The Influence of MTHFR C677T Variants on Neuropathy Risk Among T2dm Patients Receiving Monotherapy Metformin
Keywords:
MTHFR, neuropathy, metformin, and T2DM
Abstract
Neuropathy is the most common microvascular complication among type 2 diabetes mellitus (T2DM). Metformin consumption increases neuropathy risk. The Methylenetetrahydrofolate reductase (MTHFR) enzyme has confirmed its role in neuropathy. Metformin and MTHFR could decrease folate and induce hyperhomoscysteine. One of the common variants of the MTHFR gene is C677T and its located in the exon area. This study aimed to observe the association between variant C677T in the MTHFR gene and the risk of neuropathy among newly diagnosed T2DM patients with naive metformin. This cross-sectional study recruited 103 patients. The neuropathy risk was examined according to medical judgment through Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS) criteria. Genotyping C677T was performed using PCR-RFLP. This study found only one patient has a homozygote mutant, but more than 50% of patients were detected with allele mutants. There were no statistical differences in patient characteristics between CC and CT genotypes (p>0.05). Association between C677T and neuropathy risk was not significant statistically, either in the genotype model (p=0.97), allele model (p=0.82), and dominant model (p=0.91). There was still no significant association after adjusting for several confounding factors. We conclude that C677T in our population did not influence neuropathy risk. More specific criteria and laboratory parameters indicated neuropathy should be examined in the future study.
Keywords: MTHFR, neuropathy, metformin, and T2DM
References
Amelia, R., Wahyuni, A. S., & Yunanda, Y. (2019). Diabetic Neuropathy among Type 2 Diabetes Mellitus Patients at Amplas Primary Health Care in Medan City. Open Access Macedonian Journal of Medical Sciences, 7(20), 3400. https://doi.org/10.3889/OAMJMS.2019.433
American Diabetes Association. (2020). Standards of Medical Care in Diabetes. The Journal of Clinical and Applied Research and Education, 43(1), 1–212.
Cosentino, F., Grant, P. J., Aboyans, V., Bailey, C. J., Ceriello, A., Delgado, V., Federici, M., Filippatos, G., Grobbee, D. E., Hansen, T. B., Huikuri, H. V., Johansson, I., Juni, P., Lettino, M., Marx, N., Mellbin, L. G., Ostgren, C. J., Rocca, B., Roffi, M., … Chowdhury, T. A. (2020). 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. European Heart Journal, 41(2), 255–323. https://doi.org/10.1093/eurheartj/ehz486
da Silva, W. H., Dantas, D. S., da Nóbrega, B. S., de Queiroz, M. D. S. R., & Alves, H. da S. (2019). Evaluation of adherence to pharmacological treatment. Brazilian Journal of Pharmaceutical Sciences, 55, 18341. https://doi.org/10.1590/S2175-97902019000218341
Dell’Edera, D., L’Episcopia, A., Simone, F., Lupo, M. G., Epifania, A. A., & Allegretti, A. (2018). Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms and susceptibility to recurrent pregnancy loss. Biomedical Reports, 8(2), 172–175. https://doi.org/10.3892/BR.2018.1039/HTML
Dornas, R. M., Castelo, C., Pupe, B., José, O., & Nascimento, M. (2021). Evaluation of quality of life in patients with type 2 diabetes Mellitus with symptomatic distal symmetric polyneuropathy / Avaliação da qualidade de vida em doentes com diabetes Mellitus tipo 2 com polineuropatia simétrica distal sintomática. Brazilian Journal of Health Review, 4(3), 9936–9951. https://doi.org/10.34119/BJHRV4N3-030
Elhadd, T., Ponirakis, G., Dabbous, Z., Siddique, M., Chinnaiyan, S., & Malik, R. A. (2018). Metformin use is not associated with B12 deficiency or neuropathy in patients with type 2 diabetes Mellitus in Qatar. Frontiers in Endocrinology, 9(MAY), 248. https://doi.org/10.3389/FENDO.2018.00248/BIBTEX
Hashem, M. M., Esmael, A., Nassar, A. K., & El-Sherif, M. (2021). The relationship between exacerbated diabetic peripheral neuropathy and metformin treatment in type 2 diabetes mellitus. Scientific Reports 2021 11:1, 11(1), 1–9. https://doi.org/10.1038/s41598-021-81631-8
Hicks, C. W., Wang, D., Matsushita, K., Gwen Windham, B., & Selvin, E. (2021). Peripheral Neuropathy and All-Cause and Cardiovascular Mortality in US Adults. Annals of Internal Medicine, 174(2), 167. https://doi.org/10.7326/M20-1340
International Diabetes Foundation. (2019). International Diabetes Federation - Facts & figures.
