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 ...

Background-To investigate early events possibly related to the development of diabetic angiopathy, we examined whether 8-iso-prostaglandin F 2␣ (8-iso-PGF 2␣ ) formation, a marker of in vivo oxidant stress, is altered in different stages of type 1 diabetes (T1DM) and whether it correlates with the rate of thromboxane (TX) A 2 biosynthesis, a marker of in vivo platelet activation. We also investigated the relationship between inflammatory markers and F 2 -isoprostane formation in this setting. Methods and Results-A cross-sectional study was performed in 23 insulin-treated patients aged Ͻ18 years with new-onset T1DM (Յ6 weeks, group A), matched for age and gender with 23 patients with stable disease (Ͼ1 year, group B). Urinary 8-iso-PGF 2␣ and 11-dehydro-TXB 2 were measured in all patients and in age-and gender-matched controls. Circulating interleukin-6 (IL-6), tumor necrosis factor-␣, and C-reactive protein were also determined as markers of the inflammatory response. Fifteen of the 23 children in group A were reexamined after 12 months. Compared with either controls or group B, diabetic children in group A showed significantly higher levels of 8-iso-PGF 2␣ , 11-dehydro-TXB 2 , IL-6, tumor necrosis factor-␣, and C-reactive protein. Statistically significant correlations between IL-6 and both 8-iso-PGF 2␣ (rϭ0.63, PϽ0.001) and 11-dehydro-TXB 2 (rϭ0.51, PϽ0.01) were observed. The 15 patients reexamined after 1 year showed a significant reduction in lipid peroxidation and platelet activation (PϽ0.02 and PϽ0.001, respectively), consistent with reduced levels of IL-6 and tumor necrosis factor-␣. Conclusions-These

OBJECTIVES -To investigate the possible role of hyperglycemia-dependent monocyte chemoattractant protein (MCP)-1 biosynthesis in the pathophysiology of early nephropathy in type 1 diabetes. RESULTS -FPLPs, MDA, and MCP-1 were significantly higher, whereas vitamin E was significantly lower in patients with microalbuminuria and poorer glycemic control as compared with normoalbuminuric patients and healthy control subjects. Plasma MCP-1 was positively correlated with HbA 1c , FPLPs, MDA, and AER, whereas plasma MCP-1 showed an inverse correlation with vitamin E. Interestingly, both MCP-1 and AER decreased significantly after vitamin E treatment, despite no changes in HbA 1c values. RESEARCH DESIGN AND METHODSCONCLUSIONS -This study suggests that prolonged hyperglycemia may lead to early renal complications in type 1 diabetes by inducing MCP-1 biosynthesis via enhanced oxidative stress. Long-term treatment of high-dose vitamin E significantly decreased MCP-1, thus providing a rationale basis for evaluating vitamin E supplementation as therapy adjuvant to conventional insulin treatment in type 1 diabetic patients in whom an acceptable glycemic control is difficult to achieve despite appropriate insulin treatment.

OBJECTIVE—The progression of diabetic angiopathy is, in most cases, unpredictable. The aim of this study was to investigate early events that could influence the development of diabetic angiopathy. RESEARCH DESIGN AND METHODS—Circulating levels of von Willebrand factor (vWF) and tissue-plasminogen activator (tPA), defining endothelial perturbation, were measured in 40 young patients with type 1 diabetes. Patients were divided into two groups according to the duration of diabetes (group A, &lt;1 year; group B, &gt;1 year) and compared with a control group of age- and sex-matched healthy individuals. Prothrombin fragment 1 and 2 (F1+2), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) levels were also determined as markers of a prothrombotic state and inflammatory response. A total of 16 of the 20 children in group A were re-examined after 12 months. RESULTS—Compared with either normal subjects or patients in group B, children in group A showed increased levels of vWF, tPA, F1+2, TNF-α, and CRP. Significant direct correlations between TNF-α or CRP and either vWF, tPA, or F1+2 were observed. Endothelial perturbation was shown in 70% of group A and 20% of group B. After 1 year, 16 of the 20 patients in group A showed a significant reduction in vWF, tPA, F1+2, TNF-α, and CRP levels, whereas endothelial perturbation was reversed in 5 of these patients. CONCLUSIONS—Endothelial perturbation represents an early and, in some cases, reversible event in the chronology of type 1 diabetes in children. A correlation might exist between the initial inflammatory reaction and the appearance of endothelial perturbation.