{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:19:23Z","timestamp":1790785163425,"version":"4.1.0"},"reference-count":144,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T00:00:00Z","timestamp":1644969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007458","name":"Qatar Foundation","doi-asserted-by":"publisher","award":["project code QB-14"],"award-info":[{"award-number":["project code QB-14"]}],"id":[{"id":"10.13039\/100007458","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004252","name":"Qatar University","doi-asserted-by":"publisher","award":["QUHI-CMED-21\/22-1"],"award-info":[{"award-number":["QUHI-CMED-21\/22-1"]}],"id":[{"id":"10.13039\/501100004252","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The recent discovery of the glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis in cell dysfunction in model hyperglycemia has revealed a likely key initiating factor contributing to the development of insulin resistance and vascular complications in diabetes. Consequently, the increased flux of glucose metabolism without a change in the expression and activity of glycolytic enzymes produces a wave of increased glycolytic intermediates driving mitochondrial dysfunction and increased reactive oxygen species (ROS) formation, the activation of hexosamine and protein kinase C pathways, the increased formation of methylglyoxal-producing dicarbonyl stress, and the activation of the unfolded protein response. This is called HK2-linked glycolytic overload and unscheduled glycolysis. The conditions required to sustain this are GLUT1 and\/or GLUT3 glucose uptake and the expression of HK2. A metabolic biomarker of its occurrence is the abnormally increased deposition of glycogen, which is produced by metabolic channeling when HK2 becomes detached from mitochondria. These conditions and metabolic consequences are found in the vasculature, kidneys, retina, peripheral nerves, and early-stage embryo development in diabetes and likely sustain the development of diabetic vascular complications and embryopathy. In insulin resistance, HK2-linked unscheduled glycolysis may also be established in skeletal muscle and adipose tissue. This may explain the increased glucose disposal by skeletal uptake in the fasting phase in patients with type 2 diabetes mellitus, compared to healthy controls, and the presence of insulin resistance in patients with type 1 diabetes mellitus. Importantly, glyoxalase 1 inducer\u2014trans-resveratrol and hesperetin in combination (tRES-HESP)\u2014corrected HK2-linked glycolytic overload and unscheduled glycolysis and reversed insulin resistance and improved vascular inflammation in overweight and obese subjects in clinical trial. Further studies are now required to evaluate tRES-HESP for the prevention and reversal of early-stage type 2 diabetes and for the treatment of the vascular complications of diabetes.<\/jats:p>","DOI":"10.3390\/ijms23042165","type":"journal-article","created":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T21:36:24Z","timestamp":1645047384000},"page":"2165","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis\u2014Driver of Insulin Resistance and Development of Vascular Complications of Diabetes"],"prefix":"10.3390","volume":"23","author":[{"given":"Naila","family":"Rabbani","sequence":"first","affiliation":[{"name":"Department of Basic Medical Science, College of Medicine, Qatar University Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9184-2980","authenticated-orcid":false,"given":"Mingzhan","family":"Xue","sequence":"additional","affiliation":[{"name":"Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7659-443X","authenticated-orcid":false,"given":"Paul J.","family":"Thornalley","sequence":"additional","affiliation":[{"name":"Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Traut, T. (2008). Hexokinase. Allosteric Regulatory Enzymes, Springer.","DOI":"10.1007\/978-0-387-72891-9"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1083\/jcb.201503044","article-title":"Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death","volume":"210","author":"Xia","year":"2015","journal-title":"J. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"John, S., Weiss, J.N., and Ribalet, B. (2011). Subcellular Localization of Hexokinases I and II Directs the Metabolic Fate of Glucose. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017674"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.2337\/diabetes.50.6.1253","article-title":"Hexokinase Isozyme Distribution in Human Skeletal Muscle","volume":"50","author":"Ritov","year":"2001","journal-title":"Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e00205","DOI":"10.1042\/BSR20150047","article-title":"Identification of a mitochondrial-binding site on the N-terminal end of hexokinase II","volume":"35","author":"Bryan","year":"2015","journal-title":"Biosci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s10863-008-9165-7","article-title":"Voltage dependent anion channels (VDACs): A brief introduction with a focus on the outer mitochondrial compartment\u2019s roles together with hexokinase-2 in the \u201cWarburg effect\u201d in cancer","volume":"40","author":"Pedersen","year":"2008","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.nbd.2011.06.007","article-title":"Developmental profile and regulation of the glycolytic enzyme hexokinase 2 in normal brain and glioblastoma multiforme","volume":"44","author":"Wolf","year":"2011","journal-title":"Neurobiol. