Vitamin B6 and Diabetes: Relationship and Molecular Mechanisms

Elisa Mascolo, Fiammetta Vernì, Elisa Mascolo, Fiammetta Vernì

Abstract

Vitamin B6 is a cofactor for approximately 150 reactions that regulate the metabolism of glucose, lipids, amino acids, DNA, and neurotransmitters. In addition, it plays the role of antioxidant by counteracting the formation of reactive oxygen species (ROS) and advanced glycation end-products (AGEs). Epidemiological and experimental studies indicated an evident inverse association between vitamin B6 levels and diabetes, as well as a clear protective effect of vitamin B6 on diabetic complications. Interestingly, by exploring the mechanisms that govern the relationship between this vitamin and diabetes, vitamin B6 can be considered both a cause and effect of diabetes. This review aims to report the main evidence concerning the role of vitamin B6 in diabetes and to examine the underlying molecular and cellular mechanisms. In addition, the relationship between vitamin B6, genome integrity, and diabetes is examined. The protective role of this vitamin against diabetes and cancer is discussed.

Keywords: AGEs; diabetes; vitamin B6.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic vitamin B6 metabolism in humans. The diagram corresponds to the pyridoxal 5′-phosphate salvage pathway. PLP, pyridoxal 5′-phosphate; PNP, pyridoxine 5′-phosphate; PMP, pyridoxamine 5′-phosphate; PL, pyridoxal; PN, pyridoxine; PM, pyridoxamine; PDXK, pyridoxal kinase; and PNPO, pyridoxine 5′-phosphate oxidase.
Figure 2
Figure 2
Tryptophan metabolism via the kynurenine pathway. IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KYNU, kynureninase; 3OH-kynurenine, 3-hydroxy kynurenine; 3OH-anthranilic acid, 3-hydroxyanthranilic acid; B6, vitamin B6 (pyridoxal 5′-phosphate); and B2, vitamin B2 (flavin adenine dinucleotide).
Figure 3
Figure 3
Summary of main mechanisms and pathways at the basis of the association between vitamin B6 and diabetes, inferred from the studies reported in the main text.

References

    1. Hellmann H., Mooney S. Vitamin B6: A molecule for human health? Molecules. 2010;15:442–459. doi: 10.3390/molecules15010442.
    1. Percudani R., Peracchi A. A genomic overview of pyridoxal-phosphate-dependent enzymes. EMBO Rep. 2003;4:850–854. doi: 10.1038/sj.embor.embor914.
    1. Di Salvo M.L., Contestabile R., Safo M.K. Vitamin B(6) salvage enzymes: Mechanism, structure and regulation. Biochim. Biophys. Acta. 2011;1814:1597–1608. doi: 10.1016/j.bbapap.2010.12.006.
    1. Bilski P., Li M.Y., Ehrenshaft M., Daub M.E., Chignell C.F. Vitamin B6 (pyridoxine) and its derivatives are efficient singlet oxygen quenchers and potential fungal antioxidants. Photochem. Photobiol. 2000;71:129–134. doi: 10.1562/0031-8655(2000)071<0129:SIPVBP>;2.
    1. Booth A.A., Khalifah R.G., Todd P., Hudson B.G. In vitro kinetic studies of formation of antigenic advanced glycation end products (AGEs). Novel inhibition of post-Amadori glycation pathways. J. Biol. Chem. 1997;272:5430–5437. doi: 10.1074/jbc.272.9.5430.
    1. Lambrecht G., Braun K., Damer M., Ganso M., Hildebrandt C., Ullmann H., Kassack M.U., Nickel P. Structure-activity relationships of suramin and pyridoxal-5′-phosphate derivatives as P2 receptor antagonists. Curr. Pharm. Des. 2002;8:2371–2399. doi: 10.2174/1381612023392973.
    1. McCormick D.B. Two interconnected B vitamins: Riboflavin and pyridoxine. Physiol. Rev. 1989;69:1170–1198. doi: 10.1152/physrev.1989.69.4.1170.
    1. Said H.M. Recent advances in carrier-mediated intestinal absorption of water-soluble vitamins. Annu. Rev. Physiol. 2004;66:419–446. doi: 10.1146/annurev.physiol.66.032102.144611.
    1. Jang Y.M., Kim D.W., Kang T.C., Won M.H., Baek N.I., Moon B.J., Choi S.Y., Kwon O.S. Human pyridoxal phosphatase. Molecular cloning, functional expression, and tissue distribution. J. Biol. Chem. 2003;278:50040–50046. doi: 10.1074/jbc.M309619200.
    1. Cravo M.L., Camilo M.E. Hyperhomocysteinemia in chronic alcoholism: Relations to folic acid and vitamins B(6) and B(12) status. Nutrition. 2000;16:296–302. doi: 10.1016/S0899-9007(99)00297-X.
    1. Ferro Y., Carè I., Mazza E., Provenzano F., Colica C., Torti C., Romeo S., Pujia A., Montalcini T. Protein and vitamin B6 intake are associated with liver steatosis assessed by transient elastography, especially in obese individuals. Clin. Mol. Hepatol. 2017;23:249–259. doi: 10.3350/cmh.2017.0019.
