Hypoglycemia as a complication of diabetes mellitus treatment acute eff ect on central nervous system function

Česká verzia

Authors: J. Michalec ¹; K. Brožová ^2,3; J. Otáhal ⁴; S. Krejčová ⁵; J. Urbanová ⁶; A. Večeřová ¹; E. Povolná ¹; J. Brož ¹
Authors place of work: Interní klinika 2. LF UK a FN Motol, Praha ¹; Oddělení dětské neurologie, Fakultní Thomayerova nemocnice, Praha ²; 3. LF UK Praha ³; Ústav patologické fyziologie, 2. LF UK, Praha ⁴; Oddělení klinické psychologie, FN Motol, Praha ⁵; Interní klinika 3. LF UK a FNKV, Praha ⁶
Published in the journal: Cesk Slov Neurol N 2024; 87(2): 89-95
Category: Review Article
doi: https://doi.org/10.48095/cccsnn202489

Summary

Hypoglycemia is a relatively common complication of diabetes mellitus treatment with insulin or with some of its secretagogues. Changes in cognitive functions have been tested by e.g. Digit Symbol Substitution Test (DSST) or Working Memory Test (WMT), whilst using functional imaging techniques – Blood-Oxygen-Level-Dependent functional MRI (BOLD-fMRI) or PET-CT. Studies have shown that during hypoglycemia, blood flow distribution through the brain can be disrupted, leading to less efficient engagement of certain brain regions in cognitive processes and lower test scores. However, there was not always the expected decrease in test scores during hypoglycemia compared to normoglycemia, or the decrease in scores was only small. This phenomenon may be explained by a correlation from imaging, where there was a compensatory increase in blood flow in the brain regions involved, and this increase was greater in hypoglycemia than in normoglycemia. Whether or not this compensation is sufficient (and therefore does not result in a worse test result) is probably individualized and depends on other factors. The areas where flow changes occurred during hypoglycemia depended on the cognitive test used. These included activating the striatum, frontostriatal pathway, and prefrontal cortex (those reflect working memory functions), or the parietal association area responsible for more complex planning processes. Conversely, impaired deactivation of brain regions irrelevant to the activity has been observed in diabetics in hypoglycemia.

Keywords:

cognitive functions – hypoglycemia – diabetes mellitus – BOLD-fMRI – PET-CT

Zdroje

1. Jéquier E. Carbohydrates as a source of energy. Am J Clin Nutr 1994; 59 (3 Suppl): 682S–685S. doi: 10.1093/ ajcn/59.3.682S.

2. Škrha J Jr. Hypoglykemie u nediabetiků. Vnitr Lek 2020; 66 (7): 447–448. doi: 10.36290/vnl.2020.126.

3. Brož J, Urbanová J. Rámcový pohled na epidemiologii hypoglykemie u diabetes mellitus 1. a 2. typu. Vnitr Lek 2019; 65 (4): 289–294.

4. Brož J, Urbanová J, Nunes M et al. Současný pohled na léčbu hypoglykemie. Vnitr Lek 2019; 65 (4): 295–299.

5. Brož J, Malinovská J, Brunerová L et al. Glukagon v léčbě hypoglykemie – novinky. Vnitr Lek 2021; 67 (2): 103–108.

6. Brož J, Campbell MD, Urbanová J et al. Characterization of individualized glycemic excursions during a standardized bout of hypoglycemia-inducing exercise and subsequent hypoglycemia treatment – a pilot study. Nutrients 2021; 13 (11): 4165. doi: 10.3390/nu13114165.

7. Amiel SA. The consequences of hypoglycaemia. Diabetologia 2021; 64 (5): 963–970. doi: 10.1007/s00125-020-05366-3.

8. ElSayed NA, Aleppo G, Aroda VR et al. 6. glycemic targets: standards of care in diabetes – 2023. Diabetes Care 2023; 46 (Suppl 1): S97–S110. doi: 10.2337/dc23-S006.

9. Rao PN, Shashidhar A, Ashok C. In utero fuel homeostasis: lessons for a clinician. Indian J Endocrinol Metab 2013; 17 (1): 60–68. doi: 10.4103/2230-8210.107851.

10. Hoseth E, Joergensen A, Ebbesen F et al. Blood glucose levels in a population of healthy, breast fed, term infants of appropriate size for gestational age. Arch Dis Child Fetal Neonatal Ed 2000; 83 (2): F117–F119. doi: 10.1136/fn.83.2.F117.

11. Hawdon JM, Ward-Platt MP, Aynsley-Green A. Patterns of metabolic adaptation for preterm and term infants in the first neonatal week. Arch Dis Child 1992; 67 (4): 357–365. doi: 10.1136/adc.67.4_spec_no.357.

12. Güemes M, Rahman SA, Hussain K. What is a normal blood glucose? Arch Dis Child 2016; 101 (6): 569–574. doi: 10.1136/archdischild-2015-308336.

13. Shah VN, DuBose SN, Li Z et al. Continuous glucose monitoring profiles in healthy nondiabetic participants: a multicenter prospective study. J Clin Endocrinol Metab 2019; 104 (10): 4356–4364. doi: 10.1210/jc.2018-02763.

14. Brož J, Malinovská J, Nunes MA et al. Prevalence of diabetes and prediabetes and its risk factors in adults aged 25–64 in the Czech Republic: a cross-sectional study. Diabetes Res Clin Pract 2020; 170: 108470. doi: 10.1016/j.diabres.2020.108470.

15. Urbanová J, Brunerová L, Brož J. Hidden MODY – looking for a needle in a haystack. Front Endocrinol 2018; 9: 355. doi: 10.3389/fendo.2018.00355.