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1242\/dev.113.1.363","article-title":"Glucose transporter gene expression in early mouse embryos","volume":"113","author":"Hogan","year":"1991","journal-title":"Development"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3430","DOI":"10.7150\/jca.21125","article-title":"The Glycolytic Switch in Tumors: How Many Players Are Involved?","volume":"8","author":"Yu","year":"2017","journal-title":"J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ccr.2012.05.016","article-title":"Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming","volume":"22","author":"Mitsuishi","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0014-5793(96)00399-7","article-title":"Glucose catabolism in cancer cells: Regulation of the type II hexokinase promoter by glucose and cyclic AMP","volume":"385","author":"Rempel","year":"1996","journal-title":"FEBS Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16918","DOI":"10.1074\/jbc.270.28.16918","article-title":"Glucose Catabolism in Cancer Cells: Isolation, sequence, and activity of the promoter for type II hexokinase","volume":"270","author":"Mathupala","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7889","DOI":"10.1038\/s41598-019-44358-1","article-title":"Activation of the unfolded protein response in high glucose treated endothelial cells is mediated by methylglyoxal","volume":"9","author":"Irshad","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/BF00400733","article-title":"Polymorphisms of the human hexokinase II gene: Lack of association with NIDDM and insulin resistance","volume":"38","author":"Laakso","year":"1995","journal-title":"Diabetologia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1007\/BF00400608","article-title":"Human hexokinase II gene: Exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity","volume":"38","author":"Lehto","year":"1995","journal-title":"Diabetologia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1007\/BF02267071","article-title":"A novel (TA)n polymorphism in the hexokinase II gene: Application to noninsulin-dependent diabetes mellitus in the Pima Indians","volume":"97","author":"Ardehali","year":"1996","journal-title":"Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e001458","DOI":"10.1136\/bmjdrc-2020-001458","article-title":"Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer","volume":"8","author":"Ashour","year":"2020","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11577","DOI":"10.1073\/pnas.1508871112","article-title":"p63 supports aerobic respiration through hexokinase II","volume":"112","author":"Agostini","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/35008121","article-title":"Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemia damage","volume":"404","author":"Nishikawa","year":"2000","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.2337\/db06-1003","article-title":"Activation of NF-E2-Related Factor-2 Reverses Biochemical Dysfunction of Endothelial Cells Induced by Hyperglycemia Linked to Vascular Disease","volume":"57","author":"Xue","year":"2008","journal-title":"Diabetes"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"H3404","DOI":"10.1152\/ajpheart.00761.2007","article-title":"Enhanced mitochondrial superoxide in hyperglycemic endothelial cells: Direct measurements and formation of hydrogen peroxide and peroxynitrite","volume":"293","author":"Quijano","year":"2007","journal-title":"AJP\u2014Heart Circ. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/msb.2013.19","article-title":"The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns","volume":"9","author":"Noguchi","year":"2013","journal-title":"Mol. Syst. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5209","DOI":"10.1016\/S0021-9258(18)53521-3","article-title":"Hexokinase II mRNA and gene structure, regulation by insulin, and evolution","volume":"268","author":"Printz","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16690","DOI":"10.1074\/jbc.271.28.16690","article-title":"Analysis of the Signaling Pathway Involved in the Regulation of Hexokinase II Gene Transcription by Insulin","volume":"271","author":"Osawa","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1111\/j.1432-1033.1985.tb09309.x","article-title":"Activation of glycolysis by insulin with a sequential increase of the 6-phosphofructo-2-kinase activity, fructose-2,6-bisphosphate level and pyruvate kinase activity in cultured rat hepatocytes","volume":"153","author":"Probst","year":"1985","journal-title":"Eur. J. