Effect of metabolic control on nitrite and nitrate metabolism in type 2 diabetic patients.

1. The measurement of nitrite and nitrate levels in plasma and urine is an approach to assess the activity of the endogenous nitric oxide (NO) system. The aim of the present study was to evaluate whether metabolic control may affect plasma levels and urinary excretion of nitrates and nitrites in type 2 diabetic patients. 2. Twenty consecutive type 2 diabetic patients were studied twice: first (study 1), under poor metabolic control; and, second, after improved metabolic conditions. Determinations of the main metabolic parameters and of plasma nitrates and nitrites (NOX) were performed in the fasting state. A 24 h urinary specimen was obtained for glycosuria, NOX and creatinine. Diet compliance and home blood glucose monitoring was evaluated on a weekly basis until study 2 was performed after 32 +/- 7 days: then, an identical protocol was repeated (study 2). 3. Fasting plasma glucose was lower in study 2 (8.27 +/- 2.11 vs 10.77 +/- 3.88 mmol/L, respectively; P < 0.05); similarly glycosylated haemoglobin (HbA1c) improved significantly. Plasma NOX levels were similar between the first and second studies (14.3 +/- 7.8 vs 13.5 +/- 8.1 micromol/L, respectively); nor were any differences observed in urinary NOX excretion rates (726 +/- 607 vs 689 +/- 444 micromol/day, respectively). The urinary excretion fraction of NOX was higher during study 1 than during study 2 (3.22 +/- 2.38 vs 1.88 +/- 1.98%, respectively; P = 0.031). A relationship was observed between fasting plasma glucose levels and the urinary excretion fraction of NOX (r2 = 0.12; P = 0.026). 4. In type 2 diabetic patients, plasma and urinary levels of NOX do not change after improvement of metabolic control. A worse metabolic control is associated with an increased urinary fraction excretion of NOX: thus, changes in plasma NOX concentration may reflect the effect of hyperglycaemia in the renal handling of these compounds rather than the effects on the L-arginine-NO pathway.

Effect of acute ketosis on the endothelial function of type 1 diabetic patients: the role of nitric oxide.

In type 1 diabetic patients, acute loss of metabolic control is associated with increased blood flow, which is believed to favor the development of long-term complications. The mechanisms for inappropriate vasodilation are partially understood, but a role of endothelium-derived nitric oxide (NO) production can be postulated. We assessed, in type 1 diabetic patients, the effect of the acute loss of metabolic control and its restoration on forearm endothelial function in 13 type 1 diabetic patients who were studied under conditions of mild ketosis on two different occasions. In study 1, after basal determination, a rapid amelioration of the metabolic picture was obtained by insulin infusion. In study 2, seven type 1 diabetic patients underwent the same experimental procedure, except that fasting plasma glucose was maintained constant throughout. Basal plasma venous concentrations of nitrites/nitrates (NO2- + NO3-) were determined both before and after intravenous insulin infusion. Endothelium-dependent and -independent vasodilation of the brachial artery was assessed by an intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA) and sodium nitroprusside (SNP), respectively. The same parameters were determined in 13 control subjects at baseline conditions and during a hyperinsulinemic-euglycemic glucose clamp. Baseline forearm blood flow (4.89 +/- 0.86 vs. 3.65 +/- 0.59 ml x (100 ml tissue)(-1) x min(-1)) and NO2- + NO3- concentration (30 +/- 8 vs. 24 +/- 3 micromol/l) were higher in type 1 diabetic patients than in control subjects (P < 0.05). Insulin infusion was associated with lower forearm blood flow and plasma (NO2- + NO3-) concentration (P < 0.05), irrespective of the prevailing glucose levels, as compared with patients under ketotic conditions. The responses to L-NMMA were significantly lower in type 1 diabetic patients during euglycemia and hyperglycemic hyperinsulinemia (-11 +/- 5 and -10 +/- 4%, respectively, of the ratio of the infused arm to the control arm) than in control subjects at baseline (-18 +/- 6%, P < 0.05) and during hyperinsulinemia (-32 +/- 11%, P < 0.01). We conclude that the acute loss of metabolic control is associated with a functional disturbance of the endothelial function characterized by hyperemia and increased NO release during ketosis and blunted NO-mediated vasodilatory response during restoration of metabolic control by intravenous insulin. This functional alteration is unlikely to be explained by hyperglycemia itself.