Free radicals and diabetes -
However, most free radicals are extremely reactive and short-lived, qualities that render their direct detection tremendously difficult.
The spin-trapping method, in which the unstable free radical reacts with a trap molecule spin trap to form a more stable, long-lived radical species, allows the detection of many otherwise undetectable radicals 28 , In this study, we took advantage of the ability of the spin-trapping agent PBN to detect cytokine-induced free radical formation in the pancreas of the rats.
EPR spectra obtained from of the animals that received cytokines intrapancreatically exhibited the presence of a high level of at least one free radical species in this organ.
In most cases, however, the presence of more than one radical was apparent from the recorded spectra. The radicals detected in this study have hyperfine splitting constants characteristic of lipid L· or lipoxyl radicals LO· Both of these species may arise from peroxidation of the membrane lipids, a process most likely initiated by ROS.
The initially produced ROS, formed through the action of COX-2 vide infra , can abstract a hydrogen atom from a lipid molecule and thus produce the lipid radical L·. Lipoxyl radicals form as a result of metal-ion decomposition of lipid hydroperoxides generated through the reaction of L· with molecular oxygen.
For determining whether pancreatic β-cells play a role in the formation of the observed radicals, they were depleted in a group of rats before their treatment with the cytokines.
Cytokine administration to these rats generated little or no signal, indicating that β-cells serve as the origin of the detected free radicals. This finding is of extreme importance to gaining a better understanding of the mechanisms involved in the pathogenesis of type 1 diabetes, because it demonstrates for the first time that cytokines elicit free radical formation by the β-cells.
However, depletion of macrophages by previous gadolinium chloride treatment only partially inhibited the generation of free radicals. The observations that β-cell depletion leads to near total suppression of free radicals, whereas macrophage eradication only partially inhibits this process, indicate that although macrophages contribute to the formation of the detected radicals, their role is indirect.
We believe that macrophages most likely enhance the generation of free radicals by the β-cells through the release of additional cytokines. Our previous studies in the same model demonstrated that in vivo cytokine administration to the rat pancreas leads to the expression of the inflammatory enzyme COX-2 in the islets isolated from the pancreata treated in vivo with cytokines Also, in isolated rat islets, IL-1 has been shown to promote COX-2 expression and prostaglandin E 2 PGE 2 formation 35 , Consequently, COX-2 has been proposed to play a role in the pathogenesis of type 1 diabetes Furthermore, we have previously reported that selective inhibition of COX-2 protects mice from low-dose STZ-induced diabetes, pointing to a role for this enzyme in diabetes pathogenesis in this model It is interesting that it has recently been reported that there is an increased expression of COX-2 in patients with established type 1 diabetic and in individuals at higher genetic, immunologic, and familial risk for this disease In addition, inflamed islets of NOD mice have been shown to produce increased levels of COX-2 catalyzed PGE 2 formation Robertson and colleagues 41 , 42 have reported that unlike most other tissues, in pancreatic islets, COX-2 and not COX-1 constitutive isoform of COX is dominantly expressed at the basal level.
All of these findings point to a possible link between COX-2 activity and the destruction of the β-cells. Among COX-2 products, PGE 2 is known to inhibit glucose-induced insulin release by β-cells 41 , ILinduced inhibition of insulin secretion by islet 36 cells is mediated by PGE 2 However, like other prostanoids, PGE 2 has both pro- and anti-inflammatory actions 44 , and it is not yet clear whether PGE 2 formation by COX-2 in the islets has a protective or detrimental effect.
A more intriguing aspect of COX activity might be that the catalytic activity of this enzyme is accompanied by the formation of ROS 23 , COX-2 is a complex enzyme with both cyclooxygenase and peroxidase activities. Both of these activities have been shown to give rise to ROS formation 23 , Our observation that selective inhibition of COX-2 by NS abolishes the cytokine-induced free radical generation suggests that COX-2 activity is indeed the major source of ROS generation in our model.
Thus, whereas COXmediated PGE 2 formation may have detrimental consequences for the β-cells, the ROS formation that results from overexpression of COX-2 would undoubtedly damage and destroy the β-cells, particularly under the chronic inflammatory conditions preceding the death of β-cells.
