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Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin

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To investigate the associations of vitamin B12 (cobalamin and holotranscobalamin) status with depression, cognition and neuropathy in patients with type 2 diabetes using metformin.


In an observational study, among 550 type 2 diabetes patients using metformin, cobalamin and holotranscobalamin (holoTCII) levels were measured at the annual diabetes checkup, and deficiencies were defined as <148 and <21 pmol/L, respectively. Depression and cognitive function were assessed with corresponding International Classification of Primary Care codes and questionnaires; neuropathy with medical record data and a questionnaire. Confounding variables were retrieved from medical records. Multivariable logistic and linear regressions were used with cobalamin status as independent variable; depression, cognition and neuropathy as dependent variables.


The mean duration of diabetes was 8.4 years (±5.8); mean duration of metformin use was 64.1 months (±43.2), with a mean metformin dose of 1,306 mg/day. A sufficient cobalamin level was independently associated with a decreased risk of depression (OR 0.42; 95 % CI 0.23–0.78) and better cognitive performance (β = 1.79; 95 % CI 0.07–3.52) adjusted for confounders. This indicates that cobalamin-deficient patients had a 2.4 times higher chance of depression and a 1.79 point lower cognitive performance score. HoloTCII was not associated with any outcome.


Cobalamin deficiency was associated with an increased risk of depression and worse cognitive performance, while holoTCII was not. Screening for cobalamin deficiency may be warranted in diabetes patients using metformin. Physicians should consider a cobalamin deficiency in diabetes patients using metformin with a depression or cognitive decline.

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  1. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR, American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) (2012) Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 35:1364–1379

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V (2000) Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 23:1227–1231

    Article  CAS  PubMed  Google Scholar 

  3. Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM (2006) Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch Intern Med 166:1975–1979

    Article  CAS  PubMed  Google Scholar 

  4. Kibirige D, Mwebaze R (2013) Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? J Diabetes Metab Disord 12(1):17

  5. Oh R, Brown DL (2003) Vitamin B12 deficiency. Am Fam Physician 67:979–986

    PubMed  Google Scholar 

  6. Penninx BWJH, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP (2000) Vitamin B12 deficiency and depression in physically disabled older women: epidemiologic evidence from the women’s health and aging study. Am J Psychiatry 157:715–721

    Article  CAS  PubMed  Google Scholar 

  7. Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM (2002) Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry 159:2099–2101

    Article  PubMed  Google Scholar 

  8. Hin H, Clarke R, Sherliker P, Atoyebi W, Emmens K, Birks J, Schneede J, Ueland PM, Nexo E, Scott J, Molloy A, Donaghy M, Frost C, Evans JG (2006) Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. Age Ageing 35:416–422

    Article  PubMed  Google Scholar 

  9. Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J (1991) Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 70:229–245

    Article  CAS  Google Scholar 

  10. Wile DJ, Toth C (2010) Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care 33:156–161

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Ambrosch A, Dierkes J, Lobmann R, Kuhne W, Konig W, Luley C, Lehnert H (2001) Relation between homocysteinaemia and diabetic neuropathy in patients with type 2 diabetes mellitus. Diabetes Med 18:185–192

    Article  CAS  Google Scholar 

  12. Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H, Woodward M, Boundy K, Ellis KA, Bush AI, Faux NG, Martins R, Szoeke C, Rowe C, Watters DA, AIBL Investigators (2013) Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 36:2981–2987

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Beulens JW, Hart HE, Kuijs R, Kooijman-Buiting AM, Rutten GE (2014) Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetol [Epub ahead of print]

  14. Lamberts H, Wood M (eds) (1987) ICPC. International Classification of Primary Care. Oxford University Press, Oxford

    Google Scholar 

  15. Balen V (2009) Landelijke transmurale afspraak chronische nierschade. Huisarts Wet 52:586–597

    Article  Google Scholar 

  16. WHO (1998) Wellbeing Measures in Health Care: The Depcare Project: Report on a WHO Meeting Stockholm, Sweden 12–13 February 1998. København: World Health Organization Regional Office for Europe

  17. Hermanns N, Kulzer B, Krichbaum M, Kubiak T, Haak T (2006) How to screen for depression and emotional problems in patients with diabetes: comparison of screening characteristics of depression questionnaires, measurement of diabetes-specific emotional problems and standard clinical assessment. Diabetologia 49:469–477

    Article  CAS  PubMed  Google Scholar 

  18. Radloff L (1977) The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1:385–401

    Article  Google Scholar 

  19. Brown J, Pengas G, Dawson K, Brown LA, Clatworthy P (2009) Self administered cognitive screening test (TYM) for detection of Alzheimer’s disease: cross sectional study. BMJ 338:b2030