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5273","DOI":"10.1073\/pnas.87.14.5273","article-title":"An insulin response element in the glyceraldehyde-3-phosphate dehydrogenase gene binds a nuclear protein induced by insulin in cultured cells and by nutritional manipulations in vivo","volume":"87","author":"Nasrin","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4863","DOI":"10.1128\/MCB.00657-05","article-title":"MondoA-Mlx Heterodimers Are Candidate Sensors of Cellular Energy Status: Mitochondrial Localization and Direct Regulation of Glycolysis","volume":"26","author":"Sans","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Jeong, Y.S., Kim, D., Lee, Y.S., Kim, H.J., Han, J.Y., Im, S.S., Chong, H.K., Kwon, J.K., Cho, Y.H., and Kim, W.K. (2011). Integrated Expression Profiling and Genome-Wide Analysis of ChREBP Targets Reveals the Dual Role for ChREBP in Glucose-Regulated Gene Expression. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022544"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"28721","DOI":"10.1074\/jbc.M601576200","article-title":"ChREBP\u2022Mlx Is the Principal Mediator of Glucose-induced Gene Expression in the Liver","volume":"281","author":"Ma","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1042\/BJ20111280","article-title":"Fructose 2,6-bisphosphate is essential for glucose-regulated gene transcription of glucose-6-phosphatase and other ChREBP target genes in hepatocytes","volume":"443","author":"Arden","year":"2012","journal-title":"Biochem. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.tem.2019.04.011","article-title":"Hexokinase-2 Glycolytic Overload in Diabetes and Ischemia\u2013Reperfusion Injury","volume":"30","author":"Rabbani","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/414813a","article-title":"Biochemistry and molecular cell biology of diabetic complications","volume":"414","author":"Brownlee","year":"2001","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1161\/01.RES.88.2.e14","article-title":"Mechanisms underlying endothelial dysfunction in diabetes mellitus","volume":"88","author":"Hink","year":"2001","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1161\/01.CIR.0000012748.58444.08","article-title":"Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus: Role of NAD(P)H Oxidase and Endothelial Nitric Oxide Synthase","volume":"105","author":"Guzik","year":"2002","journal-title":"Circulation"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.cardiores.2004.08.007","article-title":"Vascular NADPH oxidases: Molecular mechanisms of activation","volume":"65","author":"Brandes","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.2337\/diacare.25.11.1919","article-title":"Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes\u2014Results of the HOPE study and MICRO-HOPE substudy","volume":"25","author":"Lonn","year":"2002","journal-title":"Diabetes Care"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1530\/EJE-12-0555","article-title":"A systematic review and meta-analysis of \u03b1-lipoic acid in the treatment of diabetic peripheral neuropathy","volume":"167","author":"Han","year":"2012","journal-title":"Eur. J. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1007\/s00125-010-1722-z","article-title":"Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes","volume":"53","author":"Karachalias","year":"2010","journal-title":"Diabetologia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41572-019-0092-1","article-title":"Diabetic neuropathy","volume":"5","author":"Feldman","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.brainres.2007.08.015","article-title":"Expression of hexokinase isoforms in the dorsal root ganglion of the adult rat and effect of experimental diabetes","volume":"1175","author":"Gardiner","year":"2007","journal-title":"Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3054","DOI":"10.1210\/en.2013-1097","article-title":"Glucose-Induced Metabolic Memory in Schwann Cells: Prevention by PPAR Agonists","volume":"154","author":"Kim","year":"2013","journal-title":"Endocrinology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.1083\/jcb.201702150","article-title":"Regulation and dysregulation of axon infrastructure by myelinating glia","volume":"216","author":"Pan","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1042\/BJ20111648","article-title":"Transcriptional control of glyoxalase 1 by Nrf2 provides a stress responsive defence against dicarbonyl glycation","volume":"443","author":"Xue","year":"2012","journal-title":"Biochem. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.2337\/db16-0153","article-title":"Improved glycemic control and vascular function in overweight and obese subjects by glyoxalase 1 inducer formulation","volume":"65","author":"Xue","year":"2016","journal-title":"Diabetes"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.bbadis.2008.08.012","article-title":"Glycolytic enzyme expression and pyruvate kinase activity in cultured fibroblasts from type 1 diabetic patients with and without nephropathy","volume":"1782","author":"Iori","year":"2008","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/ki.2010.99","article-title":"High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein","volume":"78","author":"Isoe","year":"2010","journal-title":"Kidney Intern."