Review Biomarkers of stress-mediated metabolic deregulation in diabetes mellitus Dina R. Johar a,b, * , Larry H. Bernstein c a Department of Biochemistry and Nutrition, Faculty of Women for Arts, Sciences and Education, Ain Shams University, Heliopolis, Cairo, Egypt b Department of Physiology and Pathophysiology, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada c Triplex Consulting, 54 Firethorn Lane, Northampton, MA 01060, USA ARTICLE INFO Article history: Received 16 December 2016 Received in revised form 19 January 2017 Accepted 14 February 2017 Available online 24 February 2017 Keywords: Diabetes mellitus Antioxidants Oxygen free radicals Nitrative stress Animal Human ABSTRACT This review illustrates the relationship of oxidative and nitrative stress to diabetes mellitus and its complications. This is of considerable interest because diabetes mellitus is a life- time systemic metabolic disease that may have childhood or adult onset and affects not only a triad of pancreatic islet cell insulin, pituitary insulin-like growth hormone, and liver steatosis, it has a long-term association with adiposity, atherosclerosis, coronary vascular disease, kidney disease of the nature afferent arteriolar sclerosis and nodular glomeru- losclerosis, cerebrovascular disease, and amyloid deposition in the pancreas and kidney. Only at the end of the 20th century do we gain insight into oxidative and nitrative stress and their consequences. Of special interest here is the fact that reactive oxygen and nitro- gen radicals are with us generated throughout the life cycle, and the roles for glutathione and Fe 3+ are key elements in the metabolic picture, which brings into the picture dietary factors. More research is required to demonstrate the clinical relivance of naturally- occuring whole-food antioxidants in ameliorating human diabetic complications in vivo. Ó 2017 Elsevier B.V. All rights reserved. Contents 1. Oxidative stress in diabetes mellitus ................................................................ 223 1.1. Free radicals generating systems ............................................................. 223 http://dx.doi.org/10.1016/j.diabres.2017.02.023 0168-8227/Ó 2017 Elsevier B.V. All rights reserved. Abbreviations: eNOS, endothelial nitric oxide synthase; NOS3, nitric oxide synthase 3; cNOS, constitutive nitric oxide synthase; nNOS, neuronal nitric oxide synthase; iNOS, induced nitric oxide synthase; kDa, kilodalton; NADPH, nicotinamide adenine dinucleotide phosphate; MDA, malondialdehyde; a-T, a-tocopherol; GSH, glutathione; SOD, superoxide dismutase; CAT, catalase; SeCys, selenocysteine; FAD, flavin adenine dinucleotide; -SH, thiol; mTOR, mammalian target of rapamycin; TLR4, toll-like receptor 4; SIRT, sirtuin; O-GlcNAc, N-acetylglucosaminyltransferase; CRTC2, CREB regulated transcription coactivator 2; PPARc, peroxisome proliferator- activated receptorgamma; RXR, retinoid X receptor alpha; TTR, plasma transthyretin; OLETF, Otsuka Long Evans Tokushima Fatty rats; hCMEC, human cerebral microvascular endothelial cell line; FR-OH, free retinol; TBARS, thiobarbituric acid reactive substrate * Corresponding author at: 301-2 Emily Street, Winnipeg, MB R3E 1Y7, Canada. E-mail addresses: dinajohar@gmail.com (D.R. Johar), larry.bernstein@gmail.com (L.H. Bernstein). diabetes research and clinical practice 126 (2017) 222 – 229 Contents available at ScienceDirect Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locate/diabres