    1. Merrill A.H., Jr., Henderson J.M. Diseases associated with defects in vitamin B6 metabolism or utilization. Annu. Rev. Nutr. 1987;7:137–156. doi: 10.1146/annurev.nu.07.070187.001033.
    1. Kowlessar O.D., Haeffner L.J., Benson G.D. Abnormal tryptophan metabolism in patients with adult celiac disease, with evidence for deficiency of vitamin B6. J. Clin. Investig. 1964;43:894–903. doi: 10.1172/JCI104975.
    1. Chiang E.P., Selhub J., Bagley P.J., Dallal G., Roubenoff R. Pyridoxine supplementation corrects vitamin B6 deficiency but does not improve inflammation in patients with rheumatoid arthritis. Arthritis Res. Ther. 2005;7:R1404-11. doi: 10.1186/ar1839.
    1. Biehl J.P., Vilter R.W. Effect of isoniazid on vitamin B6 metabolism; its possible significance in producing isoniazid neuritis. Proc. Soc. Exp. Biol. Med. 1954;85:389–392. doi: 10.3181/00379727-85-20891.
    1. Jaffe I.A., Altman K., Merryman P. The antipyridoxine effect of penicillamine in man. J. Clin. Investig. 1964;43:1869–1873. doi: 10.1172/JCI105060.
    1. Yamada K., Sawaki S., Hayami S. Inhibitory effect of cycloserine on some enzymic activities related to vitamin B6. J. Vitaminol. 1957;3:68–72. doi: 10.5925/jnsv1954.3.68.
    1. Lussana F., Zighetti M.L., Bucciarelli P., Cugno M., Cattaneo M. Blood levels of homocysteine, folate, vitamin B6 and B12 in women using oral contraceptives compared to non-users. Thromb. Res. 2003;112:37–41. doi: 10.1016/j.thromres.2003.11.007.
    1. Oxenkrug G.F. Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: The serotonin hypothesis revisited 40 years later. Isr. J. Psychiatry Relat. Sci. 2010;47:56–63.
    1. Midttun O., Ulvik A., Ringdal Pedersen E., Ebbing M., Bleie O., Schartum-Hansen H., Nilsen R.M., Nygård O., Ueland P.M. Low plasma vitamin B-6 status affects metabolism through the kynurenine pathway in cardiovascular patients with systemic inflammation. J. Nutr. 2011;141:611–617. doi: 10.3945/jn.110.133082.
    1. Di Salvo M.L., Safo M.K., Contestabile R. Biomedical aspects of pyridoxal 5′-phosphate availability. Front. Biosci. 2012;4:897–913.
    1. Merigliano C., Mascolo E., Burla R., Saggio I., Vernì F. The Relationship Between Vitamin B6, Diabetes and Cancer. Front. Genet. 2018;9:388. doi: 10.3389/fgene.2018.00388.
    1. Contestabile R., di Salvo M.L., Bunik V., Tramonti A., Vernì F. The multifaceted role of vitamin B(6) in cancer: Drosophila as a model system to investigate DNA damage. Open Biol. 2020;10:200034. doi: 10.1098/rsob.200034.
    1. American Diabetes Association Diagnosis and classification of diabetes mellitus. Diabetes Care. 2013;36(Suppl. 1):S67–S74.
    1. Plows J.F., Stanley J.L., Baker P.N., Reynolds C.M., Vickers M.H. The Pathophysiology of Gestational Diabetes Mellitus. Int. J. Mol. Sci. 2018;19:3342. doi: 10.3390/ijms19113342.
    1. Leklem J.E. Vitamin B-6: A status report. J. Nutr. 1990;120(Suppl. 11):1503–1507. doi: 10.1093/jn/120.suppl_11.1503.
    1. Satyanarayana A., Balakrishna N., Pitla S., Reddy P.Y., Mudili S., Lopamudra P., Suryanarayana P., Viswanath K., Ayyagari R., Reddy G.B. Status of B-vitamins and homocysteine in diabetic retinopathy: Association with vitamin-B12 deficiency and hyperhomocysteinemia. PLoS ONE. 2011;6:e26747. doi: 10.1371/journal.pone.0026747.
    1. Ahn H.J., Min K.W., Cho Y.O. Assessment of vitamin B(6) status in Korean patients with newly diagnosed type 2 diabetes. Nutr. Res. Pract. 2011;5:34–39. doi: 10.4162/nrp.2011.5.1.34.
    1. Nix W.A., Zirwes R., Bangert V., Kaiser R.P., Schilling M., Hostalek U., Obeid R. Vitamin B status in patients with type 2 diabetes mellitus with and without incipient nephropathy. Diabetes Res. Clin. Pract. 2015;107:157–165. doi: 10.1016/j.diabres.2014.09.058.
    1. Iwakawa H., Nakamura Y., Fukui T., Fukuwatari T., Ugi S., Maegawa H., Doi Y., Shibata K. Concentrations of Water-Soluble Vitamins in Blood and Urinary Excretion in Patients with Diabetes Mellitus. Nutr. Metab. Insights. 2016;9:85–92. doi: 10.4137/NMI.S40595.
