{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T16:47:46Z","timestamp":1793724466853,"version":"4.6.1"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Advanced Glycation End Products (AGEs) accumulate under chronic hyperglycemia and contribute to type 2 diabetes mellitus (T2DM) complications. Three chemical routes generate AGEs\n                      <jats:italic>in vivo<\/jats:italic>\n                      : the Hodge pathway (Amadori rearrangement), the Namiki pathway (Schiff base retroaldol cleavage), and the Wolff pathway (glucose auto-oxidation via Fenton-type chemistry). Each has been extensively characterized, but their integrated behavior in the clinical context \u2014 and their relationships to accessible biomarkers \u2014 has received less synthetic treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This paper provides a clinically oriented mechanistic synthesis of the three pathways, identifying their points of convergence and divergence, and proposes \u2014 as a hypothesis-generating organizing schema rather than as established biology \u2014 a clinical biomarker mapping linking each pathway to routinely accessible laboratory parameters as a basis for prospective validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach<\/jats:title>\n                    <jats:p>Narrative mechanistic review synthesizing primary biochemistry, dicarbonyl chemistry, and clinical biomarker literatures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>The three pathways converge upon a shared reactive dicarbonyl pool comprising methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG); upon the GLO1\/GLO2 glyoxalase axis (highest catalytic efficiency for MGO; complementary handling of 3-DG by aldose\/aldo-keto reductases); and upon RAGE-mediated inflammatory amplification. They diverge in their dominant kinetic drivers (sustained hyperglycemia for Hodge; glycemic variability for Namiki; oxidative-metal milieu for Wolff) and characteristic AGE adducts. Methylglyoxal also arises substantially from glycolytic triose phosphate degradation independent of the AGE synthesis pathways. We propose that routine laboratory parameters \u2014 HbA1c \u00d7 diabetes duration, glycemic variability indices, hs-CRP, ferritin, gamma-glutamyl transferase, and red cell distribution width \u2014 may serve as accessible clinical proxies for pathway-specific activity, with the caveat that these mappings require prospective validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The Hodge, Namiki, and Wolff pathways are best understood as an integrated AGE synthesis network. This has implications for therapeutic strategy, favoring approaches that act on shared downstream mediators rather than single-pathway interventions, and for the design of pathway-resolved clinical biomarker panels. The proposed mappings and temporal staging are presented as testable hypotheses, not as established clinical algorithms; their validation will require prospective biomarker studies in defined T2DM cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1856036","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:47:54Z","timestamp":1780462074000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The three pathways of advanced glycation end product synthesis: Hodge, Namiki, and Wolff \u2014 a clinically oriented mechanistic synthesis with network-based implications"],"prefix":"10.3389","volume":"17","author":[{"given":"Enrique C.","family":"Fernandez","sequence":"first","affiliation":[{"name":"Kendall Regional Medical Center","place":["Miami, FL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1021\/jf60015a004","article-title":"Dehydrated foods: chemistry of browning reactions in model systems","volume":"1","author":"Hodge","year":"1953","journal-title":"J Agric Food Chem"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.2337\/diabetes.54.6.1615","article-title":"The pathobiology of diabetic complications: a unifying mechanism","volume":"54","author":"Brownlee","year":"2005","journal-title":"Diabetes"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-013-0453-1","article-title":"Advanced glycation end products (AGE) and diabetes: cause, effect, or both","volume":"14","author":"Vlassara","year":"2014","journal-title":"Curr Diabetes Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4196\/kjpp.2014.18.1.1","article-title":"Advanced glycation end products and diabetic complications","volume":"18","author":"Singh","year":"2014","journal-title":"Korean J Physiol Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00001.2019","article-title":"Methylglyoxal, a highly reactive dicarbonyl compound, in diabetes, its vascular complications, and other age-related diseases","volume":"100","author":"Schalkwijk","year":"2020","journal-title":"Physiol Rev"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/s0167-4943(01)00103-0","article-title":"Age-related changes in cells and tissues due to advanced glycation end products (AGEs)","volume":"32","author":"Kasper","year":"2001","journal-title":"Arch Gerontol Geriatr"},{"key":"B7","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1021\/bk-1983-0215.ch002","article-title":"A new mechanism of the Maillard reaction involving sugar fragmentation and free radical formation","volume":"215","author":"Namiki","year":"1983","journal-title":"ACS Symp Ser"},{"key":"B8","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1021\/bk-1983-0215.ch002","article-title":"Role of sugar fragmentation in the Maillard reaction","volume":"13","author":"Hayashi","year":"1986","journal-title":"Dev Food Sci"},{"key":"B9","article-title":"Glucose autoxidation and protein modification. The potential role of 'autoxidative glycosylation' in diabetes","volume":"245","author":"Wolff","year":"1987","journal-title":"Biochem