Proinflammatory cytokines such as TNF-α and IL-1 have been reported to cause the activation of the transcription factor NF-κB 45 , The involvement of NF-κB activation in ILinduced PGE 2 formation by isolated rat islets has been demonstrated We have shown that under the experimental conditions used, cytokines evoke the activation and nuclear localization of NF-κB in the islets and not in the surrounding acinar tissue.
We have also demonstrated that inhibition of NF-κB activation prevents the generation of cytokine-induced free radicals. These findings indicate that cytokine-mediated activation of NF-κB in the islets leads to generation of free radicals by the β-cells. NF-κB activation leads to the expression of COX-2, further supporting the notion that COX-2 is likely the major source of free radicals.
Considering that the existence of a chronic inflammatory state in and around the islets during the insulitis phase most likely translates into chronic NF-κB activation in the islets, these findings demonstrate at least one of the detrimental outcomes of such an event.
EPR spectra of spin-trapped free radicals recorded from rat pancreatic extracts after in vivo intrapancreatic treatment with cytokines A — D or vehicle E — H. Each spectrum represents an individual animal. Computer spectral simulation of the EPR spectrum of the spin-trapped free radicals in pancreatic tissue.
A : Actual EPR spectrum for spin-trapped free radicals same as Fig. B : A computer-simulated EPR spectrum reproducing the EPR spectrum A. For producing the composite spectrum B, the individual spectra calculated for free radicals 1 C and 2 D were superimposed with a ratio of and the center of the spectrum C was shifted 0.
The highest field lines right side lines in the actual spectrum A are broadened shortened by motional effect characteristic of solution EPR spectra. Other spectra shown in Figs. Effect of various treatments on EPR spectral intensity free radical level.
EPR spectra of spin-trapped free radicals were recorded in the pancreatic extract obtained from rats after in vivo intrapancreatic cytokine administration with pre- or posttreatment with various agents and inhibitors. A : Cytokines alone, no inhibitor. B : Pretreatment with STZ to deplete β-cell.
C : Pretreatment with gadolinium chloride to deplete macrophages. D : Posttreatment with NS to inhibit COX-2 activity. E : Pretreatment with PDTC to inhibit NF-κB activation. Free radical levels obtained in the pancreatic tissue after various in vivo treatments.
Immunostaining of insulin in a pancreatic islet control; A , NF-κB p65 in a pancreatic islet of a control vehicle-treated rat B , and NF-κB p65 in a pancreatic islet of a rat C treated with cytokines for 60 min. Magnification ×.
Arrows point to the nuclear localization of NF-κB p65 in the islet. This study was supported by funds from Oklahoma Center for Advancement of Science and Technology HR Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Diabetes.
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Article Navigation. Islet August 01 Free Radicals and the Pathogenesis of Type 1 Diabetes : β-Cell Cytokine-Mediated Free Radical Generation Via Cyclooxygenase-2 Tahereh Tabatabaie ; Tahereh Tabatabaie.
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Get Permissions. Natural food, leafy vegetables and fruit sources are the richest source of antioxidants. Besides this lemon, amla, ashwagandha also contains antioxidants.
Beta carotene is also found in green leafy vegetables such as spinach, kale, and coloured greens. For healthy eyes Lutein is best green leafy vegetable. In most of developing countries wheat and rice are the main dietary source of selenium having major antioxidant enzymes.
Carrots, milk, sweet potatoes, mozzarella and egg yolks consist retinol, 3 hydroxyretinol and didehydroretinol.
Poultry, beef, cereals and fish contains vitamin C. Flavonoids, diterpenes, cinnamic acid, phenylpropanoids contains phytoconstituents with antioxidants. In wheat germ oil, corn oil, mangoes, almonds, nuts contains vitamin E. Higher plants contain natural antioxidants in leaves, pods, roots, seeds, pollen, wood and bark.
Treatment of severe diseases with oxidative stress is possibly cured by plants antioxidants including diabetic mellitus []. In humans Plasma contains antioxidants and use as a marker to measure oxidative stress.