    1. Rogers K.S., Higgins E.S., Kline E.S. Experimental diabetes causes mitochondrial loss and cytoplasmic enrichment of pyridoxal phosphate and aspartate aminotransferase activity. Biochem. Med. Metab. Biol. 1986;36:91–97. doi: 10.1016/0885-4505(86)90111-8.
    1. Okada M., Shibuya M., Yamamoto E., Murakami Y. Effect of diabetes on vitamin B6 requirement in experimental animals. Diabetes Obes. Metab. 1999;1:221–225. doi: 10.1046/j.1463-1326.1999.00028.x.
    1. Bennink H.J., Schreurs W.H. Improvement of oral glucose tolerance in gestational diabetes by pyridoxine. Br. Med. J. 1975;3:13–15. doi: 10.1136/bmj.3.5974.13.
    1. Spellacy W.N., Buhi W.C., Birk S.A. Vitamin B6 treatment of gestational diabetes mellitus: Studies of blood glucose and plasma insulin. Am. J. Obstet. Gynecol. 1977;127:599–602. doi: 10.1016/0002-9378(77)90356-8.
    1. Nair A.R., Biju M.P., Paulose C.S. Effect of pyridoxine and insulin administration on brain glutamate dehydrogenase activity and blood glucose control in streptozotocin-induced diabetic rats. Biochim. Biophys. Acta. 1998;1381:351–354. doi: 10.1016/S0304-4165(98)00054-3.
    1. Solomon L.R., Cohen K. Erythrocyte O2 transport and metabolism and effects of vitamin B6 therapy in type II diabetes mellitus. Diabetes. 1989;38:881–886. doi: 10.2337/diab.38.7.881.
    1. Kim H.H., Kang Y.R., Lee J.Y., Chang H.B., Lee K.W., Apostolidis E., Kwon Y.I. The Postprandial Anti-Hyperglycemic Effect of Pyridoxine and Its Derivatives Using In Vitro and In Vivo Animal Models. Nutrients. 2018;10:285. doi: 10.3390/nu10030285.
    1. Leklem J.E., Hollenbeck C.B. Acute ingestion of glucose decreases plasma pyridoxal 5′-phosphate and total vitamin B-6 concentration. Am. J. Clin. Nutr. 1990;51:832–836. doi: 10.1093/ajcn/51.5.832.
    1. Clark M., Kroger C.J., Tisch R.M. Type 1 Diabetes: A Chronic Anti-Self-Inflammatory Response. Front. Immunol. 2017;8:1898. doi: 10.3389/fimmu.2017.01898.
    1. Esser N., Legrand-Poels S., Piette J., Scheen A.J., Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Clin. Pract. 2014;105:141–150. doi: 10.1016/j.diabres.2014.04.006.
    1. Saltiel A.R., Olefsky J.M. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Investig. 2017;127:1–4. doi: 10.1172/JCI92035.
    1. Paul L., Ueland P.M., Selhub J. Mechanistic perspective on the relationship between pyridoxal 5′-phosphate and inflammation. Nutr. Rev. 2013;71:239–244. doi: 10.1111/nure.12014.
    1. Toyota T., Kai Y., Kakizaki M., Ohtsuka H., Shibata Y., Goto Y. The endocrine pancreas in pyridoxine deficient rats. Tohoku J. Exp. Med. 1981;134:331–336. doi: 10.1620/tjem.134.331.
    1. Rubí B. Pyridoxal 5′-phosphate (PLP) deficiency might contribute to the onset of type I diabetes. Med. Hypotheses. 2012;78:179–182. doi: 10.1016/j.mehy.2011.10.021.
    1. Marzio A., Merigliano C., Gatti M., Vernì F. Sugar and chromosome stability: Clastogenic effects of sugars in vitamin B6-deficient cells. PLoS Genet. 2014;10:e1004199. doi: 10.1371/journal.pgen.1004199.
    1. Mascolo E., Amoroso N., Saggio I., Merigliano C., Vernì F. Pyridoxine/pyridoxamine 5′-phosphate oxidase (Sgll/PNPO) is important for DNA integrity and glucose homeostasis maintenance in Drosophila. J. Cell. Physiol. 2020;235:504–512. doi: 10.1002/jcp.28990.
    1. Cipressa F., Romano S., Centonze S., zur Lage P.I., Vernì F., Dimitri P., Gatti M., Cenci G. Effete, a Drosophila chromatin-associated ubiquitin-conjugating enzyme that affects telomeric and heterochromatic position effect variegation. Genetics. 2013;195:147–158. doi: 10.1534/genetics.113.153320.
    1. Musselman L.P., Fink J.L., Narzinski K., Ramachandran P.V., Hathiramani S.S., Cagan R.L., Baranski T.J. A high-sugar diet produces obesity and insulin resistance in wild-type Drosophila. Dis. Models Mech. 2011;4:842–849. doi: 10.1242/dmm.007948.
    1. Alfa R.W., Kim S.K. Using Drosophila to discover mechanisms underlying type 2 diabetes. Dis. Models Mech. 2016;9:365–376. doi: 10.1242/dmm.023887.
    1. Graham P., Pick L. Drosophila as a Model for Diabetes and Diseases of Insulin Resistance. Curr. Top. Dev. Biol. 2017;121:397–419.
