Oxidative stress and diabetes

摘要: Type 2 diabetes mellitus is a multifaceted metabolic disorder with varied pathophysiologic and clinical manifestations. This review discusses the pathways by which oxidative glyco stress increased in hyperglycemia or diabetes. INTRODUCTION There ample evidence of an important role (carbonyl) pathogenesis diabetic complications. Some these are listed Table 1. (1) The relative importance may differ from person to cell type type. Figure 1 1Pathways Implicated Increased ROS Dicarbonyl Generation Diabetes INCREASE IN ELECTRON TRANSPORT MITOCHONDRIA Hyperglycemia cells glucose uptake not regulated insulin stimulates chain biochemical events. Glucose metabolized glycolysis tricarboxylic acid (TCA) cycle. leads generation CO2 reduction NAD + FADH, formation NADH FADH2. FADH2 deoxidized donating electrons electron transport mitochondria. activation this generates proton gradient production adenosine triphosphate (ATP), reduces O2 superoxide. (2) superoxide mitochondria suppresses glyceraldehyde-3-phosphate dehydrogenase (GADPH) diacylglyceride as well fructose-3-phosphate. Diacylglycerol activates protein kinase C (PKC) while fructose-3-phosphate increases activity hexosamine pathway. Through both pathways, increase various transcription factors such specificity factor transforming growth (TGF-β1) expansion mesangial cells. mitochondrial also advanced glycation endproducts (AGE) polyol In pathway, NADPH used cofactor convert sorbitol, it impair cellular antioxidant defence mechanisms. uncontrolled hyperglycemia, there cytosolic ratio NADH/NAD , impairs GADPH, prooxidative metabolites. Mitochondrial metabolism only but high fatty levels. major source ALTERATION ENDOTHELIAL NO SYNTHASE availability reduced, vasoconstriction, altered vascular redox state, abnormal smooth muscle cells, prothrombotic changes vessel wall. (3) eNOS diabetes, where preferentially transfers molecular oxygen, thus ‘uncoupling’ itself producing instead NO. mRNA have been noted be aortic wall animals Increase has kidneys animal models Oxidative 4 Uncoupled NONPHAGOCYTIC CELL NADH/NADPH OXIDASE Nonphagocytic endothelial renal contain exidases functionally different oxidase seen plasma membrane neutrophils. (4) Non phagocytic can use NADPH, neutrophil enzyme system prefers NADPH. continuously generate low levels intracellularly, neutrophils produce bursts, released extracellularly. subunit preassembled cytosol nonphagotic associated intracellular cytoskeleton. neutrophils, translocates catalytic components gp 91 phox p22 phox. Animal studies show that contributor kidney, contributing much less. activated upregulated TNF-α thrombin Ang II, AGE, acids platelet-derived formed implicated nephropathy, suppressing bioavailability NO, increasing glomerular TGF-β matrix accumulation, decreasing metalloproteinases. GLUCOSE AUTO OXIDATION Glycooxidation auto-oxidative glycosylation term given sequential oxidation reaction occur pentosidine, pyrraline NG-(carboxymethyl) lysine ( CML). Metal-catalyzed processes reactive oxygen species auto-oxidize other sugars. resultant accumulation AGE marker local tissue. (5) ADVANCED GLYCATION ENDPRODUCTS A variety once auto-oxidation reactions. Alteration structure function, including inter-molecular cross-linking collagen take place. Extracellular AGE-modified proteins interact several surface receptor for (RAGE). RAGE stimulate oxidase, activate PKC, mitogen-activated kinase, TGF-β, nuclear (NF)-KB, activator 1, p21, thereby generation. (6) generation, thus, contributes ENDOGENOUS ANTIOXIDANT DEPLETION lower endogenous antioxidants vitamins A,C,E, lycopine lipoic acid. Total serum capacity effect albumin densely lipoprotein impaired people It uncertain, however, whether depleted free radical scavengers cause stress. (7) ACTIVITY OF ENZYMES Conflicting results available about anti oxidant enzymes. Cystosolic Cu /Zn SOD (SOD 1) Mn (SOD2) human Renal glutathione peroxidase found rat kidneys. shows no change. Glutathione higher cortex mice than non-diabetic controls. exact contribution enzymes fully understood. Genetic enhancement SOD1 actively shown renoprotective therapy CONCLUSION mellitus. article reviewed occurs References De Rubertis FR, Craven PA. glycooxidative nephropathy. In: Cortes P, Mogensen CE. Contemporary Diabetes: Diabetic Kidney. Humana, Totowa, NJ. 2006; PP 151-172. 2. Brownlee M. Biochemistry biology Nature 2001;414:813-820. 3. Harrison DG. Cellular mechanisms 3 dysfunction. J Clin Invest 1997;100:2157. 4. Babior BM, Lambeth JD, Nauseef W. oxidase. Arch Biochem Biophys 2002;397:342-344. 5. Horie K, Miyata T, Maeda, S, et al. Immunohistochemical colocalization glycooxidation products lipid peroxidation lesions. 1997;12:2995-3004. 6. 7. Evans JL, Goldfine D, Maddux BA, Grodsky GM. stress-activated signaling pathways: unifying hypothesis Endocr Rev 2002;23(5):599-622. Author Information Navneet Agrawal Dept Medicine, GR Medical College, Gwalior, India Sanjeev Kumar Singh Biochemistry, Neelima Sanjay Kalra B.R.I.D.E., Karnal, Gautam Srivastava