There are many compounds present in plasma, which protect cell and cellular biomolecules from oxidative stress. So the combined action of all molecules in plasma represents the antioxidant capacity of plasma [17,18]. The plasma glycemic level will be low in diabetic patients than healthy ones because the antioxidants are present in low amount in diabetic patient plasma [19,20].
The increase in oxidative stress while decrease of antioxidant capacity correlated with complications of diabetes mellitus as insulin resistance and DNA damage [21]. Due to low antioxidant defense in plasma the problems like blindness, nerve damage, cardiovascular disease and nephropathy occurs [22].
Antioxidants could be obtained from different dietary sources and is used for maintaining free radicals stable and not to develop oxidative stress thus improving our defence mechanism. In nature, there are various non-enzymatic and enzymatic mechanisms for removal of reactive oxygen species.
In nonenzymatic antioxidant system includes ascorbic acid, retinol, glutathione, carotenoids, tocopherols, and trace elements like selenium, copper, zinc, coenzyme Q10, uric acid, factors of folic acid, riboflavin and thiamine.
Vitamin E is the fat soluble responsible for prevention of lipid peroxidation. Glutathione acts as a scavenger as well as a substrate for glutathione peroxidase. There are eight different forms in vitamin E exist in the fat soluble form in which A tocopherol is found in sunflower and wheat germ oil and the safflower oil is most active in biological form in humans.
Lipid peroxidation is prevented through fat soluble vitamin E. Researchers recently suggested that nitric oxide production in epithelial cells is increased through vitamin C.
In chronic cardiac complications of diabetes patient the important enzymes goes into smooth muscles. So the major organs such heart, kidneys are directly affected by diabetes. In the enzymatic antioxidant defence mechanism SOD and Glutathione reductase is important. Glutathione reductase regenerates glutathione, which can be used as hydrogen donor by glutathione peroxidase through elimination of hydrogen peroxide.
SOD converts superoxide to hydrogen peroxide []. There are various mechanisms in which antioxidant differ in their action mechanism. These are free radicals scavenging mechanism, inhibition of enzymes that humiliate free radical reactions; degradation of proteins, including transferring that can bind metals which eventually stimulate free radicals.
Oxidative stress is a pathological condition triggered by the damaging action on cells and tissues of the body Oxidative is the direct consequence of an increased generation of free radicals and or reduced physiological activity of antioxidant defenses against free radicals and reactive nitrogen species.
Non radical species are hydrochlorous acid and hydrogen peroxide molecules. Free radical species are superoxide molecules, hydroperoxyl molecules, hydroxyl molecules. Reactive nitrogen species are having free radicals are nitrogen dioxide and nitric oxide while non-radical are peroxynitrates and peroxynitrites.
By the physical, physiological and chemical factors the reactive radicals, nitric oxide peroxynitrite and superoxide molecules cause tissue damage. There are a variety of different defense mechanisms by which human body works against oxidative stress induced by free radicals as tissue repair, anticipatory mechanism, physical resistance and antioxidant defense.
Reactive oxygen species of various free radicals are involved in cardiovascular diseases, renal disorders, autoimmune disorders, neurodegenerative disorders, peptic ulcer, cataract, lung cancer Figure 1 [26,27]. Diabetes mellitus management with no side effect is still a challenge in 21 century for doctors and researchers.
In the treatment of diabetes mellitus herbal drugs is of great interest due to low cost, efficiency and less side effects and so a variety of plants are being used as an herbal treatment.
In herbal treatment phytoconstituents derived from plants are important and includes glycosides, alkaloids, glycopeptides, steroids, hypoglycans, guanidine, carbohydrates, gums, various amino acids and peptidoglycans.
The phytoconstituents greatly influence metabolic activities which directly affect glucose level in the body. For the management of some diseases such as Alzheimer disease, stroke, cardiac arrest, cancer, atherosclerosis and Parkinson disease antioxidant formulation is of great study and effort.
Diabetic complications can be reduced by dietary antioxidants and is one of promising therapeutic approach.
For the treatment of some diseases such as stroke, atherosclerosis, cancer, neurodegenerative diseases, diabetes mellitus and human ailments Figure 2 []. In recent studies, it is stated that if a traditional system of medicines like Siddha and Ayurveda is used with modern science medicines will be very effective.