    1. Merigliano C., Mascolo E., La Torre M., Saggio I., Vernì F. Protective role of vitamin B6 (PLP) against DNA damage in Drosophila models of type 2 diabetes. Sci. Rep. 2018;8:11432. doi: 10.1038/s41598-018-29801-z.
    1. Moreno-Navarrete J.M., Jove M., Ortega F., Xifra G., Ricart W., Obis È., Pamplona R., Portero-Otin M., Fernández-Real J.M. Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity. Diabetologia. 2016;59:822–832. doi: 10.1007/s00125-016-3863-1.
    1. Mascolo E., Barile A., Mecarelli L.S., Amoroso N., Merigliano C., Massimi A., Saggio I., Hansen T., Tramonti A., Di Salvo M.L., et al. The expression of four pyridoxal kinase (PDXK) human variants in Drosophila impacts on genome integrity. Sci. Rep. 2019;9:14188. doi: 10.1038/s41598-019-50673-4.
    1. Schwarcz R., Bruno J.P., Muchowski P.J., Wu H.Q. Kynurenines in the mammalian brain: When physiology meets pathology. Nat. Rev. Neurosci. 2012;13:465–477. doi: 10.1038/nrn3257.
    1. Oxenkrug G.F. Genetic and hormonal regulation of tryptophan kynurenine metabolism: Implications for vascular cognitive impairment, major depressive disorder, and aging. Ann. N. Y. Acad. Sci. 2007;1122:35–49. doi: 10.1196/annals.1403.003.
    1. Van de Kamp J.L., Smolen A. Response of kynurenine pathway enzymes to pregnancy and dietary level of vitamin B-6. Pharmacol. Biochem. Behav. 1995;51:753–758. doi: 10.1016/0091-3057(95)00026-S.
    1. Bender D.A., Njagi E.N., Danielian P.S. Tryptophan metabolism in vitamin B6-deficient mice. Br. J. Nutr. 1990;63:27–36. doi: 10.1079/BJN19900089.
    1. Rios-Avila L., Nijhout H.F., Reed M.C., Sitren H.S., Gregory J.F., 3rd A mathematical model of tryptophan metabolism via the kynurenine pathway provides insights into the effects of vitamin B-6 deficiency, tryptophan loading, and induction of tryptophan 2,3-dioxygenase on tryptophan metabolites. J. Nutr. 2013;143:1509–1519. doi: 10.3945/jn.113.174599.
    1. Yess N., Price J.M., Brown R.R., Swan P.B., Linkswiler H. Vitamin B6 depletion in man: urinary excretion of tryptophan metabolites. J. Nutr. 1964;84:229–236. doi: 10.1093/jn/84.3.229.
    1. Takeuchi F., Tsubouchi R., Izuta S., Shibata Y. Kynurenine metabolism and xanthurenic acid formation in vitamin B6-deficient rat after tryptophan injection. J. Nutr. Sci. Vitaminol. 1989;35:111–122. doi: 10.3177/jnsv.35.111.
    1. Connick J.H., Stone T.W. The role of kynurenines in diabetes mellitus. Med. Hypotheses. 1985;18:371–376. doi: 10.1016/0306-9877(85)90104-5.
    1. Hattori M., Kotake Y., Kotake Y. Studies on the urinary excretion of xanthurenic acid in diabetics. Acta Vitaminol. Enzymol. 1984;6:221–228.
    1. Ikeda S., Kotake Y. Urinary excretion of xanthurenic acid and zinc in diabetes: (3). Occurrence of xanthurenic acid-Zn2+ complex in urine of diabetic patients and of experimentally-diabetic rats. Ital. J. Biochem. 1986;35:232–241.
    1. Akarte N.R., Shastri N.V. Studies on tryptophan-niacin metabolism in streptozotocin diabetic rats. Diabetes. 1974;23:977–981. doi: 10.2337/diab.23.12.977.
    1. Patterson A.D., Bonzo J.A., Li F., Krausz K.W., Eichler G.S., Aslam S., Tigno X., Weinstein J.N., Hansen B.C., Idle J.R., et al. Metabolomics reveals attenuation of the SLC6A20 kidney transporter in nonhuman primate and mouse models of type 2 diabetes mellitus. J. Biol. Chem. 2011;286:19511–19522. doi: 10.1074/jbc.M111.221739.
    1. Favennec M., Hennart B., Caiazzo R., Leloire A., Yengo L., Verbanck M., Arredouani A., Marre M., Pigeyre M., Bessede A., et al. The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation. Obesity. 2015;23:2066–2074. doi: 10.1002/oby.21199.
    1. Manusadzhian V.G., Kniazev Iu A., Vakhrusheva L.L. [Mass spectrometric identification of xanthurenic acid in pre-diabetes] Vopr. Meditsinskoi Khimii. 1974;20:95–97.
    1. Oxenkrug G. Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways. Mol. Neurobiol. 2013;48:294–301. doi: 10.1007/s12035-013-8497-4.
    1. Kotake Y. Xanthurenic acid, an abnormal metabolite of tryptophan and the diabetic symptoms caused in albino rats by its production. J. Vitaminol. 1955;1:73–87. doi: 10.5925/jnsv1954.1.2_73.
