Cognitive impairment among patients with diabetes. Role of cobalamin
AbstractDiabetes mellitus is associated with an increased risk of cerebrovascular pathology and cognitive impairments. Genesis of cognitive impairments in patients with diabetes mellitus is complex. The leading role is given to cerebrovascular diseases. In addition, great importance is given to metabolic alterations, which are not limited to changes in glucose concentrations. Maintaining glycemic control does not allow for a statistically significant positive effect on cognitive functions. Vitamin B12 deficiency, which is often detected in patients with diabetes mellitus, plays an important role in pathogenesis of cognitive impairments. This review presents a modern view on mechanisms of neurocognitive dysfunction development in diabetes mellitus, including description of effects of cobalamin deficiency. Ways of its correction are discussed.
Keywords:diabetes mellitus; cognitive impairments; cerebrovascular pathology; vitamin B12; homocysteine
Funding. The study had no sponsor support.
Conflict of interest. The authors declare no conflict of interest.
For citation: Antonova K.V., Tanashyan M.M. Cognitive impairment among patients with diabetes. Role of cobalamin. Endokrinologiya: novosti, mneniya, obuchenie [Endocrinology: News, Opinions, Training]. 2022; 11 (4): 60–9. DOI: https://doi.org/10.33029/2304-9529-2022-11-4-60-69 (in Russian)
References
1. IDF Diabetes Atlas 2021. 10th ed. URL: www.diabetesatlas.org
2. Wen X., Zhang B., Wu B., et al. Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022; 7 (1): 298. DOI: https://doi.org/10.1038/s41392-022-01149-x
3. GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022; 7 (2): e105–25. DOI: https://doi.org/10.1016/S2468-2667(21)00249-8
4. Bai W., Chen P., Cai H., et al. Worldwide prevalence of mild cognitive impairment among community dwellers aged 50 years and older: a meta-analysis and systematic review of epidemiology studies. Age Ageing. 2022; 51 (8): afac173. DOI: https://doi.org/10.1093/ageing/afac173
5. Gudala K., Bansal D., Schifano F., Bhansali A. Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig. 2013; 4: 640–50. DOI: https://doi.org/10.1111/jdi.12087
6. Biessels G.J., Staekenborg S., Brunner E., et al. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006; 5: 64–74. DOI: https://doi.org/10.1016/S1474-4422(05)70284-2
7. Dedov I.I., Shestakova M.V., Vikulova O.K., et al. Epidemiological characteristics of diabetes mellitus in the Russian Federation: clinical and statistical analysis according to the Federal diabetes register data of 01.01.2021. Sakharniy diabet [Diabetes Mellitus]. 2021; 24 (3): 204–21. DOI: https://doi.org/10.14341/DM12759 (in Russian)
8. Mijnhout G.S., Scheltens P., Diamant M., et al. Diabetic encephalopathy: a concept in need of a definition. Diabetologia. 2006; 49 (6): 1447–8. DOI: https://doi.org/10.1007/s00125-006-0221-8
9. Koekkoek P.S., Kappelle L.J., van den Berg E., et al. Cognitive function in patients with diabetes mellitus: guidance for daily care. Lancet Neurol. 2015; 14 (3): 329–40. DOI: https://doi.org/10.1016/S1474-4422(14)70249-2
10. Biessels G.J., Strachan M.W., Visseren F.L., et al. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol. 2014; 2: 246–55. DOI: https://doi.org/10.1016/S2213-8587(13)70088-3
11. Biessels G.J., Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol. 2018; 14 (10): 591–604. DOI: https://doi.org/10.1038/s41574-018-0048-7
12. Tanashyan M.M., Surkova E.V., Antonova K.V., et al. Type 2 diabetes and cognitive functions in patients with chronic cerebrovascular diseases. Terapevticheskiy arkhiv [Therapeutic Archive]. 2021; 93 (10): 1179–85. DOI: https://doi.org/10.26442/00403660.2021.10.201108 (in Russian)
13. Zhang J., Chen C., Hua S., Liao H., et al. An updated meta-analysis of cohort studies: diabetes and risk of Alzheimer’s disease. Diabetes Res Clin Pract. 2017; 124: 41–7. DOI: https://doi.org/10.1016/j.diabres.2016.10.024
14. Abner E.L., Nelson P.T., Kryscio R.J., et al. Diabetes is associated with cerebrovascular but not Alzheimer’s disease neuropathology. Alzheimers Dement. 2016; 12 (8): 882–9. DOI: https://doi.org/10.1016/j.jalz.2015.12.006
15. Arvanitakis Z., Schneider J.A., Wilson R.S., et al. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology. 2006; 67 (11): 1960–5. DOI: https://doi.org/10.1212/01.wnl.0000247053.45483.4e PMID: 17159101.
