Risk factors for cognitive impairments in children and adolescents with type 1 diabetes mellitus: pathophysiological aspects (literature review)

Type 1 diabetes mellitus (T1DM) in children and adolescents is associated not only with metabolic disturbances but also with the development of cognitive impairments, which may initially present subclinically. These impairments reflect central nervous system involvement driven by a variety of pathophysiological mechanisms. Recent studies have demonstrated that the cognitive status of children with T1DM is influenced by both acute and chronic factors, including episodes of hypoand hyperglycemia, diabetic ketoacidosis, disease duration, and poor glycemic control.

Aim. Summarize current literature on the mechanisms underlying cognitive impairment in T1DM, as well as the possibilities for early diagnosis and prevention. The roles of neuroinflammation, oxidative stress, altered glucose transporter function, impaired neurogenesis, microvascular complications, gut dysbiosis, and psychiatric comorbidities in the pathogenesis of cerebral dysfunction are discussed. Particular attention is given to the methodological challenges of assessing cognitive status in the pediatric population, the potential use of laboratory and neuroimaging markers, and their clinical applicability. The review also highlights the impact of cognitive impairment on learning, social adaptation, and quality of life in patients. The data presented emphasize the need for the development of personalized strategies for prevention and intervention. Cognitive disturbances in T1DM are increasingly recognized as a major factor influencing long-term prognosis and the adaptive capacity of young patients.

1. Bykov Yu.V., Baturin V.A. Diabetic encephalopathy in diabetes mellitus in childhood: pathophysiology and clinical manifestations (review). Saratov Scientific and Medical Journal. 2022;18(1):46–49. (In Russ.).

2. Bykov Yu.V. Oxidative stress and diabetic encephalopathy: pathophysiological aspects. Modern problems of science and education. 2022;6–2. (In Russ.). https://doi.org/10.17513/spno.32314

3. Jin C.Y., Yu S.W., Yin J.T., Yuan X.Y., Wang X.G. Corresponding risk factors between cognitive impairment and type 1 diabetes mellitus: A narrative review. Heliyon. 2022;8(8):e10073. https://doi.org/10.1016/j.heliyon.2022.e10073

4. van Duinkerken E., Ijzerman R.G., Klein M., Moll A.C., Snoek F.J., Scheltens P. et al. Disrupted subject-specific gray matter network properties and cognitive dysfunction in type 1 diabetes patients with and without proliferative retinopathy. Hum. Brain Mapp. 2016;37:1194–1208. https://doi.org/10.1002/hbm.23096

5. Bykov Yu.V., Baturin V.A. Cognitive impairment in type 1 diabetes mellitus. Siberian Scientific Medical Journal. 2023;43(1):4–12. (In Russ.)]. https://doi.org/10.18699/SSMJ20230101

6. Moheet A., Mangia S., Seaquist E.R. Impact of diabetes on cognitive function and brain structure. Ann. N. Y. Acad. Sci. 2015;1353:60–71. https://doi.org/10.1111/nyas.12807

7. Nunley K.A., Rosano C., Ryan C.M., Jennings J.R., Aizenstein H.J., Zgibor J.C. et al. Clinically relevant cognitive impairment in middleaged adults with childhood-onset type 1 diabetes. Diabetes Care. 2015;38(9):1768–1776. https://doi.org/10.2337/dc15-0041

8. Urakami T. Severe hypoglycemia: Is it still a threat for children and adolescents with type 1 diabetes? Front. Endocrinol. (Lausanne). 2020;11:609. https://doi.org/10.3389/fendo.2020.00609

9. Koepsell H. Glucose transporters in brain in health and disease. Pflügers Archiv. 2020;472:1299–1343. https://doi.org/10.1007/s00424-02002441-x

10. Languren G., Montiel T., Ramirez-Lugo L., Balderas I., SánchezChávez G., Sotres-Bayón F. et al. Recurrent moderate hypoglycemia exacerbates oxidative damage and neuronal death leading to cognitive dysfunction after the hypoglycemic coma. J. Cerebr. Blood Flow Metabol. 2019;39:808–821. https://doi.org/10.1177/0271678X17733640