Jiménez-Ramírez, F. J., Castro, L. M., Ortiz, C., Concepción, J., Renta, J. Y., Morales-Borges, R. H., Miranda-Massari, J. R., & Duconge, J. (2017). Role of treatment-modifying MTHFR677C>T and 1298A>C polymorphisms in metformin-treated Puerto Rican patients with type-2 diabetes mellitus and peripheral neuropathy. Drug Metabolism and Personalized Therapy, 32(1), 23–32. https://doi.org/10.1515/dmpt-2016-0039
Kakavand Hamidi, A., Radfar, M., & Amoli, M. M. (2017). Association between MTHFR variant and diabetic neuropathy. Pharmacological Reports 2017 70:1, 70(1), 1–5. https://doi.org/10.1016/J.PHAREP.2017.04.017
Kementerian Kesehatan Republik Indonesia. (2018). Laporan Nasional Riset Kesehatan Dasar. In Kementrian kesehatan RI.
Kim, J., Ahn, C. W., Fang, S., Lee, H. S., & Park, J. S. (2019). Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine, 98(46), e17918. https://doi.org/10.1097/MD.0000000000017918
Liew, S. C., & Gupta, E. Das. (2015). Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. European Journal of Medical Genetics, 58(1), 1–10. https://doi.org/10.1016/J.EJMG.2014.10.004
Miyan, Z., & Waris, N. (2020). Association of vitamin B12 deficiency in people with type 2 diabetes on metformin and without metformin: a multicenter study, Karachi, Pakistan. BMJ Open Diabetes Research and Care, 8(1), e001151. https://doi.org/10.1136/BMJDRC-2019-001151
Mottaghi, T., Khorvash, F., Kheirollahi, M., Maracy, M., & Askari, G. (2019). The MTHFR C677T polymorphism influences the efficacy of folic acid supplementation on the nerve conduction studies in patients with diabetic polyneuropathy; A randomized, double blind, placebo-controlled study. Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences, 24(1). https://doi.org/10.4103/JRMS.JRMS_774_18
Nguyen, K. T., Diep, B. T. T., Nguyen, V. D. K., Van Lam, H., Tran, K. Q., & Tran, N. Q. (2019). A cross-sectional study to evaluate diabetes management, control and complications in 1631 patients with type 2 diabetes mellitus in Vietnam (DiabCare Asia). International Journal of Diabetes in Developing Countries, 1–10. https://doi.org/10.1007/s13410-019-00755-w
Ni, J., Zhang, L., Zhou, T., Xu, W. J., Xue, J. L., Cao, N., & Wang, X. (2017). Association between the MTHFR C677T polymorphism, blood folate and vitamin B12 deficiency, and elevated serum total homocysteine in healthy individuals in Yunnan Province, China. Journal of the Chinese Medical Association, 80(3), 147–153. https://doi.org/10.1016/J.JCMA.2016.07.005
Owen, M. D., Baker, B. C., Scott, E. M., & Forbes, K. (2021). Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies. International Journal of Molecular Sciences 2021, Vol. 22, Page 5759, 22(11), 5759. https://doi.org/10.3390/IJMS22115759
Russo, G. T., Giandalia, A., Romeo, E. L., Scarcella, C., Gambadoro, N., Zingale, R., Forte, F., Perdichizzi, G., Alibrandi, A., & Cucinotta, D. (2016). Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR C677T mutation in type 2 diabetic outpatients taking metformin. Journal of Endocrinological Investigation, 39(3), 305–314. https://doi.org/10.1007/s40618-015-0365-9
Sadewa, A. H., Sunarti, Sutomo, R., Hayashi, C., Lee, M. J., Ayaki, H., Sofro, A. S. M., Matsuo, M., & Nishio, H. (2002). The C677T mutation in the methylenetetrahydrofolate reductase gene among the Indonesian Javanese population. Kobe Journal of Medical Sciences, 48(5–6), 137–144.