16. Petersen R.C., Lopez O., Armstrong M.J., et al. Practice guideline update summary: Mild cognitive impairment: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018; 90: 126–35.
17. Zilliox L.A., Chadrasekaran K., Kwan J.Y., et al. Diabetes and cognitive impairment. Curr Diabetes Rep. 2016; 16 (9): 87. DOI: https://doi.org/10.1007/s11892-016-0775-x
18. Cukierman-Yaffe T., Gerstein H.C., et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol. 2020; 19 (7): 582–90. DOI: https://doi.org/10.1016/S1474-4422(20)30173-3
19. Orkaby A.R., Cho K., Cormack J., et al. Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes. Neurology. 2017; 89 (18): 1877–85. DOI: https://doi.org/10.1212/WNL.0000000000004586
20. Luo A., Ning P., Lu H., et al. Association between metformin and Alzheimer’s disease: a systematic review and meta-analysis of clinical observational studies. J Alzheimers Dis. 2022; 88 (4): 1311–23. DOI: https://doi.org/10.3233/JAD-220180 PMID: 35786654.
21. Antal B., McMahon L.P., Sultan S.F., et al. Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK Biobank and meta-analyses. Elife. 2022; 11: e73138. DOI: https://doi.org/10.7554/eLife.73138
22. Areosa Sastre A., Vernooij R.W., González-Colaço Harmand M., et al. Effect of the treatment of type 2 diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst Rev. 2017; 6 (6): CD 003804. DOI: https://doi.org/10.1002/14651858.CD 003804.pub2
23. Kamchatnov P.R., Damulin I.V. Сognitive impairments in vitamin B12 and folic acid deficiencies and hyperhomocysteinemia. Klinitsist [Clinician]. 2015; 9 (1): 18–23. DOI: https://doi.org/10.17650/1818-8338-2015-1-18-23 (in Russian)
24. Hagopian W., Lee H.S., Liu E., et al.; TEDDY Study Group. Cooccurrence of type 1 diabetes and celiac disease autoimmunity. Pediatrics. 2017; 140 (5). DOI: https://doi.org/10.1542/peds.2017-1305
25. Mrozikiewicz-Rakowska B., Chylinska A., Sienko D. Vitamin B12 in diabetes – a new treatment paradigm? Clin Diabetol. 2020; 9 (6): 489–96. DOI: https://doi.org/10.5603/DK.2020.0060
26. Alharbi T.J., Tourkmani A.M., Abdelhay O., et al. The association of metformin use with vitamin B12 deficiency and peripheral neuropathy in Saudi individuals with type 2 diabetes mellitus. PLoS One. 2018; 13: e0204420.
27. Tomkin G.H., Hadden D.R., Weaver J.A., Montgomery D.A. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J. 1971; 2: 685–7.
28. Ahmed M.A. Metformin and vitamin B12 deficiency: where do we stand? J Pharm Pharm Sci. 2016; 19: 382–98.
29. Aroda V.R., Edelstein S.L., Goldberg R.B., et al. Long-term metformin use and vitamin b12 deficiency in the diabetes prevention program outcomes study. J Clin Endocrinol Metab. 2016; 101: 1754–61.
30. Yang W., Cai X., Wu H., Ji L. Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. J Diabetes. 2019; 11 (9): 729–43. DOI: https://doi.org/10.1111/1753-0407.12900
31. Niafar M., Hai F., Porhomayon J., Nader N.D. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med. 2015; 10 (1): 93–102. DOI: https://doi.org/10.1007/s11739-014-1157-5
32. 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.
33. Hansen C.S., Jensen J.S., Ridderstrale M., et al. Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes. J Diabetes Complications. 2017; 31: 202–8.
