The Role of Oxidative Stress in the Pathogenesis of Type 2 Diabetes Mellitus Micro- and Macrovascular Complications: Avenues for a Mechanistic-Based Therapeutic Approach

Abstract

A growing body of evidence suggests that oxidative stress plays a key role in the pathogenesis of micro- and macrovascular diabetic complications. The increased oxidative stress in subjects with type 2 diabetes is a consequence of several abnormalities, including hyperglycemia, insulin resistance, hyperinsulinemia, and dyslipidemia, each of which contributes to mitochondrial superoxide overproduction in endothelial cells of large and small vessels as well as the myocardium. The unifying pathophysiological mechanism that underlies diabetic complications could be explained by increased production of reactive oxygen species (ROS) via: (1) the polyol pathway flux, (2) increased formation of advanced glycation end products (AGEs), (3) increased expression of the receptor for AGEs, (4) activation of protein kinase C isoforms, and (5) overactivity of the hexosamine pathway. Furthermore, the effects of oxidative stress in individuals with type 2 diabetes are compounded by the inactivation of two critical anti-atherosclerotic enzymes: endothelial nitric oxide synthase and prostacyclin synthase. Of interest, the results of clinical trials in patients with type 2 diabetes in whom intensive management of all the components of the metabolic syndrome (hyperglycemia, hypercholesterolemia, and essential hypertension) was attempted (with agents that exert a beneficial effect on serum glucose, serum lipid concentrations, and blood pressure, respectively) showed a decrease in adverse cardiovascular end points. The purpose of this review is (1) to examine the mechanisms that link oxidative stress to micro- and macrovascular complications in subjects with type 2 diabetes and (2) to consider the therapeutic opportunities that are presented by currently used therapeutic agents which possess antioxidant properties as well as new potential antioxidant substances.

Association of Mean Platelet Volume and Platelet Distribution Width with Hba1c

“…It can be determined by routine automated hemograms at a relatively low cost [22]. An increased of MPV is one of the risk factors for micro vascular and macro vascular complications, including cardiovascular disease (CVD), retinopathy, nephropathy occur due to chronic un control hyperglycemia in diabetics also myocardial infarction, ischemic stroke and venous thromboembolism [23][24][25][26][27][28][29].…”

Deriving at candidate genes of metabolic stress from pancreas of WNIN/GR-Ob mutant rats

“…Inflammation as an intrinsic mechanism to facilitate toward islet dysfunction have been well documented in type 1 diabetes (T1D), 15 obese-T2D 1 as well as in T2D with IR. 16 There have been several confounding factors such as tissue hypertrophy/hyperplasia, 17 oxidative stress 4,10 and apoptosis 17 eventually complementing the chronic inflammatory conditions, 2 in addition to environmental, genetic and epigenetic influences. 18 Mutants demonstrated for an increased expression of TNFα and IL-6, 8 similar to data reported in NOD mice, 19 and which correlated with an increased macrophage infiltration vis-a-vis inflammation.…”

“…These observations were significant due to the fact that these mutants have the natural occurrence of obesity/IR/IGT almost similar to the pre-clinical/clinical scenario, unlike the genetically manipulated or experimental models which have their limitations to extrapolate with human subjects. 9 It is of utmost importance to note that β-cells of pancreas have an inherent weak antioxidant system compared with any other organs in the body 4 and persistent IR, hyperglycemia, or HI predisposes them to a state of profound stress 4,10 and dysregulation of function. 4,10 We hypothesize here that, these mutants would form an ideal model system to study the gravity of metabolic insult/ inflammation using pancreas as the target tissue.…”

“…9 It is of utmost importance to note that β-cells of pancreas have an inherent weak antioxidant system compared with any other organs in the body 4 and persistent IR, hyperglycemia, or HI predisposes them to a state of profound stress 4,10 and dysregulation of function. 4,10 We hypothesize here that, these mutants would form an ideal model system to study the gravity of metabolic insult/ inflammation using pancreas as the target tissue. To prove this, we performed global gene expression (microarray) from pancreas of both mutants (−/−) and parental WNIN controls to assess the magnitude of in situ metabolic lesion.…”

Biochemistry of hyperglycemia induced vascular dysfunction

“…Firstly, NADPH is the essential cofactor required for GSH regeneration from GSSG. Therefore, being consumed in the polyol pathway causes increased susceptibility to oxidative stress [25].…”