Diabetes mellitus and its consequent pathological complications continue to pose serious and growing health care challenges across the world. One promising mechanism for linking hyperglycemia and diabetic complications is the process of spontaneous, nonenzymatic reactions between glucose and its catabolites with amino groups in macromolecules (a.k.a. Maillard reactions). The most reactive sugars in this process are two low-molecular-weight α-dicarbonyls: methylglyoxal and glyoxal (GO). While the origins of methylglyoxal are well documented, little is known about the origins of the equally important GO. This article postulates that GO is produced as an unavoidable byproduct of the transketolase reaction in the pentose-phosphate pathway.
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: A pooled analysis of 1108 population representative studies with 141 million participants. Lancet, 2024; 404(10467):2077–2093.
2.
DuncanBB, MaglianoDJ, BoykoEJ. IDF diabetes atlas 11th edition 2025: Global prevalence and projections for 2050. Nephrology Dialysis Transplantation, 2025:gfaf177.
3.
ChenQ, LiCF, JingW. Research progress on the effects of sedentary behavior and physical activity on diabetes mellitus. Sheng li xue bao. Sheng Li Xue Bao, 2025; 77(1):62–74.
4.
YouWP, HennebergM. Type 1 diabetes prevalence increasing globally and regionally: The role of natural selection and life expectancy at birth. BMJ Open Diab Res Care, 2016; 4(1):e000161.
5.
GoldneyJ, BarkerMM, ThomasM, et al.Age at onset of type 2 diabetes and prevalence of vascular disease and heart failure: Systematic review and dose-response meta- analysis. J Diabetes Complications, 2024; 38(10):108849.
6.
AlobaidT, KarallieddeJ, O’ConnellMD, et al.The prevalence and progression of microvascular complications and the interaction with ethnicity and socioeconomic status in people with type 2 diabetes: A systematic review and meta‐analysis. J Diabetes Res, 2025; 2025(1):3307594.
7.
GiardinelliS, MeliotaG, MentinoD, et al.Molecular basis of cardiomyopathies in type 2 diabetes. Int J Mol Sci, 2024; 25(15):8280.
8.
ZhouP, ZhouJS, LiJJ, et al.Prevalence and risk factors for painful diabetic peripheral neuropathy: A systematic review and meta-analysis. Front Neurol, 2025; 16:1564867.
9.
RatanY, RajputA, PareekA, et al.Comprehending the role of metabolic and hemodynamic factors alongside different signaling pathways in the pathogenesis of diabetic nephropathy. Int J Mol Sci, 2025; 26(7):3330.
10.
SinghA, ShadangiS, GuptaPK, et al.Type 2 diabetes mellitus: A comprehensive review of pathophysiology, comorbidities, and emerging therapies. Compr Physiol, 2025; 15(1):e70003.
11.
NishikawaT, EdelsteinD, BrownleeM. The missing link: A single unifying mechanism for diabetic complications. Kidney Int, 2000; 77:S26–S30.
12.
BringsS, FlemingT, FreichelM, et al.Dicarbonyls and advanced glycation end- products in the development of diabetic complications and targets for intervention. Int J Mol Sci, 2017; 18(5):984.
13.
HenningC, LiehrK, GirndtM, et al.Extending the spectrum of α-dicarbonyl compounds in vivo. J Biol Chem, 2014; 289(41):28676–28688.
14.
LapollaA, FlaminiR, VedovaAD, et al.Glyoxal and methylglyoxal levels in diabetic patients: Quantitative determination by a new GC/MS method. Clin Chem Lab Med, 2003; 41(9):1166–1173.
15.
HenningC, GlombMA. Pathways of the Maillard reaction under physiological conditions. Glycoconj J, 2016; 33(4):499–512.
16.
MalikM, JoensJA. Temperature dependent near-UV molar absorptivities of glyoxal and gluteraldehyde in aqueous solution. Spectrochim Acta A Mol Biomol Spectrosc, 2000; 56(14):2653–2658.
17.
GlushonokGK, GlushonokTG, ShadyroOI. Kinetics of equilibrium attainment between molecular glycolaldehyde structures in an aqueous solution. Kinet Catal, 2000; 41(5):620–624.
18.
