Subscribe to RSS
DOI: 10.1055/s-0043-120760
Impact of type 2 Diabetes and Metformin use on Vitamin B12 Associated Biomarkers - an Observational Study
Publication History
received 07 August 2017
revised 29 September 2017
accepted 05 October 2017
Publication Date:
02 February 2018 (online)
Abstract
Aims Assessment of the impact of type 2 diabetes (T2DM) and metformin use on vitamin B12 (VB12) associated biomarkers and their suitability to represent VB12 supply.
Methods Differences of VB12, holotranscobalamine (HoloTc), the biologically active fraction (%AB12)=HoloTc/VB12*100 and homocystein (Hcy) were analysed i) among diabetic outpatients with (DMMet+ ) and without metformin use (DMMet-) and ii) in comparison to an external non-diabetic reference group with low VB12 (<200 pmol/L).
Results VB12 associated biomarkers were distributed equally between DMMet+ (n=29, 58%) and DMMet- (n=21, 42%). Significant differences in %AB12 in diabetic patients with low VB12 (n=19) compared to the non-diabetic reference group (n=31) were found. Higher %AB12 was associated with diabetes. Hcy levels were significantly associated with age, folic acid level, renal function and HoloTc but not with VB12.
Conclusions In T2DM patients with low VB12, %AB12 was confirmed as being higher in comparison to nondiabetic patients. The effect was not clearly attributable to metformin use. HoloTc was unaffected by the lowering of VB12 and significantly associated with the functional marker Hcy. Both findings support the use of HoloTc for the assessment of VB12 supply in diabetic patients.
-
References
- 1 Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with diabetes mellitus: Is routine screening and supplementation justified?. Journal of diabetes and metabolic disorders 2013; 12: 17
- 2 Dali-Youcef N, Andres E. An update on cobalamin deficiency in adults. QJM: Monthly Journal of the Association of Physicians 2009; 102: 17-28
- 3 Stabler SP. Clinical practice. Vitamin B12 deficiency. The New England journal of medicine 2013; 368: 149-160
- 4 Bergen C, Compher C. Total homocysteine concentration and associated cardiovascular and renal implications in adults. The Journal of cardiovascular nursing 2006; 21: 40-46
- 5 Pawlak R. Is Vitamin B12 deficiency a risk factor for cardiovascular disease in vegetarians?. American Journal of Preventive Medicine 2015; 48: e11-e26
- 6 Nygard O, Nordrehaug JE, Refsum H. et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. The New England journal of medicine 1997; 337: 230-236
- 7 Seshadri S, Beiser A, Selhub J. et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. The New England journal of medicine 2002; 346: 476-483
- 8 Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes care 2010; 33: 156-161
- 9 Schrier SL. Diagnosis and treatment of vitamin B 12 and folic acid deficiency. uptodate (online, last update 09/2016) 2016;
- 10 Stabler SP. Vitamin B12 deficiency. The New England journal of medicine 2013; 368: 2041-2042
- 11 Hvas AM, Nexo E. Holotranscobalamin–a first choice assay for diagnosing early vitamin B deficiency?. Journal of internal medicine 2005; 257: 289-298
- 12 Nexo E, Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. The American journal of clinical nutrition 2011; 94: 359S-365S
- 13 Yetley EA, Pfeiffer CM, Phinney KW. et al. Biomarkers of vitamin B-12 status in NHANES: A roundtable summary. The American journal of clinical nutrition 2011; 94: 313S-321S
- 14 Aparicio-Ugarriza R, Palacios G, Alder M et al. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population. In, Clinical Chemistry and Laboratory Medicine (CCLM); 2015: 1149
- 15 Solomon LR. Diabetes as a cause of clinically significant functional cobalamin deficiency. Diabetes care 2011; 34: 1077-1080
- 16 Carlsen SM. [Metformin and vitamin B 12 deficiency]. Tidsskrift for den Norske laegeforening: tidsskrift for praktisk medicin, ny raekke 2007; 127: 764 author reply 764
- 17 Sahin M, Tutuncu NB, Ertugrul D. et al. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. Journal of diabetes and its complications 2007; 21: 118-123
- 18 Kilicdag EB, Bagis T, Tarim E. et al. Administration of B-group vitamins reduces circulating homocysteine in polycystic ovarian syndrome patients treated with metformin: A randomized trial. Hum Reprod 2005; 20: 1521-1528
- 19 Kancherla V, Elliott JL Jr., Patel BB et al. Long-term metformin therapy and monitoring for vitamin B12 deficiency among older veterans. Journal of the American Geriatrics Society 2017
- 20 Liu Q, Li S, Quan H. et al. Vitamin B12 status in metformin treated patients: Systematic review. PloS one 2014; 9: e100379
- 21 Bauman WA, Shaw S, Jayatilleke E. et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes care 2000; 23: 1227-1231