},{"key":"ref_47","first-page":"4228","article-title":"Characterization of Some Glycolytic Enzymes from Human Retina and Retinoblastoma","volume":"42","author":"Beemer","year":"1982","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1016\/S0026-0495(96)90174-2","article-title":"Glucose transporters in rat peripheral nerve: Paradonal expression of GLUT1 and GLUT3","volume":"45","author":"Magnani","year":"1996","journal-title":"Metabolism"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4516","DOI":"10.1242\/jcs.049734","article-title":"Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis","volume":"122","author":"Echave","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1089\/scd.2011.0682","article-title":"The Expression of the Class 1 Glucose Transporter Isoforms in Human Embryonic Stem Cells, and the Potential Use of GLUT2 as a Marker for Pancreatic Progenitor Enrichment","volume":"21","author":"Segev","year":"2012","journal-title":"Stem Cells Dev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"31457","DOI":"10.1074\/jbc.R300002200","article-title":"Intermediary Metabolism and Energetics during Murine Early Embryogenesis","volume":"278","author":"Johnson","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/ar.1092410212","article-title":"Altered mitochondrial morphology of rat embryos in diabetic pregnancy","volume":"241","author":"Yang","year":"1995","journal-title":"Anat. Rec."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.2337\/diabetes.47.12.1960","article-title":"Teratogenicity of 3-deoxyglucosone and diabetic embryopathy","volume":"47","author":"Eriksson","year":"1998","journal-title":"Diabetes"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/bdra.20056","article-title":"Activation of the hexosamine pathway causes oxidative stress and abnormal embryo gene expression: Involvement in diabetic teratogenesis","volume":"70","author":"Horal","year":"2004","journal-title":"Birth Defects Res. Part A Clin. Mol. Teratol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.2337\/diabetes.51.9.2804","article-title":"Diacylglycerol Production and Protein Kinase C Activity Are Increased in a Mouse Model of Diabetic Embryopathy","volume":"51","author":"Hiramatsu","year":"2002","journal-title":"Diabetes"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.2337\/diabetes.52.12.2867","article-title":"Microvascular Complications of Impaired Glucose Tolerance","volume":"52","author":"Singleton","year":"2003","journal-title":"Diabetes"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1089\/jwh.2020.8853","article-title":"Dysglycemia in Pregnancy and Maternal\/Fetal Outcomes","volume":"30","author":"Silva","year":"2021","journal-title":"J. Women\u2019s Health"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.2337\/db10-0174","article-title":"Increased Reactive Oxygen Species Production and Lower Abundance of Complex I Subunits and Carnitine Palmitoyltransferase 1B Protein Despite Normal Mitochondrial Respiration in Insulin-Resistant Human Skeletal Muscle","volume":"59","author":"Lefort","year":"2010","journal-title":"Diabetes"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"302","DOI":"10.2337\/diab.45.3.302","article-title":"Increased Glutamine: Fructose-6-Phosphate Amidotransferase Activity in Skeletal Muscle of Patients With NIDDM","volume":"45","author":"Daniels","year":"1996","journal-title":"Diabetes"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.2337\/db14-1891","article-title":"Role of PKC\u03b4 in Insulin Sensitivity and Skeletal Muscle Metabolism","volume":"64","author":"Li","year":"2015","journal-title":"Diabetes"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"R181","DOI":"10.1152\/ajpregu.00159.2017","article-title":"Dicarbonyl stress and glyoxalase enzyme system regulation in human skeletal muscle","volume":"314","author":"Mey","year":"2018","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"387","DOI":"10.2337\/diabetes.47.3.387","article-title":"Insulin-Induced hexokinase II expression is reduced in obesity and NIDDM","volume":"47","author":"Pendergrass","year":"1998","journal-title":"Diabetes"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/0026-0495(78)90156-7","article-title":"Hexokinase isozymes of normal human subcutaneous adipose tissue","volume":"27","author":"Lavis","year":"1978","journal-title":"Metabolism"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s10719-016-9692-0","article-title":"Dicarbonyl stress in clinical obesity","volume":"33","author":"Masania","year":"2016","journal-title":"Glycoconj. J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"7315","DOI":"10.1074\/jbc.RA117.001254","article-title":"Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation","volume":"293","author":"Fazakerley","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.cmet.2018.09.013","article-title":"Protein Kinase C Epsilon Deletion in Adipose Tissue, but Not in Liver, Improves Glucose Tolerance","volume":"29","author":"Brandon","year":"2019","journal-title":"Cell Metab."