AngyalSJ. The composition of reducing sugars in solution: Current aspects. In: Advances in Carbohydrate Chemistry and Biochemistry. Academic Press; 1991;Vol. 49, pp. 19–35.
19.
AhmedN, ArgirovOK, MinhasHS, et al.Assay of Advanced Glycation Endproducts (AGEs): surveying AGEs by chromatographic assay with derivatization by 6-aminoquinolyl-N- hydroxysuccinimidyl-carbamate and application to Nepsilon-carboxymethyl-lysine- and Nepsilon-(1-carboxyethyl)lysine-modified albumin. Biochem J, 2002; 364(Pt 1):1–14.
20.
AhmedN, Babaei-JadidiR, HowellSK, et al.Degradation products of proteins damaged by glycation, oxidation and nitration in clinical type 1 diabetes. Diabetologia, 2005; 48(8):1590–1603.
21.
SchalkwijkCG, MicaliLR, WoutersK. Advanced glycation endproducts in diabetes- related macrovascular complications: Focus on methylglyoxal. Trends Endocrinol Metab, 2023; 34(1):49–60.
22.
RichardJP. Mechanism for the formation of methylglyoxal from triosephosphates. Biochem Soc Trans, 1993; 21(2):549–553.
23.
AndersonMM, RequenaJR, CrowleyJR, et al.The myeloperoxidase system of human phagocytes generates N ε-(carboxymethyl) lysine on proteins: A mechanism for producing advanced glycation end products at sites of inflammation. J Clin Invest, 1999; 104(1):103–113.
24.
ManiniP, La PietraP, PanzellaL, et al.Glyoxal formation by Fenton-induced degradation of carbohydrates and related compounds. Carbohydr Res, 2006; 341(11):1828–1833.
25.
BeardKM, ShangariN, WuB, et al.Metabolism, not autoxidation, plays a role in α- oxoaldehyde-and reducing sugar-induced erythrocyte GSH depletion: Relevance for diabetes mellitus. Mol Cell Biochem, 2003; 252(1–2):331–338.
26.
LangeJN, WoodKD, KnightJ, et al.Glyoxal formation and its role in endogenous oxalate synthesis. Adv Urol, 2012; 2012(1):819202.
27.
KochetovGA, SolovjevaON. Structure and functioning mechanism of transketolase. Biochim Biophys Acta, 2014; 1844(9):1608–1618.
28.
BykovaIA, SolovjevaON, MeshalkinaLE, et al.One-substrate transketolase- catalyzed reaction. Biochem Biophys Res Commun, 2001; 280(3):845–847.
29.
SolovjevaON, KovinaMV, ZavialovaMG, et al.The mechanism of a one-substrate transketolase reaction. Biosci Rep, 2020; 40(8):BSR20180246.
30.
MaessenDE, HanssenNM, ScheijenJL, et al.Post–glucose load plasma α-dicarbonyl concentrations are increased in individuals with impaired glucose metabolism and type 2 diabetes: The CODAM study. Diabetes Care, 2015; 38(5):913–920.
31.
LalS, KapplerF, WalkerM, et al.Quantitation of 3-deoxyglucosone levels in human plasma. Arch Biochem Biophys, 1997; 342(2):254–260.
32.
ZhangX, ScheijenJL, StehouwerCD, et al.Increased methylglyoxal formation in plasma and tissues during a glucose tolerance test is derived from exogenous glucose. Clin Sci (Lond), 2023; 137(8):697–706.
33.
Solov’evaON, MeshalkinaLE, KovinaMV, et al.Acceptor substrate inhibits transketolase competitively with respect to donor substrate. Biochemistry (Mosc), 2000; 65(10):1202–1205.
34.
Solov’evaON, BykovaIA, MeshalkinaLE, et al.Cleaving of ketosubstrates by transketolase and the nature of the products formed. Biochemistry (Mosc), 2001; 66(8):932–936.
35.
SevostyanovaI, SolovjevaO, SelivanovV, et al.Half-of-the-sites reactivity of transketolase from Saccharomyces cerevisiae. Biochem Biophys Res Commun, 2009; 379(4):851–854.
36.
MeshalkinaLE, SolovjevaON, KochetovGA. Interaction of transketolase from human tissues with substrates. Biochemistry (Mosc), 2011; 76(9):1061–1064.