- 22 Inzucchi SE, Bergenstal RM, Buse JB. et al. Management of hyperglycaemia in type 2 diabetes, 2015: A patient-centred approach. Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015; 58: 429-442
- 23 Bosi E. Metformin--the gold standard in type 2 diabetes: What does the evidence tell us?. Diabetes, obesity & metabolism 2009; 11 (Suppl. 02) 3-8
- 24 de Jager J, Kooy A, Lehert P. et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 2010; 340: c2181
- 25 Leung S, Mattman A, Snyder F. et al. Metformin induces reductions in plasma cobalamin and haptocorrin bound cobalamin levels in elderly diabetic patients. Clinical biochemistry 2010; 43: 759-760
- 26 Greibe E, Miller JW, Foutouhi SH. et al. Metformin increases liver accumulation of vitamin B12 – an experimental study in rats. Biochimie 2013; 95: 1062-1065
- 27 Greibe E, Trolle B, Bor MV. et al. Metformin lowers serum cobalamin without changing other markers of cobalamin status: A study on women with polycystic ovary syndrome. Nutrients 2013; 5: 2475-2482
- 28 Metaxas C, Mathis D, Jeger C. et al. Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: A randomised parallel-group trial. Swiss medical weekly 2017; 147: w14421
- 29 Young MJ, Boulton AJ, MacLeod AF. et al. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993; 36: 150-154
- 30 Reinstatler L, Qi YP, Williamson RS. et al. Association of biochemical B(1)(2) deficiency with metformin therapy and vitamin B(1)(2) supplements: The National Health and Nutrition Examination Survey, 1999-2006. Diabetes care 2012; 35: 327-333
- 31 Golding PH. Holotranscobalamin (HoloTC, Active-B12) and Herbert's model for the development of vitamin B12 deficiency: A review and alternative hypothesis. SpringerPlus 2016; 5: 668
- 32 Baker H, Leevy CB, DeAngelis B. et al. Cobalamin (vitamin B12) and holotranscobalamin changes in plasma and liver tissue in alcoholics with liver disease. Journal of the American College of Nutrition 1998; 17: 235-238
- 33 Fragasso A, Mannarella C, Ciancio A. et al. Holotranscobalamin Is a Useful Marker of Vitamin B12 Deficiency in Alcoholics. The Scientific World Journal 2012; 2012: 128182
- 34 Nexo E, Hvas AM, Bleie O. et al. Holo-transcobalamin is an early marker of changes in cobalamin homeostasis. A randomized placebo-controlled study. Clinical chemistry 2002; 48: 1768-1771
- 35 Obeid R, Herrmann W. Holotranscobalamin in laboratory diagnosis of cobalamin deficiency compared to total cobalamin and methylmalonic acid. Clinical chemistry and laboratory medicine: CCLM/FESCC 2007; 45: 1746-1750
- 36 Valente E, Scott JM, Ueland PM. et al. Diagnostic accuracy of holotranscobalamin, methylmalonic acid, serum cobalamin, and other indicators of tissue vitamin B(1)(2) status in the elderly. Clinical chemistry 2011; 57: 856-863
- 37 Sato Y, Ouchi K, Funase Y. et al. Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Endocrine journal 2013; 60: 1275-1280
- 38 Wollesen F, Brattstrom L, Refsum H. et al. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney international 1999; 55: 1028-1035
- 39 Hannibal L, Lysne V, Bjorke-Monsen AL. et al. Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency. Frontiers in molecular biosciences 2016; 3: 27
- 40 Ting R, Szeto C, Chan M. et al. Risk factors of vitamin b12 deficiency in patients receiving metformin. Archives of internal medicine 2006; 166: 1975-1979
- 41 Kancherla V, Elliott Jr. JL, Patel BB. et al. Long-term metformin therapy and monitoring for vitamin B12 deficiency among older veterans. Journal of the American Geriatrics Society 2017; 65: 1061-1066
- 42 Roy RP, Ghosh K, Ghosh M. et al. Study of Vitamin B(12) deficiency and peripheral neuropathy in metformin-treated early Type 2 diabetes mellitus. Indian Journal of Endocrinology and Metabolism 2016; 20: 631-637
- 43 Ahmed MA, Muntingh G, Rheeder P. Vitamin B12 deficiency in metformin-treated type-2 diabetes patients, prevalence and association with peripheral neuropathy. BMC Pharmacology & Toxicology 2016; 17: 44
- 44 Chen S, Lansdown AJ, Moat SJ. et al. An observational study of the effect of metformin on B12 status and peripheral neuropathy. The British Journal of Diabetes & Vascular Disease 2012; 12: 189-193
- 45 Russo GT, Giandalia A, Romeo EL. et al. 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 2016; 39: 305-314
- 46 Wong CW. Vitamin B12 deficiency in the elderly: is it worth screening?. Hong Kong medical journal=Xianggang yi xue za zhi/Hong Kong Academy of Medicine 2015; 21: 155-164
- 47 Pflipsen MC, Oh RC, Saguil A. et al. The prevalence of vitamin b12 deficiency in patients with type 2 diabetes: A cross-sectional study. The Journal of the American Board of Family Medicine 2009; 22: 528-534