Role of Nitric Oxide Synthase Family in Diabetic Neuropathy

Abstract

Diabetes mellitus is one of the most common chronic diseases and a major health problem in nearly all countries. Its prevalence has risen sharply worldwide during the past few decades. The increase in its prevalence is largely due to an epidemic of type 2 diabetes (T2DM) but also the type 1 diabetes (T1DM) incidence is rising all over the world. The "classical" microvascular complications of both types of diabetes are represented by diabetic retinopathy, diabetic renal disease, and diabetic polyneuropathy (DPN). The latter has known to be heterogeneous regarding symptoms, pattern of neurologic involvement, and progression in time, pathologic alterations, and underlying mechanisms. DPN results from the direct damage of peripheral nerve components and of the associated vasa nervorum. The main contributor to the DPN development is the cumulative effect of chronic hyperglycemia -duration of diabetes and level of metabolic control. Apart the major role of hyperglycemia one of the most important factor is nitric oxide (NO) system. The NO production and local release are dramatically changed and contribute to the DPN development. The process takes place by the modulation of the nitric oxide synthase (NOS) enzymes responsible for NO synthesis by the diabetic milieu. While the decline in NO bioavailability is due to the decrease in neuronal (NOS1) and endothelial (NOS3) expression, the increase of local NO levels with the formation of peroxynitrites arises from the upregulation of inducible (NOS2) protein. Thus, NOS genes became natural candidates for the study of DPN genetics. In comparison with the other diabetes microvascular complications, data regarding the genetic background of DPN are rather scarce, particularly for NOS genes. The aim of this review is to present the pathogenesis of DPN in both type 1 and type 2 diabetes and the effect of the NOS genes-NOS enzymes-NO system. J ou rna l o f D ia be tes & M e ta bolism

Modifications of expression of genes and proteins involved in DNA repair and nitric oxide metabolism by carbatonides [disodium-2,6-dimethyl-1,4-dihydropyridine- 3,5-bis(carbonyloxyacetate) derivatives] in intact and diabetic rats

“…On the contrary, in the paraventricular nucleus of animals with modelled insulin resistance, eNOS was down-regulated; expression of iNOS did not change (29). Others have also shown an increased as well as decreased expression of eNOS in different tissues of diabetic animals (30). The observed increase in iNOS protein and iNos gene in the studied tissues of diabetic animals was in good correlation with published data.…”

Alterations in circulating angiogenic and anti‐angiogenic factors in type 2 diabetic patients with neuropathy

“…It was also shown that the plasma levels of NOx were significantly higher in patients with DPN than in diabetic patients without DPN. 19,65 In conclusion, our study suggests that angiogenesisrelated biomarkers (VEGF, sEng, ET-1, ET-1 mRNA gene expression and NOx) are associated with the development of DPN in patients with T2DM. Previous studies revealed that NOx levels as markers of endothelial injury were higher in neuropathic diabetic patients than those without neuropathy.…”

“…64 These events start very early, even before overt hyperglycaemia (the prediabetic state) as reported in both human and experimental T2DM models. 19,65 In conclusion, our study suggests that angiogenesisrelated biomarkers (VEGF, sEng, ET-1, ET-1 mRNA gene expression and NOx) are associated with the development of DPN in patients with T2DM. A long-standing clinical course of DM, hyperglycaemia and inflammation are factors associated with changes in the plasma levels of these markers.…”

“…Thus, sEng seems to impair endothelial function, and endothelial dysfunction is a major characteristic of patients with diabetes. 19 On the basis of the aforementioned observations, it seems that changes in circulating angiogenic regulating factors have a role in mediating diabetic microvascular complications. ET-1 contributes to endothelial abnormalities and the altered balance of vasodilatation and vasoconstriction in favour of the latter in diabetes.…”

“…18 Moreover, previous studies suggest that dysfunctional endothelial constitutive NOS might play a critical role in the pathogenic pathway leading to diabetic vascular complications including DPN. 19 On the basis of the aforementioned observations, it seems that changes in circulating angiogenic regulating factors have a role in mediating diabetic microvascular complications. However, little studies reported the association between these factors and the risk and severity of DPN in patients with T2DM.…”