Oxidative Stress and Diabetic Vascular Complications

Abstract

Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although prospective randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between diabetic hyperglycemia and the development of secondary complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that the generation of reactive oxygen species (oxidative stress) may play an important role in the etiology of diabetic complications. This hypothesis is supported by evidence that many biochemical pathways strictly associated with hyperglycemia (glucose autoxidation, polyol pathway, prostanoid synthesis, protein glycation) can increase the production of free radicals. Furthermore, exposure of endothelial cells to high glucose leads to augmented production of superoxide anion, which may quench nitric oxide, a potent endothelium-derived vasodilator that participates in the general homeostasis of the vasculature. In further support of the consequential injurious role of oxidative stress, many of the adverse effects of high glucose on endothelial functions, such as reduced endothelial-dependent relaxation and delayed cell replication, are reversed by antioxidants. A rational extension of this proposed role for oxidative stress is the suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status.

Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: Role of insulin and C‐peptide

“…Hyperglycemia-induced ROS production (in the mitochondria) occurs in endothelial cells and in platelets through auto-oxidation of glucose [Wolff and Dean, 1987], advanced glycation end (AGE) product formation and the binding of AGEs to their receptors [Yan et al, 1994;Ceriello, 1999], increased substrate flux through the polyol pathway [Giugliano et al, 1996], and/or through stimulation of the eicosanoid metabolic pathways [Tesfamariam and Cohen, 1992a,b;Quilley and Chen, 2003]. The major sources of O 2 À in cardiovascular cells are: NADH/NADPH oxidase [Griendling et al, 2000], which transfers electrons from NADH or NADPH to molecular oxygen, producing O 2 À ; xanthine oxidase [Wolin, 1996]; endothelial nitric oxide synthase [Ignarro et al, 1999]; cyclooxygenase-2 [Adeagbo et al, 2003]; myeloperoxidase [Berliner and Heinecke, 1996]; and lipoxygenases [Kunsch and Medford, 1999].…”

Protective influence of vitamin E on the antioxidant defence system in the whole blood and liver of normal and alloxan-induced diabetic rats

“…Increased production of reactive forms of oxygen and lipoperoxides together with lowered levels of substances (vitamin C, vitamin A, lipoic acid, glutathione) having antioxidative reaction and enzymes acting as antioxidative agents such as superoxide dismutase and catalase can be found in the blood and tissues of patients affected with the disease (7). According to the current views, the antioxidative stress plays a significant role in the etiopathogenesis of diabetes mellitus of both first and second types and has key importance in the occurrence and development of diabetic complications (8).…”

Study of urinary 8-hydroxydeoxyguanosine as a biomarker of oxidative DNA damage in diabetic nephropathy patients

“…Recent reports [13][14][15] found an increased 8-OHdG level in mononuclear cells and urine in patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). Giugliano et al [16] reported that the leukocyte or urinary 8-OHdG was related significantly with the severity of diabetic nephropathy and retinopathy. The study of Hinokio et al [17] provided direct evidence that increased urinary 8-OHdG at entry was associated with the development of diabetic nephropathy after 5 years.…”