34. Khattab R., Albannawi M., Alhajjmohammed D., et al. Metformin-induced vitamin B12 deficiency among type 2 diabetes mellitus’ patients: a systematic review. Curr Diabetes Rev. 2022; Apr 18. DOI: https://doi.org/10.2174/1573399818666220418080959
35. Mietlicki-Baase E.G., Liberini C.G., Workinger J.L., et al. A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents. Diabetes Obes Metab. 2018; 20 (5): 1223–34. DOI: https://doi.org/10.1111/dom.13222
36. Praticò D., Clark C.M., Liun F., et al. Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch Neurol. 2002; 59: 972–6.
37. Krinsky N.I. Mechanism of action of biological antioxidants. Proc Soc Exp Biol Med. 1992; 200: 248–54.
38. Miller J.W. Homocysteine. In: B. Caballero ed. Encyclopedia of Human Nutrition. 3rd ed. Waltham, MA: Academic Press, 2013: 424–30.
39. Olaso-Gonzalez G., Inzitari M., Bellelli G., et al. Impact of supplementation with vitamins B 6, B12 , and/or folic acid on the reduction of homocysteine levels in patients with mild cognitive impairment: a systematic review. IUBMB Life. 2022; 74 (1): 74–84. DOI: https://doi.org/10.1002/iub.2507
40. Poddar R., Chen A., Winter L., Rajagopal S., Paul S. Role of AMPA receptors in homocysteine-NMDA receptor-induced crosstalk between ERK and p38 MAPK. J Neurochem. 2017; 142 (4): 560–73. DOI: https://doi.org/10.1111/jnc.14078
41. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006; 5 (11): 949–60. DOI: https://doi.org/10.1016/S1474-4422(06)70598-1
42. Gröber U., Kisters K., Schmidt J. Neuroenhancement with vitamin B12-underestimated neurological significance. Nutrients. 2013; 5 (12): 5031–45. DOI: https://doi.org/10.3390/nu5125031 PMID: 24352086; PMCID: PMC 3875920.
43. Green R., Allen L.H., Bjorke-Monsen A.-L., et al. Vitamin B12 deficiency. Nat Rev Dis Primers. 2017; 3 (1): 1–20.
44. Herrmann W., Herrmann M. The controversial role of HCY and vitamin B deficiency in cardiovascular diseases. Nutrients. 2022; 14 (7): 1412. DOI: https://doi.org/10.3390/nu14071412
45. Hannibal L., Lysne V., Bjorke-Monsen A.L., et al. Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency. Front Mol Biosci. 2016; 3: 27. DOI: https://doi.org/10.3389/fmolb.2016.00027
46. Gillette-Guyonnet S., Secher M., Vellas B. Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. Br J Clin Pharmacol. 2013; 75: 738–55.
47. Hughes C., Ward M., Hoey L., McNulty H. Vitamin B12 and ageing: Current issues and interaction with folate. Ann Clin Biochem. 2013; 50 (pt 4): 315–29. DOI: https://doi.org/10.1177/0004563212473279
48. Sreckovic B., Sreckovic V.D., Soldatovic I., et al. Homocysteine is a marker for metabolic syndrome and atherosclerosis. Diabetes Metab Syndr. 2017; 11 (3): 179–82. DOI: https://doi.org/10.1016/j.dsx.2016.08.026
49. Tanashyan М.М., Antonova K.V., Lagoda О.V., Shabalina А.А. Resolved and unresolved issues of cerebrovascular disease in diabetes mellitus. Annaly klinicheskoy i eksperimental’noynevrologii [Annals of Clinical and Experimental Neurology]. 2021; 15 (3): 5–14. DOI: https://doi.org/10.54101/ACEN.2021.3.1 (in Russian)
50. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002; 288: 2015–22. DOI: https://doi.org/10.1001/jama.288.16.2015
51. Lindenbaum J., Healton E.B., Savage D.G., et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988; 318 (26): 1720–8. DOI: https://doi.org/10.1056/NEJM198806303182604
52. Greenberg D.A., Aminoff M.J., Simon R.P. Clinical Neurology. 5th ed. New York: McGraw-Hill Professional, 2012.
53. Khalaf K.M., Khudhair M.S., Ashor A.W. Vitamin B12 status and peripheral neuropathy in patients with type 2 diabetes mellitus. J Pak Med Assoc. 2019; 69: S 40–4.