11. McNeilly A.D., Gallagher J.R., Dinkova-Kostova A.T., Hayes J.D., Sharkey J., Ashford M.L. et al. Nrf2-Mediated neuroprotection against recurrent hypoglycemia is insufficient to prevent cognitive impairment in a rodent model of type 1 diabetes. Diabetes. 2016;65:3151–3160. https://doi.org/10.2337/db15-1653

12. Yaffe K., Falvey C.M., Hamilton N., Harris T.B., Simonsick E.M., Strotmeyer E.S. et al. Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus. JAMA Intern. Med. 2013;173:1300–1306. https://doi.org/10.1001/jamainternmed.2013.6176

13. Cato A., Hershey T. Cognition and type 1 diabetes in children and adolescents. Diabetes Spectr. 2016;29:197–202. https://doi.org/10.2337/ds16-0036

14. Shalimova A., Graff B., Gasecki D., Wolf J., Sabisz A., Szurowska E. et al. Cognitive dysfunction in type 1 diabetes mellitus. J. Clin. Endocrinol. Metab. 2019;104:2239–2249. https://doi.org/10.1210/jc.2018-01315

15. Aberdeen H., Battles K., Taylor A., Garner-Donald J., DavisWilson A., Rogers B.T. et al. The aging vasculature: glucose tolerance, hypoglycemia and the role of the serum response factor. J. Cardiovasc. Dev. Dis. 2021;8(5):58. https://doi.org/10.3390/jcdd8050058

16. Li X.R., Yu P.Q., Yu Y.H., Xu T., Liu J., Cheng Y. et al. Hydrogen sulfide ameliorates high glucose-induced pro-inflammation factors in HT-22 cells: involvement of SIRT1-mTOR/NF-κB signaling pathway. Int. Immunopharm. 2021;95:107545. https://doi.org/10.1016/j.intimp.2021.107545

17. Yang X., Chen Y.Q., Zhang W.S., Zhang Z., Yang X., Wang P. et al. Association between inflammatory biomarkers and cognitive dysfunction analyzed by MRI in diabetes patients. Diabetes Metab. Syndr. Obes. 2020;13:4059–4065. https://doi.org/10.2147/DMSO.S271160

18. Xu T., Liu J., Li X.R., Yu Y., Luo X., Zheng X. et al. The mTOR/NF-κB pathway mediates neuroinflammation and synaptic plasticity in diabetic encephalopathy. Mol. Neurobiol. 2021;58:3848–3862. https://doi.org/10.1007/s12035-021-02390-1

19. Rom S., Zuluaga-Ramirez V., Gajghate S., Seliga A., Winfield M., Heldt N.A. et al. Hyperglycemia-driven neuroinflammation compromises BBB leading to memory loss in both diabetes mellitus (DM) type 1 and type 2 mouse models. Mol. Neurobiol. 2019;56:1883–1896. https://doi.org/10.1007/s12035-018-1195-5

20. Wang J.C., Wang L., Zhou J., Qin A., Chen Z.J. The protective effect of formononetin on cognitive impairment in streptozotocin (STZ)-induced diabetic mice. Biomed. Pharmacother. 2018;106:1250–1257. https://doi.org/10.1016/j.biopha.2018.07.063

21. Chen H.J., Lee Y.J., Huang C.C., Lin Y.F., Li S.T. Serum brain-derived neurotrophic factor and neurocognitive function in children with type 1 diabetes. J. Formos. Med. Assoc. 2021;120(Pt.1):157–164. https://doi.org/10.1016/j.jfma.2020.04.011

22. Ryan C.M., van Duinkerken E., Rosano C. Neurocognitive consequences of diabetes. Am. Psychol. 2016;71(7):563–576. https://doi.org/10.1037/a0040455

23. Li W., Huang E., Gao S.J. Type 1 diabetes mellitus and cognitive impairments: a systematic review. J. Alzheimers Dis. 2017;57:29–36. https://doi.org/10.3233/JAD-161250

24. Nakano M., Nagaishi K., Konari N., Saito Y., Chikenji T., Mizuete Y. Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes. Sci. Rep. 2016;6:24805. https://doi.org/10.1038/srep24805

