Increased circulating nitric oxide in young patients with type 1 diabetes and persistent microalbuminuria: relation to glomerular hyperfiltration.

Abstract

Hyperglycemia has been causally linked to vascular and glomerular dysfunction by a variety of biochemical mechanisms, including a glucose-dependent abnormality in nitric oxide (NO) production and action. NO is a candidate for mediating hyperfiltration and the increased vascular permeability induced by diabetes. Serum nitrite and nitrate (NO 2 -+ NO 3 -) concentrations were assessed as an index of NO production in 30 adolescents and young adults with type 1 diabetes, 15 with and 15 without microalbuminuria (albumin excretion rate [AER] between 20 and 200 µg/min), compared with a well-balanced group of healthy control subjects. In all subjects, glomerular filtration rate (GFR) was determined by radionuclide imaging. Our study showed that NO 2 -+ NO 3 -serum content and GFR values were significantly higher in microalbuminuric diabetic patients than in the other 2 groups. GFR was significantly and positively related to AER levels (r 2 = 0.75, P < 0.0001), whereas NO 2 -+ NO 3 -serum content was independently associated with both AER and GFR values (␤ = 2.086, P = 0.05, ␤ = 1.273, P = 0.0085, respectively), suggesting a strong link between circulating NO, glomerular hyperfiltration, and microalbuminuria in young type 1 diabetic patients with early nephropathy. Interestingly, mean HbA 1c serum concentration was significantly higher in microalbuminuric than in normoalbuminuric diabetic subjects (P < 0.05) and was independently associated with AER values, suggesting a role for chronic hyperglycemia in the genesis of diabetic nephropathy. Moreover, HbA 1c serum concentration was significantly and positively related to NO 2 + NO 3 serum content (r 2 = 0.45, P = 0.0063) and GFR values (r 2 = 0.57, P = 0.0011), suggesting that chronic hyperglycemia may act through a mechanism that involves increased NO generation and/or action. In conclusion, we suggest that in young type 1 diabetic patients with early nephropathy, chronic hyperglycemia is associated with an increased NO biosynthesis and action that contributes to generating glomerular hyperfiltration and persistent microalbuminuria. Diabetes 49:1258-1263, 2000 E arly diabetic nephropathy in children and adolescents is caused predominantly by microangiopathy, representing functional and structural abnormalities in the microvascular system leading to microalbuminuria (1-3). Microvascular disease carries a substantive morbidity in young patients with type 1 diabetes (3,4). Long duration of diabetes and poor glycemic control have been shown to be the most important risk factors for the development of microvascular disease in these patients (5). A considerable body of evidence in humans indicates that microalbuminuria is strictly associated with a generalized endothelial vascular dysfunction (2,6). In this regard, a glucosedependent abnormality in nitric oxide (NO) production and action has become an attractive hypothesis for the pathogenesis of early diabetic nephropathy (7-11). In fact, vasodilation due to increased NO generation or action has recently been implicated in the ...

Rosiglitazone Improves Glomerular Hyperfiltration, Renal Endothelial Dysfunction, and Microalbuminuria of Incipient Diabetic Nephropathy in Patients

“…Experimental data from the single nephron model has demonstrated that NO contributes to efferent arteriolar tone (23). Our conclusion of a decreased efferent NO bioavailability in diabetic subjects that is potentially ameliorated by rosiglitazone appears to be in conflict with studies suggesting a contribution of increased NO to the glomerular hyperfiltration in the early diabetic state (24,25). These studies, however, did not test bioavailable NO (e.g., by assessment of renal hemodynamics).…”

Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetic subjects

“…The haemodynamic hypothesis of diabetic microangiopathy emphasises the importance of increases in capillary pressure and flow as key factors for the development of complications [30]. Enhanced endothelial nitric oxide synthase (eNOS) activity has been suggested to mediate renal hyperfiltration [31]. Indeed, chronic NOS inhibition abolishes glomerular hyperfiltration [32], and the afferent arterioles of streptozotocin diabetic rats show high levels of eNOS expression [33].…”

The Effect of Cyclooxygenase-2 Inhibition on Renal Hemodynamic Function in Humans With Type 1 Diabetes

“…A lterations in renal hemodynamic function are prevalent in diabetes (1,2) and include increased intraglomerular capillary pressure and hyperfiltration (3)(4)(5). Because blockade of the renin angiotensin system (RAS) does not completely normalize hyperfiltration (6), it is clear that other factors are operative in the renal microcirculation in diabetes.…”