{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:27:03Z","timestamp":1787614023720,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,4]],"date-time":"2023-02-04T00:00:00Z","timestamp":1675468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["NIH RO1 DK 38325-35"],"award-info":[{"award-number":["NIH RO1 DK 38325-35"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This perspective examines the proposition that chronically elevated blood glucose levels caused by type 2 diabetes (T2D) harm body tissues by locally generating reactive oxygen species (ROS). A feed-forward scenario is described in which the initial onset of defective beta cell function T2D becomes sustained and causes chronic elevations in blood glucose, which flood metabolic pathways throughout the body, giving rise to abnormally high local levels of ROS. Most cells can defend themselves via a full complement of antioxidant enzymes that are activated by ROS. However, the beta cell itself does not contain catalase or glutathione peroxidases and thereby runs a greater risk of ROS-induced damage. In this review, previously published experiments are revisited to examine the concept that chronic hyperglycemia can lead to oxidative stress in the beta cell, how this relates to the absence of beta cell glutathione peroxidase (GPx) activity, and whether this deficiency might be ameliorated by genetic enrichment of beta cell GPx and by oral antioxidants, including ebselen, a GPx mimetic.<\/jats:p>","DOI":"10.3390\/ijms24043082","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T02:57:32Z","timestamp":1675652252000},"page":"3082","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Nrf2 and Antioxidant Response in Animal Models of Type 2 Diabetes"],"prefix":"10.3390","volume":"24","author":[{"given":"R. Paul","family":"Robertson","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology and Nutrition, Department of Internal Medicine, University of Washington, Seattle, WA 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"42351","DOI":"10.1074\/jbc.R400019200","article-title":"Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes","volume":"279","author":"Robertson","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37316","DOI":"10.1074\/jbc.M403070200","article-title":"D-glyceraldehyde causes production of intracellular peroxide in pancreatic islets, oxidative stress, and defective beta cell function via non-mitochondrial pathways","volume":"279","author":"Takahashi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1042\/bj1990393","article-title":"CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse","volume":"199","author":"Tajiedal","year":"1981","journal-title":"Biochem. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.2337\/diab.46.11.1733","article-title":"Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells","volume":"46","author":"Tiedge","year":"1997","journal-title":"Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.2337\/diabetes.47.10.1578","article-title":"Complementary action of antioxidant enzymes in the protection of bioengineered insulin-producing RINm5F cells against the toxicity of reactive oxygen species","volume":"47","author":"Tiedge","year":"1998","journal-title":"Diabetes"},{"key":"ref_6","first-page":"147","article-title":"Protective effect of allopurinol, alpha-tocopherol and chlorpromazine on rat pancreatic islets stored prior to transplantation","volume":"44","author":"Gembal","year":"1993","journal-title":"Endokrynol. Pol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1097\/00006676-199608000-00008","article-title":"Improved insulin secretion of cryopreserved human islets by antioxidant treatment","volume":"13","author":"Janjic","year":"1996","journal-title":"Pancreas"},{"key":"ref_8","first-page":"1487","article-title":"Prevention of pancreatic islet xenograft rejection by dietary vitamin E","volume":"150","author":"Vajkoczy","year":"1997","journal-title":"Am. J. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1097\/00006676-199904000-00009","article-title":"Interactions between vitamin E and glucose on B-cell functions in the rat: An in vivo and in vitro study","volume":"18","author":"Tajiri","year":"1999","journal-title":"Pancreas"},{"key":"ref_10","first-page":"301","article-title":"Effects of anti-oxidizing vitamins on in vitro cultured porcine neonatal pancreatic islet cells","volume":"13","author":"Luca","year":"2000","journal-title":"Diabetes Nutr. