Free radicals and diabetes
TL;DR: Not only are oxygen radicals involved in the cause of diabetes, they also appear to play a role in some of the complications seen in long-term treatment of diabetes.
About: This article is published in Free Radical Biology and Medicine.The article was published on 1988-01-01. It has received 1136 citations till now. The article focuses on the topics: Streptozotocin & Diabetes mellitus.
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TL;DR: There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
Abstract: At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...
9,131 citations
TL;DR: Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes.
Abstract: N epsilon-(carboxymethyl)lysine, N epsilon-(carboxymethyl)hydroxylysine, and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds, termed glycoxidation products, accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations, even in diabetic collagen, studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress, tissue damage, and cell death, leading to increased free radical production and compromised free radical inhibitory and scavenger systems, which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes.
3,933 citations
TL;DR: There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.
Abstract: Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. These consequences of oxidative stress can promote the development of complications of diabetes mellitus. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes, and their consequences, are discussed in this review. In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed. There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.
2,930 citations
Cites background from "Free radicals and diabetes"
...Extensive studies of pharmacological interventions based on biological antioxidants have been carried out since the last review by Oberley [48]....
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TL;DR: The controversial role of ROS in tumour development and in responses to anticancer therapies is addressed, and the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact is elaborate.
Abstract: The regulation of oxidative stress is an important factor in both tumour development and responses to anticancer therapies. Many signalling pathways that are linked to tumorigenesis can also regulate the metabolism of reactive oxygen species (ROS) through direct or indirect mechanisms. High ROS levels are generally detrimental to cells, and the redox status of cancer cells usually differs from that of normal cells. Because of metabolic and signalling aberrations, cancer cells exhibit elevated ROS levels. The observation that this is balanced by an increased antioxidant capacity suggests that high ROS levels may constitute a barrier to tumorigenesis. However, ROS can also promote tumour formation by inducing DNA mutations and pro-oncogenic signalling pathways. These contradictory effects have important implications for potential anticancer strategies that aim to modulate levels of ROS. In this Review, we address the controversial role of ROS in tumour development and in responses to anticancer therapies, and elaborate on the idea that targeting the antioxidant capacity of tumour cells can have a positive therapeutic impact.
2,639 citations
TL;DR: The suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status is suggested.
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.
1,966 citations
Cites background from "Free radicals and diabetes"
...Like reduced glutathione, vitamins E and C may be decreased in diabetic patients (58-61), although not all studies were able to show reduced antioxidant vitamins in diabetes (62)....
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References
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TL;DR: The results point to a reaction between H2O2 and O2- (Haber-Weiss reaction) as a major source of the ·OH radicals and to a combined action of blocking ·OH formation as well as accelerating its removal.
896 citations
Journal Article•
775 citations
TL;DR: It is described that both Streptozotocin and alloxan cause DNA strand breaks which stimulate nuclear poly(ADP–ribose) synthetase, thereby depleting intracellular NAD and inhibiting proinsulin synthesis in isolated pancreatic islets of rats.
Abstract: Streptozotocin, which produces diabetes mellitus in experimental animals1–3, has been reported to reduce the level of NAD in pancreatic islets4,5 and to inhibit islet synthesis of proinsulin6. The decrease in NAD is due to increased NAD degradation mediated by islet nuclear poly(ADP–ribose) synthetase7,8. Evidence suggests that poly(ADP–ribose) synthetase is activated when DNA is fragmented9–17. Here we describe that both Streptozotocin and alloxan, which also produces experimental diabetes mellitus1,2, cause DNA strand breaks which stimulate nuclear poly(ADP–ribose) synthetase, thereby depleting intracellular NAD and inhibiting proinsulin synthesis in isolated pancreatic islets of rats.
573 citations
TL;DR: Pancreatic islets were found to belong to tissues with relatively little activity of the protective enzymes, and the deviation from other tissues in this respect is probably not large enough to explain the especially great susceptibility of islet cells to alloxan.
Abstract: Exogenous superoxide dismutase, catalase and scavengers of the hydroxyl radical protect pancreatic-islet cells against the toxic actions of alloxan in vitro [Grankvist et al. (1979) Biochem. J. 182, 17--25]. To test whether the extraordinary sensitivity of islet cells to alloxan is due to a deficiency of endogenous enzymes protecting against oxygen-reduction products, we assayed CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in mouse islets and other tissues. To correct for any blood contamination, haemoglobin was also measured in the tissue samples. Pancreatic islets were found to belong to tissues with relatively little activity of the protective enzymes. However, the deviation from other tissues in this respect is probably not large enough to explain the especially great susceptibility of islet cells to alloxan.
496 citations
TL;DR: The data obtained with a large sample of patients, and the relation between the lipid peroxide level and the different features of the disease are dealt with.
484 citations