Correlation of low molecular weight advanced glycation end products and nitric oxide metabolites with chronic complications in type 1 diabetic patients

Abstract

Advanced glycation end products (AGEs) are involved in the occurrence of vascular complications in diabetes. The present study was undertaken to investigate the level of low-molecular weight products of AGEs (LMW-AGEs) in relation to microvascular complications in type 1 diabetes, and the possible relationship with nitric oxide (NO) as a marker of endothelial function. Patients with normal renal function (NRF) were classified into two groups: (1) without, and (2) with diabetic neuropathy; and patients with renal impairment also into two groups: (3) diabetic renal disease, and (4) end-stage renal disease. The fluorescence of LMW-AGEs and measurement of NO metabolites was assessed in 277 serum samples. In addition, multiple regression analysis was performed. In group 1, LMW-AGEs level (9.3±1.1 AF%) was higher than in the control group (2.4±0.3 AF%). A trend in the increase of LMW-AGEs with neuropathy (29.7±5.5 AF%, group 2), and further with renal impairment (47.0±8.0, group 3 and 137.8±25.5 AF%, group 4), was observed. In multivariate regression analysis LMW-AGEs were associated with NO metabolites in group 2. In NRF patients, diabetic neuropathy was significantly correlated with LMW-AGEs and NO metabolites, independently of serum creatinine and duration of diabetes. This relationship suggests that the NO and LMW-AGEs' actions (possibly synergistic) in endothelial activation possess a role in the initiation and development of diabetic microvascular complications.

Polymorphism in exon 7 of the endothelial nitric oxide synthase gene is associated with low incidence of microvascular damage in type 1 diabetic neuropathy

“…It is evident that NO plays a regulatory role in the peripheral nervous system [7], and recent reports have indicated that excessive local NO levels are present at sites of diabetic neuropathy [8]. Recently we showed a significant correlation between NO metabolites and LMW-AGEs and diabetic neuropathy in T1DM [9].…”

“…We previously used this T1DM group to estimate the relationship between LMW-AGEs and diabetesassociated microvascular complications; this study reported details on body mass index, fasting blood glucose, total cholesterol, triglycerides, HbA1c, systolic and diastolic blood pressure, and serum creatinine clearance [9].…”

High glucose-induced increased expression of endothelin-1 in human endothelial cells is mediated by activated CCAAT/enhancer-binding proteins

“…Hyperglycemia, the primary clinical manifestation of diabetes, contributes to diabetic complications [1] by inducing vascular inflammation, oxidative stress, impaired vascular relaxation, changing vascular cell metabolism, altering the vascular matrix molecules, and circulating proteins/lipoproteins. [2][3][4] Nevertheless, the precise mechanisms by which hyperglycemia induce pathological outcomes and the molecular nature of its downstream effectors is still a debatable issue.…”

Genetic Determinants of Microvascular Complications in Type 1 Diabetes

“…This phenomenon occurs early in the natural course of diabetes and independently of the presence of microvascular complications. So, we suggest that the high NO levels found in diabetic patients (including those without any clinically manifested microangiopaties) might represent an overproduction of NO that is associated with diffuse endothelial dysfunction (Heltianu et al, 2008). There is a family of NOS enzymes which produces NO.…”

“…In active progressive DR, aqueous NO levels are significantly high, while plasma NO levels remained at the level of diabetics without DR (Yilmaz et al, 2000). Raised plasma NO levels in T1DM patients were reported (Heltianu et al, 2008) indicating that pathogenesis of diabetic-associated vascular complications is connected with a generalized increased synthesis of NO throughout the body. This phenomenon occurs early in the natural course of diabetes and independently of the presence of microvascular complications.…”