25. Wang X., Yu S., Hu J.P., Wang C.Y., Wang Y., Liu H.X. Streptozotocininduced diabetes increases amyloid plaque deposition in AD transgenic mice through modulating AGEs/RAGE/NF-κB pathway. Int. J. Neurosci. 2014;124:601–608. https://doi.org/10.3109/00207454.2013.866110

26. Glaser N., Sasaki-Russell J., Cohen M., Little C., O'Donnell M., Sall J. Histological and cognitive alterations in adult diabetic rats following an episode of juvenile diabetic ketoacidosis: Evidence of permanent cerebral injury. Neurosci. Lett. 2017;650:161–167. https://doi.org/10.1016/j.neulet.2017.04.035

27. Glaser N., Chu S., Hung B., Fernandez L., Wulff H., Tancredi D. et al. Acute and chronic neuroinflammation is triggered by diabetic ketoacidosis in a rat model. BMJ Open Diabetes Res. Care. 2020;8(2):e001793. https://doi.org/10.1136/bmjdrc-2020-001793

28. Tomkins M., McCormack R., O’Connell K., Agha A., Merwick A. Metabolic encephalopathy secondary to diabetic ketoacidosis: a case report. BMC Endocr. Disord. 2019;19:71. https://doi.org/10.1186/s12902-019-0398-8

29. Ghetti S., Kuppermann N., Rewers A., Myers S.R., Schunk J.E., Stoner M.J. et al. Cognitive function following diabetic ketoacidosis in children with new-onset or previously diagnosed type 1 diabetes. Diabetes Care. 2020;43:2768–2775. https://doi.org/10.2337/dc20-0187

30. Sayed M.H., Hegazi M.A., Abdulwahed K., Moussa K., El-Deek B.S., Gabel H. et al. Risk factors and predictors of uncontrolled hyperglycemia and diabetic ketoacidosis in children and adolescents with type 1 diabetes mellitus in Jeddah, western Saudi Arabia. J. Diabetes. 2017;9(2):190–199. https://doi.org/10.1111/1753-0407.12404

31. Zheng F.F., Yan L., Yang Z.C., Zhong B.L., Xie W.X. HbA1c, diabetes and cognitive decline: the English longitudinal study of ageing. Diabetologia. 2018;61(4):839–848. https://doi.org/10.1007/s00125-017-4541-7

32. He J., Li S.C., Liu F., Zheng H., Yan X., Xie Y. et al. Glycemic control is related to cognitive dysfunction in Chinese children with type 1 diabetes mellitus. J. Diabetes. 2018;10(12):948–957. https://doi.org/10.1111/1753-0407.12775

33. Kirchhoff B.A., Jundt D.K., Doty T., Hershey T. A longitudinal investigation of cognitive function in children and adolescents with type 1 diabetes mellitus. Pediatr. Diabetes. 2017;18(6):443–449. https://doi.org/10.1111/pedi.12414

34. Pourabbasi A., Tehrani-Doost M., Qavam S.E., Karijani B. Evaluation of the correlation between type 1 diabetes and cognitive function in children and adolescents, and comparison of this correlation with structural changes in the central nervous system: a study protocol. BMJ Open. 2016;6(4):e007917. https://doi.org/10.1136/bmjopen-2015-007917

35. Song J.W., Cui S.H., Chen Y.M., Ye X., Huang X., Su H. et al. Disrupted regional cerebral blood flow in children with newly-diagnosed type 1 diabetes mellitus: an arterial spin labeling perfusion magnetic resonance imaging study. Front. Neurol. 2020;11:572. https://doi.org/10.3389/fneur.2020.00572

36. Bjornstad P., Schäfer M., Truong U., Cree-Green M., Pyle L., Baumgartner A. et al. Metformin improves insulin sensitivity and vascular health in youth with type 1 diabetes mellitus. Circulation. 2018;138:2895– 2907. https://doi.org/10.1161/CIRCULATIONAHA.118.035525

