Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes
Abstract
1. Introduction
2. Methods
3. Results
4. Discussion
5. Limitations
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Sicree, R.; Shaw, J.; Zimmet, P. Diabetes and impaired glucose tolerance. International Diabetes Federation, 3rd ed.; International Diabetes Federation: Brussels, Belgium, 2006; pp. 15–103. [Google Scholar]
- International Diabetes Federation. Diabetes Atlas 10th edition. 2022. Available online: https://diabetesatlas.org (accessed on 7 April 2016).
- WHO Country Office for India. Available online: https://www.who.int/india (accessed on 7 April 2016).
- Shimizu, T.; Nathan, D.M.; Buse, J.B.; Davidson, M.B.; Ferrannini, E.; Holman, R.R.; Sherwin, R.; Zinman, B. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009, 32, 193–203. [Google Scholar]
- Andres, E.; Noel, E.; Goichot, B. Metformin-associated vitamin B12 deficiency. Arch. Intern. Med. 2002, 162, 2251–2252. [Google Scholar] [CrossRef] [PubMed]
- Bell, D.S. Metformin-Induced Vitamin B12 Deficiency Presenting as a Peripheral Neuropathy. South Med. J. 2010, 103, 265–267. [Google Scholar] [CrossRef] [PubMed]
- Filioussi, K.; Bonovas, S.; Katsaros, T. Should we screen diabetic patients using biguanides for megaloblastic anaemia? Aust. Fam. Physician 2003, 32, 383–384. [Google Scholar]
- Liu, K.W.; Dai, L.K.; Jean, W. Metformin-related vitamin B12 deficiency. Age Ageing 2006, 35, 200–201. [Google Scholar] [CrossRef][Green Version]
- De Jager, J.; Kooy, A.; Lehert, P.; Wulffele, M.G.; van der Kolk, J.; Bets, D.; Verburg, J.; Donker, A.J.M.; Stehouwer, C.D.A. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: A randomised placebo-controlled trial. BMJ 2010, 340, c2181. [Google Scholar] [CrossRef]
- Wile, D.J.; Toth, C. Association of Metformin, Elevated Homocysteine, and Methylmalonic Acid Levels and Clinically Worsened Diabetic Peripheral Neuropathy. Diabetes Care 2009, 33, 156–161. [Google Scholar] [CrossRef]
- Sahin, M.; Tutuncu, N.B.; Ertugrul, D.; Tanaci, N.; Guvener, N.D. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. J. Diabetes Its Complicat. 2007, 21, 118–123. [Google Scholar] [CrossRef]
- Tomkin, G.H.; Hadden, D.R.; Weaver, J.A.; Montgomery, D.A.D. Vitamin-B12 Status of Patients on Long-term Metformin Therapy. BMJ 1971, 2, 685–687. [Google Scholar] [CrossRef]
- Heyssel, R.M.; Bozian, R.C.; Darby, W.C.; Bell, M.C. Vitamin B12 turnover in man: The assimilation of vitamin B12 from natural foodstuff by man and estimates of minimal daily dietary requirements. Am. J. Clin. Nutr. 1966, 18, 176. [Google Scholar] [CrossRef]
- Laboratory Procedure Manual. Available online: https://wwwn.cdc.gov/nchs/data/nhanes/2011-2012/labmethods/vitb12_g_met.pdf (accessed on 7 April 2016).