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Morton, N.M., Nelson, Y.B., Michailidou, Z., Di Rollo, E.M., Ramage, L., Hadoke, P.W.F., Seckl, J.R., Bunger, L., Horvat, S., and Kenyon, C.J. (2011). A stratified transcriptomics analysis of polygenic fat and lean mouse adipose tissues identifies novel candidate obesity genes. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023944"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"716","DOI":"10.4067\/S0717-95022013000200060","article-title":"Histological and Histochemical Studies of the Aorta and Pulmonary Trunk in STZ-induced Diabetic Wistar Rats Treated with Momordica charantia","volume":"31","author":"Komolafe","year":"2013","journal-title":"Int. J. Morphol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s00592-005-0188-9","article-title":"Glycogen accumulation in renal tubules, a key morphological change in the diabetic rat kidney","volume":"42","author":"Kang","year":"2005","journal-title":"Acta Diabetol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e12043","DOI":"10.14814\/phy2.12043","article-title":"Differential effects of glyoxalase 1 overexpression on diabetic atherosclerosis and renal dysfunction in streptozotocin-treated, apolipoprotein E-deficient mice","volume":"2","author":"Geoffrion","year":"2014","journal-title":"Physiol. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Cortes, P., and Mogensen, C.E. (2006). The Hexosamine Biosynthesis Pathway. The Diabetic Kidney, Humana Press.","DOI":"10.1007\/978-1-59745-153-6"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.2337\/diabetes.52.10.2570","article-title":"Reactive oxygen species from mitochondria Induce cyclooxygenase-2 gene expression in human mesangial cells: Potential role in diabetic nephropathy","volume":"52","author":"Kiritoshi","year":"2003","journal-title":"Diabetes"},{"key":"ref_73","first-page":"E783","article-title":"Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation","volume":"265","author":"Shiba","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/BF00690832","article-title":"Microangiopathy in human diabetic neuropathy","volume":"68","author":"Powell","year":"1985","journal-title":"Acta Neuropathol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1038\/nm.2750","article-title":"Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy","volume":"18","author":"Bierhaus","year":"2012","journal-title":"Nat. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1021\/pr900818g","article-title":"Hyperglycemia alters the schwann cell mitochondrial proteome and decreases coupled respiration in the absence of superoxide production","volume":"9","author":"Zhang","year":"2010","journal-title":"J. Proteome Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.nbd.2008.02.013","article-title":"Oxidative injury and neuropathy in diabetes and impaired glucose tolerance","volume":"30","author":"Russell","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.2337\/db09-0320","article-title":"Advanced Glycation Endproducts in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes","volume":"58","author":"Dobler","year":"2009","journal-title":"Diabetes"},{"key":"ref_79","first-page":"977","article-title":"Muller cells and diabetic-retinopathy","volume":"28","author":"Schellini","year":"1995","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"31038","DOI":"10.1074\/jbc.M704703200","article-title":"High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A","volume":"282","author":"Yao","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1167\/iovs.16-21355","article-title":"High Glucose Induces Mitochondrial Dysfunction in Retinal M\u00fcller Cells: Implications for Diabetic Retinopathy","volume":"58","author":"Tien","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1002\/prca.201300076","article-title":"The role of O-GlcNAc signaling in the pathogenesis of diabetic retinopathy","volume":"8","author":"Semba","year":"2014","journal-title":"Proteom. Clin. Appl."},{"key":"ref_83","first-page":"299","article-title":"Effects of excess glucose on mammalian post-implantation embryos","volume":"41","author":"Ellington","year":"1997","journal-title":"Int. J. Dev. BioI."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1159\/000045884","article-title":"Influence of Long-Term Diabetes on Renal Glycogen Metabolism in the Rat","volume":"87","author":"Nannipieri","year":"2001","journal-title":"Nephron"},{"key":"ref_85","first-page":"3879","article-title":"Glycogen Levels in the Normal and Diabetic Rat Retina","volume":"44","author":"Salceda","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1620\/tjem.129.357","article-title":"Ultrastructural pathology of peripheral nerves in patients with diabetic neuropathy","volume":"129","author":"Yagihashi","year":"1979","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/0022-510X(81)90012-5","article-title":"Glycogen accumulation in tibial nerves of experimentally diabetic and aging control rats","volume":"52","author":"Moore","year":"1981","journal-title":"J. Neurol. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3653459","DOI":"10.1155\/2016\/3653459","article-title":"The Expanded Bead Size of Corneal C-Nerve Fibers Visualized by Corneal Confocal Microscopy Is Associated with Slow Conduction Velocity of the Peripheral Nerves in Patients with Type 2 Diabetes Mellitus","volume":"2016","author":"Ishibashi","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1056\/NEJM198805123181901","article-title":"Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians","volume":"318","author":"Lillioja","year":"1988","journal-title":"N. Engl. J. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"909","DOI":"10.7326\/0003-4819-113-12-909","article-title":"Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents","volume":"113","author":"Warram","year":"1990","journal-title":"Ann. Intern. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"S157","DOI":"10.2337\/dc09-S302","article-title":"Skeletal muscle insulin resistance is the primary defect in type 2 diabetes","volume":"32","author":"DeFronzo","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"795","DOI":"10.2337\/diab.31.9.795","article-title":"Insulin Resistance is a Prominent Feature of Insulin-dependent Diabetes","volume":"31","author":"DeFronzo","year":"1982","journal-title":"Diabetes"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1053\/meta.2000.6245","article-title":"Regulation of hexokinase II expression in human skeletal muscle in vivo","volume":"49","author":"Vogt","year":"2000","journal-title":"Metab.\u2014Clin. Exp."},{"key":"ref_94","first-page":"230","article-title":"Effects of Insulin on Subcellular Localization of Hexokinase II in Human Skeletal Muscle in Vivo","volume":"83","author":"Vogt","year":"1998","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"23798","DOI":"10.1074\/jbc.M113.482026","article-title":"Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes","volume":"288","author":"Roberts","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1172\/JCI118329","article-title":"Impaired activity and gene expression of hexokinase II in muscle from non-insulin-dependent diabetes mellitus patients","volume":"96","author":"Vestergaard","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.2337\/diab.30.12.1000","article-title":"The Effect of Insulin on the Disposal of Intravenous Glucose: Results from Indirect Calorimetry and Hepatic and Femoral Venous Catheterization","volume":"30","author":"DeFronzo","year":"1981","journal-title":"Diabetes"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"865","DOI":"10.2337\/diab.39.7.865","article-title":"Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM","volume":"39","author":"Pedersen","year":"1990","journal-title":"Diabetes"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1210\/jc.2004-0516","article-title":"Skeletal Muscle GLUT1 Transporter Protein Expression and Basal Leg Glucose Uptake Are Reduced in Type 2 Diabetes","volume":"90","author":"Ciaraldi","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"18442","DOI":"10.1016\/S0021-9258(17)46645-2","article-title":"Germline manipulation of glucose homeostasis via alteration of glucose transporter levels in skeletal muscle","volume":"268","author":"Marshall","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"18366","DOI":"10.1016\/S0021-9258(17)32316-5","article-title":"Glucose transport activity in skeletal muscles from transgenic mice overexpressing GLUT1. Increased basal transport is associated with a defective response to diverse stimuli that activate GLUT4","volume":"269","author":"Gulve","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"E241","DOI":"10.1152\/ajpendo.00060.2002","article-title":"Enhanced O-GlcNAc protein modification is associated with insulin resistance in GLUT1-overexpressing muscles","volume":"283","author":"Buse","year":"2002","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1194\/jlr.R087510","article-title":"Muscle and adipose tissue insulin resistance: Malady without mechanism?","volume":"60","author":"Fazakerley","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1016\/S0021-9258(18)85410-2","article-title":"Skeletal muscle glucose transport and metabolism are enhanced in transgenic mice overexpressing the Glut4 glucose transporter","volume":"270","author":"Hansen","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"22517","DOI":"10.1074\/jbc.274.32.22517","article-title":"Hexokinase II-deficient mice: Prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes","volume":"274","author":"Heikkinen","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"14834","DOI":"10.1074\/jbc.271.25.14834","article-title":"Overexpression of hexokinase II in transgenic mice. Evidence that increased phosphorylation augments muscle