Diabetic complications associated with oxidative stress can be minimized to some extent by natural antioxidants. But there is no perfect mechanism developed till to date in which the diabetic complications are known exactly.
In various there are various clinical, epidemiological and experimental antioxidants are developed to cure of diabetes and other diseases. Received: February 29, Accepted: March 13, Published: March 19, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Mariyam S, Jose J, Kumar S and Parmar MY Super power of antioxidant in oxidative stress and Diabetes Mellitus.
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Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Moller W, Tritschler HJ, Mehnert H: Treatment of diabetic polyneuropathy with the antioxidant thioctic acid alpha-lipoic acid : a two year multicenter randomized double-blind placebo-controlled trial ALADIN II.
Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res. Ziegler D, Hanefeld M, Ruhnau K, Hasche H, Lobisch M, Schutte K, Kerum G, Malessa R: Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial ALADIN III Study.
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Ziegler D, Nowak H, Kempler P, Vargha P, Low PA: Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Dobrian AD, Davies MJ, Schriver SD, Lauterio TJ, Prewitt RL: Oxidative stress in a rat model of obesity-induced hypertension.
Bagi Z, Koller A, Kaley G: PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. Fukui T, Noma T, Mizushige K, Aki Y, Kimura S, Abe Y: Dietary troglitazone decreases oxidative stress in early stage type II diabetic rats.
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Download references. This work was supported by grants from NIH HL , American Heart Association Scientist Development Grant and American Diabetes Association to Adviye Ergul and an AHA Southeast Affiliate Predoctoral Fellowship Award to Alex K.
University of Georgia College of Pharmacy, Athens, Georgia, USA. Medical College of Georgia Vascular Biology Center, Augusta, Georgia, USA. You can also search for this author in PubMed Google Scholar.
Correspondence to Adviye Ergul. AKH and JSJ contribute equally to writing the evidence-based sections and drafting of this review. DR was responsible for critical revision and formatting. AE participated in all aspects and areas of this review.
Open Access This article is published under license to BioMed Central Ltd. Reprints and permissions. Johansen, J. et al. Oxidative stress and the use of antioxidants in diabetes: Linking basic science to clinical practice. Cardiovasc Diabetol 4 , 5 Download citation.
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Provided by the Springer Nature SharedIt content-sharing initiative. View archived comments 1. Skip to main content. Search all BMC articles Search. Download PDF. Download ePub. Abstract Cardiovascular complications, characterized by endothelial dysfunction and accelerated atherosclerosis, are the leading cause of morbidity and mortality associated with diabetes.
Introduction It is a well-established fact that diabetes is a risk factor for cardiovascular disease [ 1 , 2 ]. What is oxidative stress? Figure 1.
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Diabetee Diabetology volume 4Article number: radicald Organic pre-workout supplements this article. Free details. Rdaicals complications, characterized by endothelial dysfunction and Nutrient-rich diet choices atherosclerosis, are the leading cause of morbidity Organic pre-workout supplements mortality associated Frse diabetes. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Despite overwhelming evidence on the damaging consequences of oxidative stress and its role in experimental diabetes, large scale clinical trials with classic antioxidants failed to demonstrate any benefit for diabetic patients. Fred mellitus is a syndrome initially characterized Ftee a loss Free radicals and diabetes glucose homeostasis. The disease is progressive and Free associated with diabetex risk of atherosclerosis, kidney and nerve damage rdicals Organic pre-workout supplements as blindness. Abnormalities Free radicals and diabetes radicsls regulation of radicaps and Organic pre-workout supplements metal Fueling for explosive power are postulated to result in establishment of the disease as well as its longer term complications. Diabetes mellitus is associated with oxidative reactions, particularly those which are catalyzed by decompartmentalized transition metals, but their causative significance in diabetic tissue damage remains to be established. Access to content on Oxford Academic is often provided through institutional subscriptions and purchases. If you are a member of an institution with an active account, you may be able to access content in one of the following ways:. Typically, access is provided across an institutional network to a range of IP addresses.
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