J"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2337\/diab.39.11.1420","article-title":"Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose","volume":"39","author":"Hunt","year":"1990","journal-title":"Diabetes"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-010-0783-0","article-title":"Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome","volume":"42","author":"Rabbani","year":"2012","journal-title":"Amino Acids"},{"key":"B12","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCRESAHA.109.212217","article-title":"The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature","volume":"106","author":"Yan","year":"2010","journal-title":"Circ Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.18.6.896","article-title":"Tests of glycemia in diabetes","volume":"27","author":"Goldstein","year":"2004","journal-title":"Diabetes Care"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/science.12192669","article-title":"Reaction of monosaccharides with proteins: possible evolutionary significance","volume":"213","author":"Bunn","year":"1981","journal-title":"Science"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1042\/bj3440109","article-title":"Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose","volume":"344","author":"Thornalley","year":"1999","journal-title":"Biochem J"},{"key":"B16","article-title":"Compendium of Chemical Terminology, 2nd ed. (the \"Gold Book\")","author":"McNaught","year":"1997"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/s0021-9258(20)88225-8","article-title":"Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process","volume":"264","author":"Sell","year":"1989","journal-title":"J Biol Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/s0021-9258(19)89188-3","article-title":"Identification of N-epsilon-carboxymethyllysine as a degradation product of fructoselysine in glycated protein","volume":"261","author":"Ahmed","year":"1986","journal-title":"J Biol Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1042\/bj3240565","article-title":"N-epsilon-(carboxyethyl)lysine, a product of the chemical modification of proteins by methylglyoxal, increases with age in human lens proteins","volume":"324","author":"Ahmed","year":"1997","journal-title":"Biochem J"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.30.18714","article-title":"Role of the Maillard reaction in aging of tissue proteins. Advanced glycation end product-dependent increase in imidazolium cross-links in human lens proteins","volume":"273","author":"Frye","year":"1998","journal-title":"J Biol Chem"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1333.065","article-title":"Glycation products as markers and predictors of the progression of diabetic complications","volume":"1043","author":"Monnier","year":"2005","journal-title":"Ann N Y Acad Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1097\/00006982-199414030-00022","article-title":"The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus","volume":"329","year":"1993","journal-title":"N Engl J Med"},{"key":"B23","article-title":"Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)","volume":"352","year":"1998","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2006.00595.x","article-title":"Advanced glycation endproducts: what is their relevance to diabetic complications","volume":"9","author":"Ahmed","year":"2007","journal-title":"Diabetes Obes Metab"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18050984","article-title":"Dicarbonyls and advanced glycation end products in the development of diabetic complications and targets for intervention","volume":"18","author":"Brings","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1001\/jama.295.14.1681","article-title":"Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes","volume":"295","author":"Monnier","year":"2006","journal-title":"JAMA"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.24.4.726","article-title":"\u03b1-Dicarbonyls increase in the postprandial period and reflect the degree of hyperglycemia","volume":"24","author":"Beisswenger","year":"2001","journal-title":"Diabetes Care"},{"key":"B28","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/0014-5793(90)80974-n","article-title":"Hydrogen peroxide production during experimental protein glycation","volume":"268","author":"Jiang","year":"1990","journal-title":"FEBS Lett"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119176","article-title":"Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to convert hydroxy-amino acids into glycolaldehyde, 2-hydroxypropanal, and acrolein. A mechanism for the generation of highly reactive alpha-hydroxy and alpha,beta-unsaturated aldehydes by phagocytes at sites of inflammation","volume":"99","author":"Anderson","year":"1997","journal-title":"J Clin Invest"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(86)90305-x","article-title":"Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts","volume":"246","author":"Halliwell","year":"1986","journal-title":"Arch Biochem Biophys"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(13)70174-8","article-title":"Effects of iron overload on chronic metabolic diseases","volume":"2","author":"Fern\u00e1ndez-Real","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.02.007","article-title":"Iron and diabetes risk","volume":"17","author":"Simcox","year":"2013","journal-title":"Cell Metab"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1993.tb17638.x","article-title":"The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal","volume":"212","author":"Phillips","year":"1993","journal-title":"Eur J Biochem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00023","article-title":"Methylglyoxal, the dark side of glycolysis","volume":"9","author":"Allaman","year":"2015","journal-title":"Front Neurosci"},{"key":"B35","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/0098-2997(93)90002-u","article-title":"The glyoxalase system in health and