glucose uptake","volume":"271","author":"Chang","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"306","DOI":"10.2337\/diabetes.53.2.306","article-title":"Hexokinase II overexpression improves exercise-stimulated but not insulin-stimulated muscle glucose uptake in high-fat-fed C57BL\/6J mice","volume":"53","author":"Fueger","year":"2004","journal-title":"Diabetes"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"22381","DOI":"10.1074\/jbc.M001946200","article-title":"Transgenic Overexpression of Hexokinase II in Skeletal Muscle Does Not Increase Glucose Disposal in Wild-type or Glut1-overexpressing Mice","volume":"275","author":"Hansen","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"957","DOI":"10.2337\/diacare.31.11.957","article-title":"The Effect of Graded Doses of Insulin on Total Glucose Uptake, Glucose Oxidation, and Glucose Storage in Man","volume":"31","author":"Thiebaud","year":"1982","journal-title":"Diabetes"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.molmet.2015.10.001","article-title":"Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans","volume":"5","author":"Ejarque","year":"2016","journal-title":"Mol. Metab."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0014-5793(98)01149-1","article-title":"Insulin-independent glucose transport regulates insulin sensitivity","volume":"436","author":"Ebeling","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"6912","DOI":"10.1073\/pnas.0712199105","article-title":"Glucose sensing by MondoA:Mlx complexes: A role for hexokinases and direct regulation of thioredoxin-interacting protein expression","volume":"105","author":"Stoltzman","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1172\/JCI87382","article-title":"MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling","volume":"126","author":"Ahn","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e129119","DOI":"10.1172\/jci.insight.129119","article-title":"MondoA drives muscle lipid accumulation and insulin resistance","volume":"5","author":"Ahn","year":"2019","journal-title":"JCI Insight"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"e010889","DOI":"10.1136\/bmjopen-2015-010889","article-title":"Change in fasting plasma glucose and incident type 2 diabetes mellitus: Results from a prospective cohort study","volume":"6","author":"Mozaffary","year":"2016","journal-title":"BMJ Open"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.2337\/db06-1776","article-title":"Contribution of Hepatic and Extrahepatic Insulin Resistance to the Pathogenesis of Impaired Fasting Glucose: Role of Increased Rates of Gluconeogenesis","volume":"56","author":"Bock","year":"2007","journal-title":"Diabetes"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1016\/j.metabol.2015.09.002","article-title":"Insulin resistance in type 1 diabetes mellitus","volume":"64","author":"Kaul","year":"2015","journal-title":"Metabolism"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"E642","DOI":"10.1210\/jc.2011-2542","article-title":"Adiponectin Dysregulation and Insulin Resistance in Type 1 Diabetes","volume":"97","author":"Pereira","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s10719-021-09980-0","article-title":"Dicarbonyl stress, protein glycation and the unfolded protein response","volume":"38","author":"Rabbani","year":"2021","journal-title":"Glycoconj. J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1042\/CS20160025","article-title":"Methylglyoxal-induced dicarbonyl stress in aging and disease: First steps towards glyoxalase 1-based treatments","volume":"130","author":"Rabbani","year":"2016","journal-title":"Clin. Sci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.cmet.2012.07.007","article-title":"IRE1\u03b1 induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress","volume":"16","author":"Lerner","year":"2012","journal-title":"Cell Metab."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1016\/j.celrep.2017.05.041","article-title":"Phosphorylation of TXNIP by AKT Mediates Acute Influx of Glucose in Response to Insulin","volume":"19","author":"Waldhart","year":"2017","journal-title":"Cell Rep."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.cmet.2012.07.005","article-title":"Thioredoxin-interacting protein mediates ER stress-induced \u03b2 cell death through initiation of the inflammasome","volume":"16","author":"Oslowski","year":"2012","journal-title":"Cell Metab."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1007\/s00125-013-3050-6","article-title":"Txnip contributes to impaired glucose tolerance by upregulating the expression of genes involved in hepatic gluconeogenesis in mice","volume":"56","author":"Jo","year":"2013","journal-title":"Diabetologia"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"26771","DOI":"10.1074\/jbc.M802800200","article-title":"Role of the Histone H3 Lysine 4 Methyltransferase, SET7\/9, in the Regulation of NF-\u03baB-dependent Inflammatory Genes: Relevance to Diabetes and Inflammation","volume":"283","author":"Li","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"F916","DOI":"10.1152\/ajprenal.00697.2012","article-title":"ER stress triggers MCP-1 expression through SET7\/9-induced histone methylation in the kidneys of db\/db mice","volume":"306","author":"Chen","year":"2014","journal-title":"Am. J. Physiol.