Schwartz, S. S., Epstein, S., Corkey, B. E., Grant, S. F. A., Gavin, J. R., & Aguilar, R. B. (2016). The time is right for a new classification system for diabetes: Rationale and implications of the β-cell-centric classification schema. In Diabetes Care (Vol. 39, Issue 2, pp. 179–186). American Diabetes Association Inc. https://doi.org/10.2337/dc15-1585
Suryandari, D. A., Yurnadi, Wiweko, B., & Yunaini, L. (2012). Genotype distribution of methylenetetrahydrofolate reductase A1298C and C677T gene in Indonesian infertile men. Medical Journal of Indonesia, 21(1), 23–27. https://doi.org/10.13181/mji.v21i1.470
T. Hsu, R., Bumanlag, F., K. Mehta, A., Si, X., Yuan, Y., J. Dun, N., & Jun Luo, J. (2020). Homocysteine and Peripheral Neuropathy. Journal of Neurology and Experimental Neuroscience, 6(2), 58–61. https://doi.org/10.17756/JNEN.2020-076
Wu, S., Han, Y., Hu, Q., Zhang, X., Cui, G., Li, Z., & Guan, Y. (2017). Effects of Common Polymorphisms in the MTHFR and ACE Genes on Diabetic Peripheral Neuropathy Progression: a Meta-Analysis. Molecular Neurobiology, 54(4), 2435–2444. https://doi.org/10.1007/s12035-016-9823-4
Yigit, S., Karakus, N., & Inanir, A. (2013). Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy. Molecular Vision, 19(July), 1626–1630.
Zilliox, L. A., & Russell, J. W. (2019). Physical Activity and Dietary Interventions in Diabetic Neuropathy: A Systemic Review. Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society, 29(4), 443. https://doi.org/10.1007/S10286-019-00607-X
American Diabetes Association. (2020). Standards of Medical Care in Diabetes. The Journal of Clinical and Applied Research and Education, 43(1), 1–212.
Cosentino, F., Grant, P. J., Aboyans, V., Bailey, C. J., Ceriello, A., Delgado, V., Federici, M., Filippatos, G., Grobbee, D. E., Hansen, T. B., Huikuri, H. V., Johansson, I., Juni, P., Lettino, M., Marx, N., Mellbin, L. G., Ostgren, C. J., Rocca, B., Roffi, M., … Chowdhury, T. A. (2020). 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. European Heart Journal, 41(2), 255–323. https://doi.org/10.1093/eurheartj/ehz486
da Silva, W. H., Dantas, D. S., da Nóbrega, B. S., de Queiroz, M. D. S. R., & Alves, H. da S. (2019). Evaluation of adherence to pharmacological treatment. Brazilian Journal of Pharmaceutical Sciences, 55, 18341. https://doi.org/10.1590/S2175-97902019000218341
Dell’Edera, D., L’Episcopia, A., Simone, F., Lupo, M. G., Epifania, A. A., & Allegretti, A. (2018). Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms and susceptibility to recurrent pregnancy loss. Biomedical Reports, 8(2), 172–175. https://doi.org/10.3892/BR.2018.1039/HTML
Dornas, R. M., Castelo, C., Pupe, B., José, O., & Nascimento, M. (2021). Evaluation of quality of life in patients with type 2 diabetes Mellitus with symptomatic distal symmetric polyneuropathy / Avaliação da qualidade de vida em doentes com diabetes Mellitus tipo 2 com polineuropatia simétrica distal sintomática. Brazilian Journal of Health Review, 4(3), 9936–9951. https://doi.org/10.34119/BJHRV4N3-030