    Article  PubMed Central  PubMed  Google Scholar 

  20. Koekkoek PS, Rutten GE, van den Berg E, van Sonsbeek S, Gorter KJ, Kappelle LJ, Biessels GJ (2013) The “Test Your Memory” test performs better than the MMSE in a population without known cognitive dysfunction. J Neurol Sci 328:92–97

    Article  PubMed  Google Scholar 

  21. Feng Y, Schlosser FJ, Sumpio BE (2009) The Semmes Weinstein monofilament examination as a screening tool for diabetic peripheral neuropathy. J Vasc Surg 50:675–682

    Article  PubMed  Google Scholar 

  22. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA (1994) A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 17:1281–1289

    Article  CAS  PubMed  Google Scholar 

  23. Yetley EA, Pfeiffer CM, Phinney KW, Bailey RL, Blackmore S, Bock JL, Brody LC, Carmel R, Curtin LR, Durazo-Arvizu RA, Eckfeldt JH, Green R, Gregory JF III, AN Hoofnagle, Jacobsen DW, Jacques PF, Lacher DA, Molloy AM, Massaro J, Mills JL, Nexo E, Rader JI, Selhub J, Sempos C, Shane B, Stabler S, Stover P, Tamura T, Tedstone A, Thorpe SJ, Coates PM, Johnson CL, Picciano MF (2011) Biomarkers of vitamin B-12 status in NHANES: a roundtable summary. Am J Clin Nutr 94:313S–321S

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Stabler SP (2013) Clinical practice. Vitamin B12 deficiency. N Engl J Med 368:149–160

    Article  CAS  PubMed  Google Scholar 

  25. Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP Jr (2012) 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 35:327–333

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Heil SG, de Jonge R, de Rotte MC, van Wijnen M, Heiner-Fokkema RM, Kobold AC, Pekelharing JM, Adriaansen HJ, Sanders E, Trienekens PH, Rammeloo T, Lindemans J (2012) Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: a multicentre study. Ann Clin Biochem 49:184–189

    Article  CAS  PubMed  Google Scholar 

  27. Verweij A. (2008) Scholing en opleiding: Indeling opleidingsniveau. Volksgezondheid Toekomst Verkenning, Nationaal Kompas Volksgezondheid. Bilthoven: RIVM, Nationaal Kompas Volksgezondheid\Bevolking\Scholing en opleiding

  28. McCracken C, Hudson P, Ellis R, McCaddon A (2006) Methylmalonic acid and cognitive function in the medical research council cognitive function and ageing study. Am J Clin Nutr 84:1406–1411

    CAS  PubMed  Google Scholar 

  29. Chen S, Lansdown AJ, Moat SJ, Ellis R, Goringe A, Dunstan FD, Rees JAE (2012) An observational study of the effect of metformin on B12 status and peripheral neuropathy. Br J Diabetes Vasc Dis 12:189–193

    Article  Google Scholar 

  30. Nexo E, Hoffmann-Lucke E (2011) Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr 94:359S–365S

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Hvas AM, Nexo E (2006) Diagnosis and treatment of vitamin B12 deficiency—an update. Haematologica 91:1506–1512

    CAS  PubMed  Google Scholar 

  32. Charles M, Ejskjaer N, Witte DR, Borch-Johnsen K, Lauritzen T, Sandbaek A (2011) Prevalence of neuropathy and peripheral arterial disease and the impact of treatment in people with screen-detected type 2 diabetes: the ADDITION-Denmark study. Diabetes Care 34:2244–2249

    Article  PubMed Central  PubMed  Google Scholar 

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Conflict of interest

Elke Biemans, Huberta E. Hart, Guy E.H.M. Rutten, Viviana G. Cuellar Renteria, Antoinette M.J. Kooijman-Buiting and Joline W. J. Beulens declare that they have no conflict of interest.

Human and animal rights

The Medical Research Ethics Committee at the University Medical Center Utrecht reviewed a brief protocol of the study and decided that the Medical Research Involving Human Subject Act (WMO) did not apply on this study because it was conducted with routine health care data. Therefore, full protocol review was not required since data from this study were routine care data.

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Informed consent from all patients in the study was not necessary.

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Correspondence to Huberta E. Hart.

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Biemans, E., Hart, H.E., Rutten, G.E.H.M. et al. Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin. Acta Diabetol 52, 383–393 (2015).

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