\u2014Ren. Physiol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.cell.2010.02.034","article-title":"Endoplasmic reticulum stress and the inflammatory basis of metabolic disease","volume":"140","author":"Hotamisligil","year":"2010","journal-title":"Cell"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1055\/s-0029-1212086","article-title":"Mechanisms of TNF-alpha-induced insulin resistance","volume":"107","author":"Hotamisligil","year":"1999","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Rabbani, N., Xue, M., Weickert, M.O., and Thornalley, P.J. (2021). Reversal of Insulin Resistance in Overweight and Obese Subjects by trans-Resveratrol and Hesperetin Combination\u2014Link to Dysglycemia, Blood Pressure, Dyslipidemia, and Low-Grade Inflammation. Nutrients, 13.","DOI":"10.3390\/nu13072374"},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Parikh, H., Carlsson, E., Chutkow, W.A., Johansson, L.E., Storgaard, H., Poulsen, P., Saxena, R., Ladd, C., Schulze, P.C., and Mazzini, M.J. (2007). TXNIP Regulates Peripheral Glucose Metabolism in Humans. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040158"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1128\/MCB.01095-15","article-title":"Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism","volume":"36","author":"Uruno","year":"2016","journal-title":"Mol. Cell. Biol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.cell.2012.01.017","article-title":"Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases","volume":"148","author":"Park","year":"2012","journal-title":"Cell"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1039\/c2fo30100h","article-title":"Pro-Cellular survival and neuroprotection of citrus flavonoid: The actions of hesperetin in PC12 cells","volume":"3","author":"Hwang","year":"2012","journal-title":"Food Funct."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1089\/ars.2014.5962","article-title":"Frequency modulated translocational oscillations of Nrf2 mediate the ARE cytoprotective transcriptional response","volume":"23","author":"Xue","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1042\/BST20150060","article-title":"Frequency modulated translocational oscillations of Nrf2, a transcription factor functioning like a wireless sensor","volume":"43","author":"Xue","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.molcel.2011.12.005","article-title":"The cAMP\/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(+)","volume":"44","author":"Dominy","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"169","DOI":"10.2337\/dbi17-0039","article-title":"Cellular Energy Sensing and Metabolism\u2014Implications for Treating Diabetes: The 2017 Outstanding Scientific Achievement Award Lecture","volume":"67","author":"Steinberg","year":"2018","journal-title":"Diabetes"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1007\/s00125-017-4342-z","article-title":"The mechanisms of action of metformin","volume":"60","author":"Rena","year":"2017","journal-title":"Diabetologia"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1038\/ncomms3192","article-title":"Metformin improves healthspan and lifespan in mice","volume":"4","author":"Mercken","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/11534750-000000000-00000","article-title":"Clinical Pharmacokinetics of Metformin","volume":"50","author":"Graham","year":"2011","journal-title":"Clin. Pharmacokinet."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1056\/NEJM199508313330903","article-title":"Metabolic Effects of Metformin in Non-Insulin-Dependent Diabetes Mellitus","volume":"333","author":"Stumvoll","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI13505","article-title":"Role of AMP-activated protein kinase in mechanism of metformin action","volume":"108","author":"Zhou","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1038\/sj.ijo.0802172","article-title":"In search of normoglycaemia in diabetes: Controlling postprandial glucose","volume":"26","year":"2002","journal-title":"Int. J. Obes."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"198","DOI":"10.2337\/diabetes.48.1.198","article-title":"Metformin reduces systemic methylglyoxal levels in type 2 diabetes","volume":"48","author":"Beisswenger","year":"1999","journal-title":"Diabetes"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/2165\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:20:35Z","timestamp":1760134835000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/4\/2165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,16]]},"references-count":144,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23042165"],"URL":"https:\/\/doi.org\/10.3390\/ijms23042165","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,16]]}}}