Elhadd, T., Ponirakis, G., Dabbous, Z., Siddique, M., Chinnaiyan, S., & Malik, R. A. (2018). Metformin use is not associated with B12 deficiency or neuropathy in patients with type 2 diabetes Mellitus in Qatar. Frontiers in Endocrinology, 9(MAY), 248. https://doi.org/10.3389/FENDO.2018.00248/BIBTEX
Hashem, M. M., Esmael, A., Nassar, A. K., & El-Sherif, M. (2021). The relationship between exacerbated diabetic peripheral neuropathy and metformin treatment in type 2 diabetes mellitus. Scientific Reports 2021 11:1, 11(1), 1–9. https://doi.org/10.1038/s41598-021-81631-8
Hicks, C. W., Wang, D., Matsushita, K., Gwen Windham, B., & Selvin, E. (2021). Peripheral Neuropathy and All-Cause and Cardiovascular Mortality in US Adults. Annals of Internal Medicine, 174(2), 167. https://doi.org/10.7326/M20-1340
International Diabetes Foundation. (2019). International Diabetes Federation - Facts & figures.
Jiménez-Ramírez, F. J., Castro, L. M., Ortiz, C., Concepción, J., Renta, J. Y., Morales-Borges, R. H., Miranda-Massari, J. R., & Duconge, J. (2017). Role of treatment-modifying MTHFR677C>T and 1298A>C polymorphisms in metformin-treated Puerto Rican patients with type-2 diabetes mellitus and peripheral neuropathy. Drug Metabolism and Personalized Therapy, 32(1), 23–32. https://doi.org/10.1515/dmpt-2016-0039
Kakavand Hamidi, A., Radfar, M., & Amoli, M. M. (2017). Association between MTHFR variant and diabetic neuropathy. Pharmacological Reports 2017 70:1, 70(1), 1–5. https://doi.org/10.1016/J.PHAREP.2017.04.017
Kementerian Kesehatan Republik Indonesia. (2018). Laporan Nasional Riset Kesehatan Dasar. In Kementrian kesehatan RI.
Kim, J., Ahn, C. W., Fang, S., Lee, H. S., & Park, J. S. (2019). Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine, 98(46), e17918. https://doi.org/10.1097/MD.0000000000017918
Liew, S. C., & Gupta, E. Das. (2015). Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. European Journal of Medical Genetics, 58(1), 1–10. https://doi.org/10.1016/J.EJMG.2014.10.004
Miyan, Z., & Waris, N. (2020). Association of vitamin B12 deficiency in people with type 2 diabetes on metformin and without metformin: a multicenter study, Karachi, Pakistan. BMJ Open Diabetes Research and Care, 8(1), e001151. https://doi.org/10.1136/BMJDRC-2019-001151
Mottaghi, T., Khorvash, F., Kheirollahi, M., Maracy, M., & Askari, G. (2019). The MTHFR C677T polymorphism influences the efficacy of folic acid supplementation on the nerve conduction studies in patients with diabetic polyneuropathy; A randomized, double blind, placebo-controlled study. Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences, 24(1). https://doi.org/10.4103/JRMS.JRMS_774_18
Nguyen, K. T., Diep, B. T. T., Nguyen, V. D. K., Van Lam, H., Tran, K. Q., & Tran, N. Q. (2019). A cross-sectional study to evaluate diabetes management, control and complications in 1631 patients with type 2 diabetes mellitus in Vietnam (DiabCare Asia). International Journal of Diabetes in Developing Countries, 1–10. https://doi.org/10.1007/s13410-019-00755-w
Ni, J., Zhang, L., Zhou, T., Xu, W. J., Xue, J. L., Cao, N., & Wang, X. (2017). Association between the MTHFR C677T polymorphism, blood folate and vitamin B12 deficiency, and elevated serum total homocysteine in healthy individuals in Yunnan Province, China. Journal of the Chinese Medical Association, 80(3), 147–153. https://doi.org/10.1016/J.JCMA.2016.07.005