- Bril, V.; Tomioka, S.; Buchanan, R.A.; Perkins, B.A.; the mTCNS Study Group. Reliability and validity of the modified Toronto Clinical Neuropathy Score in diabetic sensorimotor polyneuropathy. Diabet. Med. 2009, 26, 240–246. [Google Scholar] [CrossRef] [PubMed]
- Wulffele, M.G.; Kooy, A.; Lehert, P.; Bets, D.; Ogterop, J.C.; Van Der Burg, B.B.; Donker, A.J.M.; Stehouwer, C.D.A. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: A randomized, placebo-controlled trial. J. Intern. Med. 2003, 254, 455–463. [Google Scholar] [CrossRef] [PubMed]
- Lindenbaum, J.; Savage, D.G.; Stabler, S.P.; Allen, R.H. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am. J. Hematol. 1990, 34, 99–107. [Google Scholar] [CrossRef]
- Holleland, G.; Schneede, J.; Ueland, P.M.; Lund, P.K.; Refsum, H.; Sandberg, S. Cobalamin deficiency in general practice. Assessment of the diagnostic utility and cost-benefit analysis of methylmalonic acid determination about current diagnostic strategies. Clin. Chem. 1999, 45, 189–198. [Google Scholar] [CrossRef] [PubMed]
- Snow, C.F. Laboratory diagnosis of vitamin B12 and folate deficiency: A guide for the primary care physician. Arch. Intern. Med. 1999, 159, 1289–1298. [Google Scholar] [CrossRef] [PubMed]
- Klee, G.G. Cobalamin and folate evaluation: Measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate. Clin. Chem. 2000, 46, 1277–1283. [Google Scholar] [CrossRef] [PubMed]
- Yao, Y.; Yao, S.L.; Yao, G.; Lou, W. Prevalence of vitamin B12 deficiency among geriatric outpatients. J. Fam. Pract. 1992, 35, 524–528. [Google Scholar]
- Carmel, R. Pernicious anemia. The expected findings of very low serum cobalamin levels, anaemia, and macrocytosis are often lacking. Arch. Intern. Med. 1988, 148, 1712–1714. [Google Scholar] [CrossRef]
- Kwok, T.; Cheng, G.; Woo, J.; Lai, W.K.; Pang, C.P. Independent effect of vitamin B12 deficiency on haematological status in older Chinese vegetarian women. Am. J. Hematol. 2002, 70, 186–190. [Google Scholar] [CrossRef]
- Singh, A.; Kumar, A.; Karmakar, D.; Jha, R.K. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. J. Postgrad. Med. 2013, 59, 253. [Google Scholar] [CrossRef]
- Gupta, K.; Jain, A.; Rohatgi, A. An observational study of vitamin b12 levels and peripheral neuropathy profile in patients of diabetes mellitus on metformin therapy. Diabetes Metab. Syndr. Clin. Res. Rev. 2018, 12, 51–58. [Google Scholar] [CrossRef] [PubMed]
- Iftikhar, R.; Qadir, A.; Iqbal, Z.; Kamran, S.M.; Usman, H.B. Prevalence of Vitamin B12 deficiency in patients of type 2 diabetes mellitus on metformin: A case-control study from Pakistan. Pan Afr. Med. J. 2013, 16, 67. [Google Scholar] [CrossRef] [PubMed]
- Marar, O.; Sentur, S.; Agha, A.; Thompson, C.; Smith, D. The prevalence of vitamin B12 deficiency in patients with type 2 diabetes mellitus on metformin. R. Coll. Surg. Irel. Stud. Med. J. 2011, 4, 16–20. [Google Scholar]
- Beulens, J.W.J.; Hart, H.E.; Kuijs, R.; Kooijman-Buiting, A.M.J.; Rutten, G.E.H.M. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Geol. Rundsch. 2014, 52, 47–53. [Google Scholar] [CrossRef]
- Chen, S.; Lansdown, A.J.; Moat, S.J.; Ellis, R.; Goringe, A.; Dunstan, F.D.; Rees, J.A.E. An observational study of the effect of metformin on B12 status and peripheral neuropathy. Br. J. Diabetes 2012, 12, 189–193. [Google Scholar] [CrossRef]
- Nisar, M.U.; Asad, A.; Waqas, A.; Ali, N.; Nisar, A.; Qayyum, M.A.; Maryam, H.; Javaid, M.; Jamil, M. Association of Diabetic Neuropathy with Duration of Type 2 Diabetes and Glycemic Control. Cureus 2015, 7, e302. [Google Scholar] [CrossRef]
- Bahou, Y.G. A clinical and electrodiagnostic study of diabetic neuropathy at Jordan University Hospital. Neurosciences 2007, 12, 215–220. [Google Scholar]
- DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 1993, 329, 977–986. [Google Scholar] [CrossRef]
- UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UK PDS 33). Lancet 1998, 352, 854–865. [Google Scholar] [CrossRef]
- Ohkubo, Y.; Kishikawa, H.; Araki, E.; Miyata, T.; Isami, S.; Motoyoshi, S.; Kojima, Y.; Furuyoshi, N.; Shichiri, M. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: A randomized prospective 6-year study. Diabetes Res. Clin. Pract. 1995, 28, 103–117. [Google Scholar] [CrossRef]
- Huang, C.C.; Chen, T.W.; Weng, M.C.; Lee, C.L.; Tseng, H.C.; Huang, M.H. Effect of glycemic control on electrophysiologic changes of diabetic neuropathy in type 2 diabetic patients. Kaohsiung J. Med. Sci. 2005, 21, 15. [Google Scholar] [CrossRef]
Number | Duration of Treatment (Months) | |
---|---|---|
Metformin Group | 451 | 56 ± 5.9 |
Non-metformin group | 249 | 76 ± 6.5 |
B12 Deficiency (pmol/L) | No. of | Mean (g) | SD | Min. (g) | Max. (g) | p Value |
---|---|---|---|---|---|---|
Patients | ||||||
Vitamin BI2 | 205 | 4663 | 1506.8 | 720 | 8640 | |
Deficient (<150) | ||||||
Borderline | 42 | 3637.9 | 776.7 | 720 | 4320 | <0.001 |
Vitamin BI2 | ||||||
Deficient (150–220) | ||||||
Vitamin BI2 | 204 | 2230.3 | 1051.8 | 180 | 5040 | |
Sufficient (>220) | ||||||
Total | 451 | 2999.8 | 1606.3 | 180 | 8640 |
B12 Deficiency | Sig. | |
---|---|---|
Yes | Borderline | 0.002 |
No | 0.000 | |
Borderline | Yes | 0.002 |
No | 0.000 | |
No | Yes | 0.000 |
Borderline | 0.000 |
Group | TCSS Score | p-Value |
---|---|---|
All patients | 5.9 ± 2.9 | |
Metformin-exposed | 6.3 ± 3.4 | <0.001 |
Non-Metformin group | 5.1 ± 3.9 |
Neuropathy | p-Value | ||||
---|---|---|---|---|---|
Yes | No | ||||
Age | 31–40 | No. of Patients | 7 | 46 | |
Percentage | 2.5% | 11% | |||
41–50 | No. of Patients | 36 | 220 | 0.5 (NS) | |
Percentage | 12.7% | 52.9% | |||
51–60 | No. of Patients | 121 | 114 | ||
Percentage | 42.6% | 27.4% | |||
61–70 | No. of Patients | 120 | 36 | ||
Percentage | 42.2% | 8.7% | |||
Total | No. of Patients | 284 | 416 | ||
Percentage | 100.0% | 100.0% |
No. of Patients | Percentage | p-Value | |
---|---|---|---|
Neuropathy in the study population | 283/700 | 40.4 | 0.001 |
Neuropathy in the metformin group | 203/451 | 45.0 | |
(Sig.) | |||
Neuropathy in Non-metformin group | 80/249 | 31.8 |
Coefficients | |||||||
---|---|---|---|---|---|---|---|
Unstandardized | Standardized | 95.0% Confidence | |||||
Coefficients | Coefficients | t | p-Value | Interval for B | |||
B | SE | Beta | Lower | Upper | |||
Bound | Bound | ||||||
(Constant) | 3.7 | 0.2 | 15.0 | <0.001 | 3.2 | 4.2 | |
Metformin | −2.9 | 0.1 | −0.5 | −15.4 | <0.001 | −3.3 | −2.6 |
Use | |||||||
Duration of | 0.09 | 0.003 | 0.9 | 31.1 | <0.001 | 0.091 | 0.1 |
Diabetes | |||||||
(months) | |||||||
Dependent Variable: TCSS Score Using linear regression analysis, it was observed that metformin use worsened the clinical neuropathy score (coeff. = −2.947, p-value < 0.001) |
Neuropathy | No. of Patients | Mean HbA1c | Std. | p-Value |
---|---|---|---|---|
(%) | Deviation | |||
Present | 284 | 8.7 | 1.2 | <0.001 |
Absent | 416 | 7.9 | 0.9 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Farooq, M.D.; Tak, F.A.; Ara, F.; Rashid, S.; Mir, I.A. Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes. J. Xenobiot. 2022, 12, 122-130. https://doi.org/10.3390/jox12020011
Farooq MD, Tak FA, Ara F, Rashid S, Mir IA. Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes. Journal of Xenobiotics. 2022; 12(2):122-130. https://doi.org/10.3390/jox12020011
Chicago/Turabian StyleFarooq, Malik Dilaver, Farooq Ahmad Tak, Fauzia Ara, Samia Rashid, and Irfan Ahmad Mir. 2022. "Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes" Journal of Xenobiotics 12, no. 2: 122-130. https://doi.org/10.3390/jox12020011
APA StyleFarooq, M. D., Tak, F. A., Ara, F., Rashid, S., & Mir, I. A. (2022). Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes. Journal of Xenobiotics, 12(2), 122-130. https://doi.org/10.3390/jox12020011