    1. Kotake Y., Ueda T., Mori T., Igaki S., Hattori M. Abnormal tryptophan metabolism and experimental diabetes by xanthurenic acid (XA) Acta Vitaminol. Enzymol. 1975;29:236–239.
    1. Meyramov G., Korchin V., Kocheryzkina N. Diabetogenic activity of xanturenic acid determined by its chelating properties? Transplant. Proc. 1998;30:2682–2684. doi: 10.1016/S0041-1345(98)00788-X.
    1. Rogers K.S., Evangelista S.J. 3-Hydroxykynurenine, 3-hydroxyanthranilic acid, and o-aminophenol inhibit leucine-stimulated insulin release from rat pancreatic islets. Proc. Soc. Exp. Biol. Med. Soc. Exp. Biol. Med. 1985;178:275–278. doi: 10.3181/00379727-178-42010.
    1. Malina H.Z., Richter C., Mehl M., Hess O.M. Pathological apoptosis by xanthurenic acid, a tryptophan metabolite: Activation of cell caspases but not cytoskeleton breakdown. BMC Physiol. 2001;1:7. doi: 10.1186/1472-6793-1-7.
    1. Munipally P.K., Agraharm S.G., Valavala V.K., Gundae S., Turlapati N.R. Evaluation of indoleamine 2,3-dioxygenase expression and kynurenine pathway metabolites levels in serum samples of diabetic retinopathy patients. Arch. Physiol. Biochem. 2011;117:254–258. doi: 10.3109/13813455.2011.623705.
    1. Debnath S., Velagapudi C., Redus L., Thameem F., Kasinath B., Hura C.E., Lorenzo C., Abboud H.E., O’Connor J.C. Tryptophan Metabolism in Patients with Chronic Kidney Disease Secondary to Type 2 Diabetes: Relationship to Inflammatory Markers. Int. J. Tryptophan Res. 2017;10:1178646917694600. doi: 10.1177/1178646917694600.
    1. Cnop M. Fatty acids and glucolipotoxicity in the pathogenesis of Type 2 diabetes. Biochem. Soc. Trans. 2008;36:348–352. doi: 10.1042/BST0360348.
    1. Longo M., Zatterale F., Naderi J., Parrillo L., Formisano P., Raciti G.A., Beguinot F., Miele C. Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications. Int. J. Mol. Sci. 2019;20:2358. doi: 10.3390/ijms20092358.
    1. Choe S.S., Huh J.Y., Hwang I.J., Kim J.I., Kim J.B. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders. Front. Endocrinol. 2016;7:30. doi: 10.3389/fendo.2016.00030.
    1. Dubois S.G., Heilbronn L.K., Smith S.R., Albu J.B., Kelley D.E., Ravussin E. Decreased expression of adipogenic genes in obese subjects with type 2 diabetes. Obesity. 2006;14:1543–1552. doi: 10.1038/oby.2006.178.
    1. Huber A.M., Gershoff S.N., Hegsted D.M. Carbohydrate and fat metabolism and response to insulin in vitamin B6-deficient rats. J. Nutr. 1964;82:371–378. doi: 10.1093/jn/82.3.371.
    1. Ribaya J.D., Gershoff S.N. Effects of vitamin B6 deficiency on liver, kidney, and adipose tissue enzymes associated with carbohydrate and lipid metabolism, and on glucose uptake by rat epididymal adipose tissue. J. Nutr. 1977;107:443–452. doi: 10.1093/jn/107.3.443.
    1. Radhakrishnamurty R., Angel J.F., Sabry Z.I. Response of lipogenesis to repletion in the pyridoxine-deficient rat. J. Nutr. 1968;95:341–348. doi: 10.1093/jn/95.3.341.
    1. Yanaka N., Kanda M., Toya K., Suehiro H., Kato N. Vitamin B6 regulates mRNA expression of peroxisome proliferator-activated receptor-γ target genes. Exp. Ther. Med. 2011;2:419–424. doi: 10.3892/etm.2011.238.
    1. Sanada Y., Kumoto T., Suehiro H., Nishimura F., Kato N., Hata Y., Sorisky A., Yanaka N. RASSF6 expression in adipocytes is down-regulated by interaction with macrophages. PLoS ONE. 2013;8:e61931. doi: 10.1371/journal.pone.0061931.
    1. Sanada Y., Kumoto T., Suehiro H., Yamamoto T., Nishimura F., Kato N., Yanaka N. IκB kinase epsilon expression in adipocytes is upregulated by interaction with macrophages. Biosci. Biotechnol. Biochem. 2014;78:1357–1362. doi: 10.1080/09168451.2014.925776.
    1. Aasheim E.T., Hofsø D., Hjelmesaeth J., Birkeland K.I., Bøhmer T. Vitamin status in morbidly obese patients: A cross-sectional study. Am. J. Clin. Nutr. 2008;87:362–369. doi: 10.1093/ajcn/87.2.362.
    1. Huq M.D., Tsai N.P., Lin Y.P., Higgins L., Wei L.N. Vitamin B6 conjugation to nuclear corepressor RIP140 and its role in gene regulation. Nat. Chem. Biol. 2007;3:161–165. doi: 10.1038/nchembio861.