Owen, M. D., Baker, B. C., Scott, E. M., & Forbes, K. (2021). Interaction between Metformin, Folate and Vitamin B12 and the Potential Impact on Fetal Growth and Long-Term Metabolic Health in Diabetic Pregnancies. International Journal of Molecular Sciences 2021, Vol. 22, Page 5759, 22(11), 5759. https://doi.org/10.3390/IJMS22115759
Russo, G. T., Giandalia, A., Romeo, E. L., Scarcella, C., Gambadoro, N., Zingale, R., Forte, F., Perdichizzi, G., Alibrandi, A., & Cucinotta, D. (2016). Diabetic neuropathy is not associated with homocysteine, folate, vitamin B12 levels, and MTHFR C677T mutation in type 2 diabetic outpatients taking metformin. Journal of Endocrinological Investigation, 39(3), 305–314. https://doi.org/10.1007/s40618-015-0365-9
Sadewa, A. H., Sunarti, Sutomo, R., Hayashi, C., Lee, M. J., Ayaki, H., Sofro, A. S. M., Matsuo, M., & Nishio, H. (2002). The C677T mutation in the methylenetetrahydrofolate reductase gene among the Indonesian Javanese population. Kobe Journal of Medical Sciences, 48(5–6), 137–144.
Schwartz, S. S., Epstein, S., Corkey, B. E., Grant, S. F. A., Gavin, J. R., & Aguilar, R. B. (2016). The time is right for a new classification system for diabetes: Rationale and implications of the β-cell-centric classification schema. In Diabetes Care (Vol. 39, Issue 2, pp. 179–186). American Diabetes Association Inc. https://doi.org/10.2337/dc15-1585
Suryandari, D. A., Yurnadi, Wiweko, B., & Yunaini, L. (2012). Genotype distribution of methylenetetrahydrofolate reductase A1298C and C677T gene in Indonesian infertile men. Medical Journal of Indonesia, 21(1), 23–27. https://doi.org/10.13181/mji.v21i1.470
T. Hsu, R., Bumanlag, F., K. Mehta, A., Si, X., Yuan, Y., J. Dun, N., & Jun Luo, J. (2020). Homocysteine and Peripheral Neuropathy. Journal of Neurology and Experimental Neuroscience, 6(2), 58–61. https://doi.org/10.17756/JNEN.2020-076
Wu, S., Han, Y., Hu, Q., Zhang, X., Cui, G., Li, Z., & Guan, Y. (2017). Effects of Common Polymorphisms in the MTHFR and ACE Genes on Diabetic Peripheral Neuropathy Progression: a Meta-Analysis. Molecular Neurobiology, 54(4), 2435–2444. https://doi.org/10.1007/s12035-016-9823-4
Yigit, S., Karakus, N., & Inanir, A. (2013). Association of MTHFR gene C677T mutation with diabetic peripheral neuropathy and diabetic retinopathy. Molecular Vision, 19(July), 1626–1630.
Zilliox, L. A., & Russell, J. W. (2019). Physical Activity and Dietary Interventions in Diabetic Neuropathy: A Systemic Review. Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society, 29(4), 443. https://doi.org/10.1007/S10286-019-00607-X
Published
2024-03-25
How to Cite
Yanuar, M. R. S., Istyastono, E. P., & Virginia, D. M. (2024). The Influence of MTHFR C677T Variants on Neuropathy Risk Among T2dm Patients Receiving Monotherapy Metformin . Indonesian Journal of Pharmacy, 35(1), 147-153. https://doi.org/10.22146/ijp.5328
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Research Article