54. Alvarez M., Rincon O., et al. Vitamin B12 deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional study. Endocr Connect. 2019; 8: 1324–9.
55. Stabler S.P. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013; 368 (2): 149–60. DOI: https://doi.org/10.1056/NEJMcp1113996
56. Alghamdi A. Structural and functional brain changes associated with vitamin B12 deficiency using magnetic resonance imaging: a systematic review and meta-analysis. Curr Med Imaging. 2022; May 16. DOI: https://doi.org/10.2174/1573405618666220516113758
57. Hsu Y.H., Huang C.F., Lo C.P., et al. Vitamin B12 deficiency: Characterization of psychometrics and MRI morphometrics. Nutr Neurosci. 2016; 19 (2): 47–54. DOI: https://doi.org/10.1179/1476830515Y.0000000045
58. Pavlov C.S., Damulin I.V., Shul’pekova Y.O., Andreev E.A. Neurological disorders in vitamin B12 deficiency. Terapevticheskiy arkhiv [Therapeutic Archive]. 2019; 91 (4): 122–9. DOI: https://doi.org/10.26442/00403660.2019.04.000116 (in Russian)
59. Pyrgioti E.E., Karakousis N.D. B12 levels and frailty syndrome. J Frailty Sarcopenia Falls. 2022; 7 (1): 32–7. DOI: https://doi.org/10.22540/JFSF-07-032
60. Moore E.M., Mander A.G., Ames D., et al. AIBL Investigators. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care. 2013; 36 (10): 2981–7. DOI: https://doi.org/10.2337/dc13-0229
61. Pop-Busui R., Ang L., Boulton A.J.M., et al. Diagnosis and treatment of painful diabetic peripheral neuropathy. ADA Clin Compend. 2022; 2022: 1–32. DOI: https://doi.org/10.2337/db2022-01
62. Bailey R.L., Carmel R., Green R., et al. Monitoring of vitamin B-12 nutritional status in the United States by using plasma methylmalonic acid and serum vitamin B-12. Am J Clin Nutr. 2011; 94 (2): 552–61. DOI: https://doi.org/10.3945/ajcn.111.015222
63. Jatoi S., Hafeez A., Riaz S.U., et al. Low vitamin B12 levels: an underestimated cause of minimal cognitive impairment and dementia. Cureus. 2020; 12 (2): e6976. DOI: https://doi.org/10.7759/cureus.6976
64. Chen H., Liu S., Ge B., et al. Effects of folic acid and vitamin B12 supplementation on cognitive impairment and inflammation in patients with Alzheimer’s disease: a randomized, single-blinded, placebo-controlled trial. J Prev Alzheimers Dis. 2021; 8 (3): 249–56. DOI: https://doi.org/10.14283/jpad.2021.22
65. Sanz-Cuesta T., Escortell-Mayor E., Cura-Gonzalez I., et al. OB12 Group. Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12). BMJ Open. 2020; 10 (8): e033687. DOI: https://doi.org/10.1136/bmjopen-2019-033687
66. Bolaman Z., Kadikoylu G., Yukselen V., et al. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study. Clin Ther. 2003; 25 (12): 3124–34. DOI: https://doi.org/10.1016/s0149-2918(03)90096-8
67. Didangelos T., Karlafti E., Kotzakioulafi E., et al. Vitamin B12 supplementation in diabetic neuropathy: a 1-year, randomized, double-blind, placebo-controlled trial. Nutrients. 2021; 13 (2): 395.
68. Pratama S., Lauren B.C., Wisnu W. The efficacy of vitamin B12 supplementation for treating vitamin B12 deficiency and peripheral neuropathy in metformin-treated type 2 diabetes mellitus patients: a systematic review. Diabetes Metab Syndr. 2022; 16 (10): 102634.
69. Satapathy S., Bandyopadhyay D., Patro B.K., et al. Folic acid and vitamin B12 supplementation in subjects with type 2 diabetes mellitus: a multi-arm randomized controlled clinical trial. Complement Ther Med. 2020; 53: 102526.