    1. Bird R.P. The Emerging Role of Vitamin B6 in Inflammation and Carcinogenesis. Adv. Food Nutr. Res. 2018;83:151–194.
    1. Nilsson E., Jansson P.A., Perfilyev A., Volkov P., Pedersen M., Svensson M.K., Poulsen P., Ribel-Madsen R., Pedersen N.L., Almgren P., et al. Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. Diabetes. 2014;63:2962–2976. doi: 10.2337/db13-1459.
    1. Liu Z., Li P., Zhao Z.H., Zhang Y., Ma Z.M., Wang S.X. Vitamin B6 Prevents Endothelial Dysfunction, Insulin Resistance, and Hepatic Lipid Accumulation in Apoe (−/−) Mice Fed with High-Fat Diet. J. Diabetes Res. 2016;2016:1748065. doi: 10.1155/2016/1748065.
    1. Meigs J.B., Jacques P.F., Selhub J., Singer D.E., Nathan D.M., Rifai N., D’Agostino R.B., Sr., Wilson P.W. Fasting plasma homocysteine levels in the insulin resistance syndrome: The Framingham offspring study. Diabetes Care. 2001;24:1403–1410. doi: 10.2337/diacare.24.8.1403.
    1. Ala O.A., Akintunde A.A., Ikem R.T., Kolawole B.A., Ala O.O., Adedeji T.A. Association between insulin resistance and total plasma homocysteine levels in type 2 diabetes mellitus patients in south west Nigeria. Diabetes Metab. Syndr. 2017;11(Suppl. 2):S803–S809. doi: 10.1016/j.dsx.2017.06.002.
    1. Azzini E., Ruggeri S., Polito A. Homocysteine: Its Possible Emerging Role in At-Risk Population Groups. Int. J. Mol. Sci. 2020;21:1421. doi: 10.3390/ijms21041421.
    1. Khoury T., Ben Ya’acov A., Shabat Y., Zolotarovya L., Snir R., Ilan Y. Altered distribution of regulatory lymphocytes by oral administration of soy-extracts exerts a hepatoprotective effect alleviating immune mediated liver injury, non-alcoholic steatohepatitis and insulin resistance. World J. Gastroenterol. 2015;21:7443–7456. doi: 10.3748/wjg.v21.i24.7443.
    1. Li F.J., Zheng S.R., Wang D.M. Adrenomedullin: An important participant in neurological diseases. Neural Regen. Res. 2020;15:1199–1207.
    1. Zhao M., Lamers Y., Ralat M.A., Coats B.S., Chi Y.Y., Muller K.E., Bain J.R., Shankar M.N., Newgard C.B., Stacpoole P.W., et al. Marginal vitamin B-6 deficiency decreases plasma (n-3) and (n-6) PUFA concentrations in healthy men and women. J. Nutr. 2012;142:1791–1797. doi: 10.3945/jn.112.163246.
    1. Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes. 2005;54:1615–1625. doi: 10.2337/diabetes.54.6.1615.
    1. Nowotny K., Jung T., Höhn A., Weber D., Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules. 2015;5:194–222. doi: 10.3390/biom5010194.
    1. Forbes J.M., Cooper M.E. Mechanisms of diabetic complications. Physiol. Rev. 2013;93:137–188. doi: 10.1152/physrev.00045.2011.
    1. Goldin A., Beckman J.A., Schmidt A.M., Creager M.A. Advanced glycation end products: Sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605. doi: 10.1161/CIRCULATIONAHA.106.621854.
    1. Yang P., Feng J., Peng Q., Liu X., Fan Z. Advanced Glycation End Products: Potential Mechanism and Therapeutic Target in Cardiovascular Complications under Diabetes. Oxidative Med. Cell. Longev. 2019;2019:9570616. doi: 10.1155/2019/9570616.
    1. Rowan S., Bejarano E., Taylor A. Mechanistic targeting of advanced glycation end-products in age-related diseases. Biochim. Biophys. Acta Mol. Basis Dis. 2018;1864:3631–3643. doi: 10.1016/j.bbadis.2018.08.036.
    1. Marques C.M.S., Nunes E.A., Lago L., Pedron C.N., Manieri T.M., Sato R.H., Oliveira V.X.J., Cerchiaro G. Generation of Advanced Glycation End-Products (AGEs) by glycoxidation mediated by copper and ROS in a human serum albumin (HSA) model peptide: Reaction mechanism and damage in motor neuron cells. Mutat. Res. 2017;824:42–51. doi: 10.1016/j.mrgentox.2017.10.005.
    1. Deo P., McCullough C.L., Almond T., Jaunay E.L., Donnellan L., Dhillon V.S., Fenech M. Dietary sugars and related endogenous advanced glycation end-products increase chromosomal DNA damage in WIL2-NS cells, measured using cytokinesis-block micronucleus cytome assay. Mutagenesis. 2020;35:169–177. doi: 10.1093/mutage/geaa002.
    1. Ellis J.M., Folkers K., Minadeo M., VanBuskirk R., Xia L.J., Tamagawa H. A deficiency of vitamin B6 is a plausible molecular basis of the retinopathy of patients with diabetes mellitus. Biochem. Biophys. Res. Commun. 1991;179:615–619. doi: 10.1016/0006-291X(91)91416-A.