ZengJ, DaviesMJ. Evidence for the formation of adducts and S- (carboxymethyl)cysteine on reaction of alpha-dicarbonyl compounds with thiol groups on amino acids, peptides, and proteins. Chem Res Toxicol, 2005; 18(8):1232–1241.
39.
ZengJ, DunlopRA, RodgersKJ, et al.Evidence for inactivation of cysteine proteases by reactive carbonyls via glycation of active site thiols. Biochem J, 2006; 398(2):197–206.
40.
KlausA, BaldenspergerT, FiedlerR, et al.Influence of Transketolase-Catalyzed reactions on the formation of glycolaldehyde and glyoxal specific posttranslational modifications under physiological conditions. J Agric Food Chem, 2018; 66(6):1498–1508.
41.
HarkinC, CobiceD, WattJ, et al.Analysis of reactive aldehydes in urine and plasma of type-2 diabetes mellitus patients through liquid chromatography-mass spectrometry: Reactive aldehydes as potential markers of diabetic nephropathy. Front Nutr, 2022; 9:997015.
42.
MetzgerRP, SauerheberRD, LyonsSA, et al.The effect of streptozotocin diabetes on the levels of glycolate and lactate excreted in rat urine. Arch Biochem Biophys, 1975; 169(2):555–559.
43.
NikiforovaVJ, GiesbertzP, WiemerJ, et al.Glyoxylate, a new marker metabolite of type 2. J Diabetes Res, 2014; 2014:685204–685209.
44.
PadbergI, PeterE, González-MaldonadoS, et al.A new metabolomic signature in type-2 diabetes mellitus and its pathophysiology. PLoS One, 2014; 9(1):e85082.
45.
EfeO, VermaA, WaikarSS. Urinary oxalate as a potential mediator of kidney disease in diabetes mellitus and obesity. Curr Opin Nephrol Hypertens, 2019; 28(4):316–320.
46.
KnightJ, WoodKD, LangeJN, et al.Oxalate formation from glyoxal in erythrocytes. Urology, 2016; 88:226.e11–226.e15.
47.
AlangariAS, El-MetwallyAA, AlanaziA, et al.Epidemiology of glucose-6-phosphate dehydrogenase deficiency in Arab Countries: Insights from a systematic review. J Clin Med, 2023; 12(20):6648.
48.
NiaziGA. Glucose-6-phosphate dehydrogenase deficiency and diabetes mellitus. Int J Hematol, 1991; 54(4):295–298.
49.
HeymannAD, CohenY, ChodickG. Glucose-6-phosphate dehydrogenase deficiency and type 2 diabetes. Diabetes Care, 2012; 35(8):e58.
50.
LaiYK, LaiNM, LeeSW. Glucose-6-phosphate dehydrogenase deficiency and risk of diabetes: A systematic review and meta-analysis. Ann Hematol, 2017; 96(5):839–845.
51.
CappaiG, SonginiM, DoriaA, CavalleranoJD, LorenziM. Increased prevalence of proliferative retinopathy in patients with type 1 diabetes who are deficient in glucose-6- phosphate dehydrogenase. Diabetologia, 2011; 54(6):1539–1542.
52.
ScuteriA, MorrellCH, AlGhatrifM, et al.Glucose-6-phosphate dehydrogenase deficiency accelerates arterial aging in diabetes. Acta Diabetol, 2024; 61(1):127–130.
53.
DoreMP, ParodiG, PortogheseM, et al.The controversial role of glucose-6-phosphate dehydrogenase deficiency on cardiovascular disease: A narrative review. Oxid Med Cell Longev, 2021; 2021:5529256.
54.
KuzanA. Toxicity of advanced glycation end products (Review). Biomed Rep, 2021; 14(5):46.
55.
GuMJ, HyonJY, LeeHW, et al.Glycolaldehyde, an advanced glycation end products precursor, induces apoptosis via ROS-Mediated mitochondrial dysfunction in renal mesangial cells. Antioxidants (Basel), 2022; 11(5):934.
56.
LorenziR, AndradesME, BortolinRC, et al.Glycolaldehyde induces oxidative stress in the heart: A clue to diabetic cardiomyopathy? Cardiovasc Toxicol, 2010; 10(4):244–249.