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1016\/S0041-1345(02)03273-6","article-title":"Influence of antioxidant therapy on islet graft survival","volume":"34","author":"Winter","year":"2002","journal-title":"Transplant. Proc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1074\/jbc.M307907200","article-title":"Metallothionein protects islets from hypoxia and extends islet graft survival by scavenging most kinds of reactive oxygen species","volume":"279","author":"Li","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.2337\/diabetes.53.10.2559","article-title":"Response of human islets to isolation stress and the effect of antioxidant treatment","volume":"53","author":"Bottino","year":"2004","journal-title":"Diabetes"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.transproceed.2004.11.019","article-title":"Effect of perioperative antioxidant therapy on suboptimal islet transplantation in rats","volume":"37","author":"Brown","year":"2005","journal-title":"Transplant. Proc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1111\/j.1399-0012.2007.00736.x","article-title":"Glutathione peroxidase protein expression and activity in human islets isolated for transplantation","volume":"21","author":"Tonooka","year":"2007","journal-title":"Clin. Transplant."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10857","DOI":"10.1073\/pnas.96.19.10857","article-title":"Prevention of Glucose toxicity in HIT-T15 cells and Zucker diabetic fatty (ZDF) rats by antioxidants","volume":"96","author":"Tanaka","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12363","DOI":"10.1073\/pnas.192445199","article-title":"A role for glutathione peroxidase in protecting pancreatic B cells against oxidative stress in a model of glucose toxicity","volume":"99","author":"Tanaka","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"581","DOI":"10.2337\/diabetes.52.3.581","article-title":"Glucose toxicity in beta cells: Type 2 diabetes, good radicals gone bad, and the glutathione connection","volume":"52","author":"Robertson","year":"2003","journal-title":"Diabetes"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11107","DOI":"10.1074\/jbc.M410345200","article-title":"Oxidative stress-mediated, post-translational loss of MafA protein as a contributing mechanism to loss of insulin gene expression in glucotoxic beta cells","volume":"280","author":"Harmon","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1016\/j.febslet.2007.03.087","article-title":"Pancreatic islet beta-cell and oxidative stress: The importance of glutathione peroxidase","volume":"581","author":"Robertson","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4855","DOI":"10.1210\/en.2009-0708","article-title":"\u00df-cell specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db\/db mice","volume":"150","author":"Harmon","year":"2009","journal-title":"Endocrinology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3582","DOI":"10.2337\/db13-0357","article-title":"Ebselen treatment prevents islet apoptosis, maintains intranuclearPdx-1 and MafA levels, and preserves \u03b2-cell mass and function in ZDF rats","volume":"62","author":"Mahadevan","year":"2013","journal-title":"Diabetes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"92854","DOI":"10.1172\/jci.insight.92854","article-title":"Nrf2\/antioxidant pathway mediates \u03b2 cell self-repair after damage by high-fat diet-induced oxidative stress","volume":"2","author":"Abebe","year":"2017","journal-title":"JCI Insight"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1172\/JCI115865","article-title":"Preservation of insulin mRNA levels and insulin secretion in HIT cells by avoidance of chronic exposure to high glucose concentrations","volume":"90","author":"Robertson","year":"1992","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"44","DOI":"10.2337\/diab.38.1.44","article-title":"Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships","volume":"38","author":"Zhang","year":"1989","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1172\/JCI116596","article-title":"Chronic exposure of HIT cells to high glucose concentrations paradoxically decreases insulin gene transcription and alters binding of insulin gene regulatory protein","volume":"92","author":"Olson","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9127","DOI":"10.1073\/pnas.92.20.9127","article-title":"Reduction of insulin gene transcription in HIT-T15 \u03b2-cells chronically exposed to a supraphysiologic glucose concentration is associated with loss of STF-1 transcription factor expression","volume":"92","author":"Olson","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","first-page":"1127","article-title":"The reduction of insulin gene transcription in HIT-T15 \u03b2-cells chronically exposed to high glucose concentration is associated with the loss of RIPE3b1 and STF-1 transcription factor expression","volume":"9","author":"Sharma","year":"1995","journal-title":"Mol. