non-diabetic control subjects. 30 Consistent with this observation, our study also demonstrated a reduction in serum NO levels in the diabetic patients with incipient DN relative to those without DN and the non-diabetic control subjects. Indeed, NO may be extremely important for renoprotection in the diabetic state.…”

Enhanced Glucose Tolerance and Pancreatic Beta Cell Function by Low Dose Aspirin in Hyperglycemic Insulin-Resistant Type 2 Diabetic Goto-Kakizaki (GK) Rats

“…Low levels of H 2 O 2 have also been shown to induce NO production. There are reports that NO synthesis is reduced in T2D and hypertension and that insulin regulates NO production [29,30]. We observed that NO level was low in GK rats and ASA treatment increased NO production, which may have stimulated glucose tolerance and increased insulin response.…”

Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy

“…Reduced bioavailability or uncoupling of nitric oxide (NO) leading to decreased intracellular levels of the NO pathway effector molecule, cyclic guanosine monophosphate (cGMP), in the kidney has been proposed as a key contributor to mechanisms driving progression of DN. [9][10][11][12][13] In particular, altered NO-dependent intrarenal hemodynamics demonstrated in experimental in vivo studies of the cortical and medullary renal vasculature in diabetes, 13 and uncoupling of NO by scavenging of reactive oxygen species 14 have been implicated in the pathogenesis of DN. Preclinical in vivo studies demonstrate that restoring the NO pathway by elevating the intracellular pool of cGMP, through inhibition of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5), is renoprotective, with reductions in albuminuria, inflammation, fibrosis, and improvement in creatinine clearance.…”