title: 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.
authors.affiliation: Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio, USA. folli@uthscsa.edu
authors.forename: Franco
authors.initials: F
authors.lastname: Folli
authors.forename: Domenico
authors.initials: D
authors.lastname: Corradi
authors.forename: Paolo
authors.initials: P
authors.lastname: Fanti
authors.forename: Alberto
authors.initials: A
authors.lastname: Davalli
authors.forename: Ana
authors.initials: A
authors.lastname: Paez
authors.forename: Andrea
authors.initials: A
authors.lastname: Giaccari
authors.forename: Carla
authors.initials: C
authors.lastname: Perego
authors.forename: Giovanna
authors.initials: G
authors.lastname: Muscogiuri
mesh_terms: D000975:Antioxidants / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D007333:Insulin Resistance; D018384:Oxidative Stress
chemical_list: D000975:Antioxidants