    1. Cohen K.L., Gorecki G.A., Silverstein S.B., Ebersole J.S., Solomon L.R. Effect of pyridoxine (vitamin B6) on diabetic patients with peripheral neuropathy. J. Am. Podiatry Assoc. 1984;74:394–397. doi: 10.7547/87507315-74-8-394.
    1. Nakamura S., Li H., Adijiang A., Pischetsrieder M., Niwa T. Pyridoxal phosphate prevents progression of diabetic nephropathy. Nephrol. Dial. Transplant. 2007;22:2165–2174. doi: 10.1093/ndt/gfm166.
    1. Elbarbary N.S., Ismail E.A.R., Zaki M.A., Darwish Y.W., Ibrahim M.Z., El-Hamamsy M. Vitamin B complex supplementation as a homocysteine-lowering therapy for early stage diabetic nephropathy in pediatric patients with type 1 diabetes: A randomized controlled trial. Clin. Nutr. 2020;39:49–56. doi: 10.1016/j.clnu.2019.01.006.
    1. Horikawa C., Aida R., Kamada C., Fujihara K., Tanaka S., Tanaka S., Araki A., Yoshimura Y., Moriya T., Akanuma Y., et al. Vitamin B6 intake and incidence of diabetic retinopathy in Japanese patients with type 2 diabetes: Analysis of data from the Japan Diabetes Complications Study (JDCS) Eur. J. Nutr. 2019 doi: 10.1007/s00394-017-1592-y.
    1. Stitt A., Gardiner T.A., Alderson N.L., Canning P., Frizzell N., Duffy N., Boyle C., Januszewski A.S., Chachich M., Baynes J.W., et al. The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes. 2002;51:2826–2832. doi: 10.2337/diabetes.51.9.2826.
    1. Degenhardt T.P., Alderson N.L., Arrington D.D., Beattie R.J., Basgen J.M., Steffes M.W., Thorpe S.R., Baynes J.W. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int. 2002;61:939–950. doi: 10.1046/j.1523-1755.2002.00207.x.
    1. Chiazza F., Cento A.S., Collotta D., Nigro D., Rosa G., Baratta F., Bitonto V., Cutrin J.C., Aragno M., Mastrocola R., et al. Protective Effects of Pyridoxamine Supplementation in the Early Stages of Diet-Induced Kidney Dysfunction. Biomed. Res. Int. 2017;2017:2682861. doi: 10.1155/2017/2682861.
    1. Muellenbach E.A., Diehl C.J., Teachey M.K., Lindborg K.A., Archuleta T.L., Harrell N.B., Andersen G., Somoza V., Hasselwander O., Matuschek M., et al. Interactions of the advanced glycation end product inhibitor pyridoxamine and the antioxidant alpha-lipoic acid on insulin resistance in the obese Zucker rat. Metabolism. 2008;57:1465–1472. doi: 10.1016/j.metabol.2008.05.018.
    1. Abdullah K.M., Abul Qais F., Hasan H., Naseem I. Anti-diabetic study of vitamin B6 on hyperglycaemia induced protein carbonylation, DNA damage and ROS production in alloxan induced diabetic rats. Toxicol. Res. 2019;8:568–579. doi: 10.1039/C9TX00089E.
    1. Nakamura S., Niwa T. Pyridoxal phosphate and hepatocyte growth factor prevent dialysate-induced peritoneal damage. J. Am. Soc. Nephrol. 2005;16:144–150. doi: 10.1681/ASN.2004020120.
    1. Adrover M., Vilanova B., Frau J., Muñoz F., Donoso J. The pyridoxamine action on Amadori compounds: A reexamination of its scavenging capacity and chelating effect. Bioorganic Med. Chem. 2008;16:5557–5569. doi: 10.1016/j.bmc.2008.04.002.
    1. Ortega-Castro J., Adrover M., Frau J., Salvà A., Donoso J., Muñoz F. DFT studies on Schiff base formation of vitamin B6 analogues. Reaction between a pyridoxamine-analogue and carbonyl compounds. J. Phys. Chem. A. 2010;114:4634–4640. doi: 10.1021/jp909156m.
    1. Ramis R., Ortega-Castro J., Caballero C., Casasnovas R., Cerrillo A., Vilanova B., Adrover M., Frau J. How Does Pyridoxamine Inhibit the Formation of Advanced Glycation End Products? The Role of Its Primary Antioxidant Activity. Antioxidants. 2019;8:344. doi: 10.3390/antiox8090344.
    1. Hunter S.J., Boyd A.C., O’Harte F.P., McKillop A.M., Wiggam M.I., Mooney M.H., McCluskey J.T., Lindsay J.R., Ennis C.N., Gamble R., et al. Demonstration of glycated insulin in human diabetic plasma and decreased biological activity assessed by euglycemic-hyperinsulinemic clamp technique in humans. Diabetes. 2003;52:492–498. doi: 10.2337/diabetes.52.2.492.
    1. Vlassara H., Uribarri J. Advanced glycation end products (AGE) and diabetes: Cause, effect, or both? Curr. Diabetes Rep. 2014;14:453. doi: 10.1007/s11892-013-0453-1.