37. Awad A., Lundqvist R., Rolandsson O., Sundstrom A., Eliasson M. Lower cognitive performance among long-term type 1 diabetes survivors: a case–control study. J. Diabet. Complicat. 2017;31(8):1328–1331. https://doi.org/10.1016/j.jdiacomp.2017.04.023

38. Tonoli C., Heyman E., Roelands B., Pattyn N., Buyse L., Piacentini M.F. et al. Type 1 diabetes-associated cognitive decline: a meta-analysis and update of the current literature. J. Diabetes. 2014;6(6):499–513. https://doi.org/10.1111/1753-0407.12193

39. Pal K., Mukadam N., Petersen I., Cooper C. Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-analysis. Soc. Psychiatr. Psychiatr. Epidemiol. 2018;53(11):1149–1160. https://doi.org/10.1007/s00127-018-1581-3

40. Amutha A., Ranjit U., Anjana R.M., Shanthi C.S., Rajalakshmi R., Venkatesan U. et al. Clinical profile and incidence of microvascular complications of childhood and adolescent onset type 1 and type 2 diabetes seen at a tertiary diabetes center in India. Pediatr. Diabetes. 2021;22(1):67–74. https://doi.org/10.1111/pedi.13033

41. Sacre J.W., Magliano D.J., Zimmet P.Z., Polkinghorne K.R., Chadban S.J., Anstey K.J., Shaw J.E. Associations of chronic kidney disease markers with cognitive function: a 12-year follow-up study. J. Alzheimers Dis. 2019;70(s1):S19– S30. https://doi.org/10.3233/JAD180498

42. Gupta P., Gan A.T.L., Man R.E.K. Fenwick E.K., Sabanayagam C., Mitchell P. et al. Association between diabetic retinopathy and incident cognitive impairment. Br. J. Ophthalmol. 2019;103:1605–1609. https://doi.org/10.1136/bjophthalmol-2018-312807

43. Fakih W., Mroueh A., Salah H., Eid A.H., Obeid M., Kobeissy F. et al. Dysfunctional cerebrovascular tone contributes to cognitive impairment in a non-obese rat model of prediabetic challenge: role of suppression of autophagy and modulation by anti-diabetic drugs. Biochem. Phramacol. 2020;178:114041. https://doi.org/10.1016/j.bcp.2020.114041

44. Daulatzai M.A. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer's disease. J. Neurosci. Res. 2017;95(4):943–972. https://doi.org/10.1002/jnr.23777

45. Gareau M.G. Cognitive function and the microbiome. Int. Rev. Neurobiol. 2016;131:227–246. https://doi.org/10.1016/bs.irn.2016.08.001

46. Zheng H., Xu P.T., Jiang Q.Y., Xu Q., Zheng Y., Yan J. et al. Depletion of acetate-producing bacteria from the gut microbiota facilitates cognitive impairment through the gut-brain neural mechanism in diabetic mice. Microbiome. 2021;9:145. https://doi.org/10.1186/s40168-021-01088-9

47. Ma X.Y., Xiao W.C., Li H., Pang J., Xue F., Wan L. et al. Metformin restores hippocampal neurogenesis and learning and memory via regulating gut microbiota in the obese mouse model. Brain Behav. Immun. 2021;95:68–83. https://doi.org/10.1016/j.bbi.2021.02.011

48. Kumar N., Singh V.B., Meena B.L., Kumar D., Kumar H., Saini M.L. et al. Mild cognitive impairment in young type 1 diabetes mellitus patients and correlation with diabetes control, lipid profile, and high-sensitivity C-reactive protein. Indian J. Endocrinol. Metab. 2018;22(6):780–784. https://doi.org/10.4103/ijem.IJEM_58_18

49. Noori H., Gheini M.R., Rezaeimanesh N., Saeedi R., Aliabadi H.R., Sahraian M.A. et al. The correlation between dyslipidemia and cognitive impairment in multiple sclerosis patients. Mult. Scler. Relat. Disord. 2019;36:101415. https://doi.org/10.1016/j.msard.2019.101415

50. Salameh T.S., Rhea E.M., Banks W.A., Hanson A.J. Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease. Exp. Biol. Med. 2016;241(15):1676–1683. https://doi.org/10.1177/1535370216660770