Are Oxidative Stress−Activated Signaling Pathways Mediators of Insulin Resistance and β-Cell Dysfunction?

Abstract

In both type 1 and type 2 diabetes, diabetic complications in target organs arise from chronic elevations of glucose. The pathogenic effect of high glucose, possibly in concert with fatty acids, is mediated to a significant extent via increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and subsequent oxidative stress. ROS and RNS directly oxidize and damage DNA, proteins, and lipids. In addition to their ability to directly inflict damage on macromolecules, ROS and RNS indirectly induce damage to tissues by activating a number of cellular stress-sensitive pathways. These pathways include nuclear factor-B, p38 mitogen-activated protein kinase, NH 2 -terminal Jun kinases/stress-activated protein kinases, hexosamines, and others. In addition, there is evidence that in type 2 diabetes, the activation of these same pathways by elevations in glucose and free fatty acid (FFA) levels leads to both insulin resistance and impaired insulin secretion. Therefore, we propose here that the hyperglycemia-induced, and possibly FFA-induced, activation of stress pathways plays a key role in the development of not only the late complications in type 1 and type 2 diabetes, but also the insulin resistance and impaired insulin secretion seen in type 2 diabetes. Diabetes

Coffee and tea consumption and risk of type 2 diabetes

“…Antioxidants may reduce the amount of reactive oxygen species, which activate stress-sensitive pathways. These pathways can lead to insulin resistance, impaired insulin secretion and beta cell dysfunction [39,40].…”

Reconvene and Reconnect the Antioxidant Hypothesis in Human Health and Disease

“…Since FR were accused as causal factors in a large number of diseases, these were sometimes referred as ''Free Radical Diseases''. Some of the important diseases and health issues in this category are cancer [61][62][63][64][65][66][67], cardiovascular diseases [68][69][70][71][72][73], atherosclerosis [74][75][76][77][78][79][80][81], neurological disorders [82][83][84][85][86], renal disorders [87][88][89][90], liver disorders [91][92][93], hypertension [50,94,95], rheumatoid arthritis [96,97], adult respiratory distress syndrome, auto-immune deficiency diseases [98,99], inflammation, degenerative disorders associated with aging [100][101][102][103], diabetes mellitus [104][105]…”

Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2

“…Diabetes mellitus with an alarmingly rising incidence (1) is a cluster of abnormal metabolic paradigm having a common of environmental factors which may act independently or in concert with genetic disposition, fifth, in due course of time a large number of DMT-2 patients develop multiple macro-or micro-vascular complications or both, sixth, the new molecular mechanisms involved in pathogenesis of the disease are now emerging, are more vigorously investigated and their interaction among themselves and their superimposition or intertwining with genetic factors are being critically evaluated, yet the etiopathogenesis of the disease is not fully understood (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Obviously, clinicians have limited armamentarium for the treatment of the disease, and so far no drug is known to cure it permanently.…”

“…Progressively, beta-cells start getting tired and exhausted and level of insulin secretion starts declining with the result hypoinsulinemia develops along with overt DMT-2 (2,9,38). In the next phase, beta-cell dysfunction develops (17,18,(38)(39)(40). Cells in various tissues develop metabolic stress of various types with varying magnitude which may culminate in diabetic complications (12,16,(41)(42)(43)(44)(45)(46).…”