    1. Rains J.L., Jain S.K. Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med. 2011;50:567–575. doi: 10.1016/j.freeradbiomed.2010.12.006.
    1. Bravi M.C., Armiento A., Laurenti O., Cassone-Faldetta M., De Luca O., Moretti A., De Mattia G. Insulin decreases intracellular oxidative stress in patients with type 2 diabetes mellitus. Metabolism. 2006;55:691–695. doi: 10.1016/j.metabol.2006.01.003.
    1. Blasiak J., Arabski M., Krupa R., Wozniak K., Zadrozny M., Kasznicki J., Zurawska M., Drzewoski J. DNA damage and repair in type 2 diabetes mellitus. Mutat. Res. 2004;554:297–304. doi: 10.1016/j.mrfmmm.2004.05.011.
    1. Zhong A., Chang M., Yu T., Gau R., Riley D.J., Chen Y., Chen P.L. Aberrant DNA damage response and DNA repair pathway in high glucose conditions. J. Cancer Res. Updates. 2018;7:64–74. doi: 10.6000/1929-2279.2018.07.03.1.
    1. Goodarzi M.T., Navidi A.A., Rezaei M., Babahmadi-Rezaei H. Oxidative damage to DNA and lipids: Correlation with protein glycation in patients with type 1 diabetes. J. Clin. Lab. Anal. 2010;24:72–76. doi: 10.1002/jcla.20328.
    1. Tatsch E., Bochi G.V., Piva S.J., De Carvalho J.A., Kober H., Torbitz V.D., Duarte T., Signor C., Coelho A.C., Duarte M.M., et al. Association between DNA strand breakage and oxidative, inflammatory and endothelial biomarkers in type 2 diabetes. Mutat. Res. 2012;732:16–20. doi: 10.1016/j.mrfmmm.2012.01.004.
    1. Umemura T., Sai K., Takagi A., Hasegawa R., Kurokawa Y. Formation of 8-hydroxydeoxyguanosine (8-OH-dG) in rat kidney DNA after intraperitoneal administration of ferric nitrilotriacetate (Fe-NTA) Carcinogenesis. 1990;11:345–347. doi: 10.1093/carcin/11.2.345.
    1. Dandona P., Thusu K., Cook S., Snyder B., Makowski J., Armstrong D., Nicotera T. Oxidative damage to DNA in diabetes mellitus. Lancet. 1996;347:444–445. doi: 10.1016/S0140-6736(96)90013-6.
    1. Hinokio Y., Suzuki S., Hirai M., Chiba M., Hirai A., Toyota T. Oxidative DNA damage in diabetes mellitus: Its association with diabetic complications. Diabetologia. 1999;42:995–998. doi: 10.1007/s001250051258.
    1. Binici D.N., Karaman A., Coşkun M., Oğlu A.U., Uçar F. Genomic damage in patients with type-2 diabetes mellitus. Genet. Couns. 2013;24:149–156.
    1. Boehm B.O., Möller P., Högel J., Winkelmann B.R., Renner W., Rosinger S., Seelhorst U., Wellnitz B., März W., Melzner J., et al. Lymphocytes of type 2 diabetic women carry a high load of stable chromosomal aberrations: A novel risk factor for disease-related early death. Diabetes. 2008;57:2950–2957. doi: 10.2337/db08-0274.
    1. Martínez-Pérez L.M., Cerda-Flores R.M., Gallegos-Cabriales E.C., Dávila-Rodríguez M.I., Ibarra-Costilla E., Cortés-Gutiérrez E.I. Frequency of micronuclei in Mexicans with type 2 diabetes mellitus. Prague Med. Rep. 2007;108:248–255.
    1. Grindel A., Brath H., Nersesyan A., Knasmueller S., Wagner K.H. Association of Genomic Instability with HbA1c levels and Medication in Diabetic Patients. Sci. Rep. 2017;7:41985. doi: 10.1038/srep41985.
    1. Mocellin S., Briarava M., Pilati P. Vitamin B6 and Cancer Risk: A Field Synopsis and Meta-Analysis. J. Natl. Cancer Inst. 2017;109:1–9. doi: 10.1093/jnci/djw230.
    1. Zuo H., Ueland P.M., Midttun Ø., Tell G.S., Fanidi A., Zheng W., Shu X., Xiang Y., Wu J., Prentice R., et al. Vitamin B6 catabolism and lung cancer risk: Results from the Lung Cancer Cohort Consortium (LC3) Ann. Oncol. 2019;30:478–485. doi: 10.1093/annonc/mdz002.
    1. Gylling B., Myte R., Schneede J., Hallmans G., Häggström J., Johansson I., Ulvik A., Ueland P.M., Van Guelpen B., Palmqvist R. Vitamin B-6 and colorectal cancer risk: A prospective population-based study using 3 distinct plasma markers of vitamin B-6 status. Am. J. Clin. Nutr. 2017;105:897–904. doi: 10.3945/ajcn.116.139337.
    1. Vigneri P., Frasca F., Sciacca L., Pandini G., Vigneri R. Diabetes and cancer. Endocr. Relat. Cancer. 2009;16:1103–1123. doi: 10.1677/ERC-09-0087.

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