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1172\/JCI118496","article-title":"Chronic exposure of \u03b2TC-6 cells to supraphysiologic concentrations of glucose decreases binding of the RIPE3b1 insulin gene transcription activator","volume":"97","author":"Poitout","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"900","DOI":"10.2337\/diabetes.47.6.900","article-title":"Reconstitution of glucotoxic HIT-T15 cells with somatostatin transcription factor-1 partially restores insulin promoter activity","volume":"47","author":"Harmon","year":"1998","journal-title":"Diabetes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3235","DOI":"10.1016\/0006-2952(84)90083-2","article-title":"A novel biologically active seleno-organic compound-1. Glutathione-like activity in vitro and antioxidant capacity of PZ 51 (Ebselen)","volume":"33","author":"Muller","year":"1984","journal-title":"Biochem. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1161\/01.RES.0000111802.09964.EF","article-title":"Prevention and reversal of premature endothelial cell senescence and vasculopathy in obesity -induce diabetes by ebselen","volume":"94","author":"Brodsky","year":"2004","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/0003-9861(92)90534-4","article-title":"Antioxidant effect effect pf Ebselen (PZ 51) peroxidase mimetic activity on phospholipid and cholesterol hydroperoxides vs free radical scavenger activity","volume":"295","author":"Maiorino","year":"1992","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1055\/s-0028-1111106","article-title":"Development of ebselen, a glutathione peroxidase mimetic, for the prevention and treatment of noise-induced hearing loss","volume":"30","author":"Lynch","year":"2009","journal-title":"Semin. Hear."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1161\/01.STR.29.1.12","article-title":"Ebselen in acute middle cerebral artery occlusion: A placebo-controlled, double-blind clinical trial. Ebselen Study Group","volume":"29","author":"Yamaguchi","year":"1998","journal-title":"Stroke"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1159\/000015908","article-title":"Ebselen in acute middle cerebral artery occlusion: A placebo-controlled, double-blind clinical trial","volume":"9","author":"Ogawa","year":"1999","journal-title":"Cerebrovasc. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.freeradbiomed.2015.07.147","article-title":"Nrf2-a therapeutic target for the treatment of neurodegenerative diseases","volume":"88 Pt B","author":"Johnson","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.freeradbiomed.2015.06.013","article-title":"Epigenetic regulation of Keap1-Nrf2 signaling","volume":"88 Pt B","author":"Guo","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.freeradbiomed.2015.06.037","article-title":"Applications of the Keap1-Nrf2 system for gene and cell therapy","volume":"88 Pt B","author":"Kanninen","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3892\/ijmm.2015.2256","article-title":"The cytoprotective effects of 7,8-dihydroxyflavone against oxidative stress are mediated by the upregulation of Nrf2-dependent HO-1 expression through the activation of the PI3K\/Akt and ERK pathways in C2C12 myoblasts","volume":"36","author":"Kang","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.freeradbiomed.2015.06.021","article-title":"Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease","volume":"88 Pt B","author":"Tebay","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"605","DOI":"10.2337\/db13-0909","article-title":"Nrf2 protects pancreatic beta-cells from oxidative and nitrosative stress in diabetic model mice","volume":"63","author":"Yagishita","year":"2014","journal-title":"Diabetes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2996","DOI":"10.1128\/MCB.00225-13","article-title":"The Keap1-Nrf2 system prevents onset of diabetes mellitus","volume":"33","author":"Uruno","year":"2013","journal-title":"Mol. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Masuda, Y., Vaziri, N.D., Li, S., Le, A., Hajighasemi-Ossareh, M., Robles, L., Foster, C.E., Stamos, M.J., Al-Abodullah, I., and Ricordi, C. (2015). The effect of Nrf2 pathway activation on human pancreatic islet cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131012"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"10878","DOI":"10.1073\/pnas.91.23.10878","article-title":"Beta cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: Impairment in adipocyte-beta cell relationships","volume":"91","author":"Lee","year":"1994","journal-title":"Proc. Natl. Acad. Sci USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.2337\/diabetes.50.11.2481","article-title":"Antecedent hyperglycemia, not hyperlipidemia, is associated with increased islet triacylglycerol content and decreased insulin gene mRNA level in Zucker Diabetic Fatty rats","volume":"50","author":"Harmon","year":"2001","journal-title":"Diabetes"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3082\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:24:16Z","timestamp":1760120656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,4]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043082"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043082","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,4]]}}}