disease","volume":"14","author":"Thornalley","year":"1993","journal-title":"Mol Aspects Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/s0009-2797(02)00212-0","article-title":"Methylglyoxal metabolism and diabetic complications: roles of aldose reductase, glyoxalase-I, betaine aldehyde dehydrogenase and 2-oxoaldehyde dehydrogenase","author":"Vander Jagt","year":"2003","journal-title":"Chem Biol Interact"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1172\/JCI14002","article-title":"The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses","volume":"108","author":"Schmidt","year":"2001","journal-title":"J Clin Invest"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-005-0688-7","article-title":"Understanding RAGE, the receptor for advanced glycation end products","volume":"83","author":"Bierhaus","year":"2005","journal-title":"J Mol Med (Berl)"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-04-154112","article-title":"Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c","volume":"112","author":"Cohen","year":"2008","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","first-page":"95","DOI":"10.7326\/M16-2596","article-title":"Racial differences in the relationship of glucose concentrations and hemoglobin A1c levels","volume":"167","author":"Bergenstal","year":"2017","journal-title":"Ann Intern Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man","volume":"28","author":"Matthews","year":"1985","journal-title":"Diabetologia"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.22.9.1462","article-title":"Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp","volume":"22","author":"Matsuda","year":"1999","journal-title":"Diabetes Care"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-004-1451-2","article-title":"Simple non-invasive assessment of advanced glycation endproduct accumulation","volume":"47","author":"Meerwaldt","year":"2004","journal-title":"Diabetologia"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1177\/089686080902902s10","article-title":"Quantitation of markers of protein damage by glycation, oxidation, and nitration in peritoneal dialysis","volume":"29","author":"Rabbani","year":"2009","journal-title":"Perit Dial Int"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.164.19.2090","article-title":"Postprandial glucose regulation and diabetic complications","volume":"164","author":"Ceriello","year":"2004","journal-title":"Arch Intern Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/nxy236","article-title":"Quercetin, but not epicatechin, decreases plasma concentrations of methylglyoxal in adults in a randomized, double-blind, placebo-controlled, crossover trial with pure flavonoids","volume":"148","author":"Van den Eynde","year":"2018","journal-title":"J Nutr"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14977","article-title":"Pyridoxamine reduces methylglyoxal and markers of glycation and endothelial dysfunction, but does not improve insulin sensitivity or vascular function in abdominally obese individuals: a randomized double-blind placebo-controlled trial","volume":"25","author":"Van den Eynde","year":"2023","journal-title":"Diabetes Obes Metab"},{"key":"B48","doi-asserted-by":"publisher","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"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1371818","article-title":"Effect of metformin on methylglyoxal metabolism in patients with type 2 diabetes","volume":"122","author":"Kender","year":"2014","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2007.04.005","article-title":"N-Acetylcysteine \u2014 a safe antidote for cysteine\/glutathione deficiency","volume":"7","author":"Atkuri","year":"2007","journal-title":"Curr Opin Pharmacol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-0503","article-title":"Efficacy and safety of antioxidant treatment with \u03b1-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial","volume":"34","author":"Ziegler","year":"2011","journal-title":"Diabetes Care"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1159\/000108104","article-title":"Effects of pyridoxamine in combined Phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy","volume":"27","author":"Williams","year":"2007","journal-title":"Am J Nephrol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1120","article-title":"Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications","volume":"61","author":"Nagai","year":"2012","journal-title":"Diabetes"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2010.01101.x","article-title":"The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats","volume":"15","author":"Aldini","year":"2011","journal-title":"J Cell Mol Med"},{"key":"B55","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1159\/000075627","article-title":"Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy","volume":"24","author":"Bolton","year":"2004","journal-title":"Am J Nephrol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1161\/hc3801.097806","article-title":"Improved arterial compliance by a novel advanced glycation end-product crosslink breaker","volume":"104","author":"Kass","year":"2001","journal-title":"Circulation"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2018.18","article-title":"Development of azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild Alzheimer's disease","volume":"5","author":"Burstein","year":"2018","journal-title":"J Prev Alzheimers Dis"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1856036\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:48:05Z","timestamp":1780462085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1856036\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":57,"alternative-id":["10.3389\/fendo.2026.1856036"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1856036","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]},"article-number":"1856036"}}