16. Nunes MA, Kučerová K, Lukáč O et al. Prevalence of diabetes mellitus among Roma populations – a systematic review. Int J Environ Res Public Health 2018; 15 (11): 2607. doi: 10.3390/ijerph15112607.

17. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018; 14 (2): 88–98. doi: 10.1038/nrendo.2017.151.

18. Kvapil M. Počet diabetiků v České republice. VVV 2019; S34.

19. Brož J, Janíčková Žďárská D, Urbanová J et al. Current level of glycemic control and clinical inertia in subjects using insulin for the treatment of type 1 and type 2 diabetes in the Czech Republic and the Slovak Republic: results of a multinational, multicenter, observational survey (DIAINFORM). Diabetes Ther 2018; 9 (5): 1897–1906. doi: 10.1007/s13300-018-0485-2.

20. Brož J, Brabec M, Janíčková Žďárská D et al. Fear of driving license withdrawal in patients with insulin-treated diabetes mellitus negatively influences their decision to report severe hypoglycemic events to physicians. Patient Prefer Adherence 2015; 9: 1367–1370. doi: 10.2147/PPA.S87393.

21. Brož J, Halčiaková K, Janíčková Žďárská D et al. Zdravotní způsobilost k řízení motorových vozidel a diabetes mellitus: legislativní změny v roce 2018 a souhrn zdravotních aspektů. Vnitr Lek 2019; 65 (4): 321–325.

22. Urbanová J, Frier BM, Taniwall A et al. Optimal carbohydrate dose for treatment of nonsevere hypoglycemia in insulin-treated patients with diabetes: a narrative review. Can J Diabetes 2022; 6: S1499–2671 (22) 00074-0. doi: 10.1016/j.jcjd.2022.03.011.

23. Urbanová J, Brunerova L, Brož J. Hypoglycemia and antihyperglycemic treatment in the adult MODY patients – a systematic review of literature. Diab Res Clin Pract 2019; 158: 107914. doi: 10.1016/j.diabres.2019.107914.

24. Urbanová J, Michalec J, Brož J. Špičkové technologie v medicíně – vliv nastavení hodnot alarmů u systémů pro kontinuální monitoraci glykemie na metabolickou kompenzaci u diabetiků 1. typu: systematické review. Vnitr Lek 2021; 67 (6): 346–350.

25. Goodwin ML. Blood glucose regulation during prolonged, submaximal, continuous exercise: a guide for clinicians. J Diabetes Sci Technol 2010; 4 (3): 694–705. doi: 10.1177/193229681000400325.

26. Rizza RA, Cryer PE, Gerich JE. Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha- and beta-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia. J Clin Invest 1979; 64 (1): 62–71. doi: 10.1172/JCI109464.

27. Stanley S, Moheet A, Seaquist ER. Central mechanisms of glucose sensing and counterregulation in defense of hypoglycemia. Endocr Rev 2019; 40 (3): 768–788. doi: 10.1210/er.2018-00226.

28. Gerich JE, Langlois M, Noacco C et al. Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science 1973; 182 (4108): 171–173. doi: 10.1126/science.182.4108.171.

29. Parikh L, Seo D, Lacadie C et al. Differential resting state connectivity responses to glycemic state in type 1 diabetes. J Clin Endocrinol Metab 2020; 105 (1): 1–13. doi: 10.1210/clinem/dgz004.

30. Anderson AW, Heptulla RA, Driesen N et al. Effects of hypoglycemia on human brain activation measured with fMRI. Magn Reson Imaging 2006; 24 (6): 693–697. doi: 10.1016/j.mri.2006.03.013.

31. Kim E, Bahk Y, Oh H et al. Current status of cognitive remediation for psychiatric disorders: a review. Front Psychiatry 2018; 9: 461. doi: 10.3389/fpsyt.2018.00461.

32. Stroop JR. Studies of interference in serial verbal reactions. J Experiment Psychology 1935; 18 (6): 643–662. doi: 10.1037/h0054651.

33. Fromm-Auch D, Yeudall LT. Normative data for the Halstead-Reitan neuropsychological tests. J Clin Neuropsychol 1983; 5 (3): 221–238. doi: 10.1080/01 688638308401171.

34. Wechsler D. WAIS-R manual: Wechsler adult intelligence scale-revised. New York: Psychological Corporation 1981.

35. Warren R, Frier B. Hypoglycaemia and cognitive function. Diabetes Obes Metab 2005; 7 (5): 493–503. doi: 10.1111/j.1463-1326.2004.00421.x.

36. Maran A, Crepaldi C, Trupiani S et al. Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and type I diabetic subjects. Diabetologia 2000; 43 (6): 733–741. doi: 10.1007/s001250051371.

37. Widom B. Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin-dependent diabetes mellitus. Ann Intern Med 1990; 112 (12): 904–912. doi: 10.7326/0003-4819-112-12-904.

38. Fanelli C, Pampanelli S, Epifano L et al. Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in hypoglycaemia in male and female humans. Diabetologia 1994; 37 (8): 797–807. doi: 10.1007/BF00404337.

39. Schwartz N, Clutter W, Shah S et al. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest 1987; 79 (3): 777–781. doi: 10.1172/JCI112884.

40. Mitrakou A, Ryan C, Veneman T et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991; 260 (1): E67–E74. doi: 10.1152/ajpendo.1991.260. 1.E67.

41. Evans M, Pernet A, Lomas J et al. Delay in onset of awareness of acute hypoglycemia and of restoration of cognitive performance during recovery. Diabetes Care 2000; 23 (7): 893–897. doi: 10.2337/diacare.23.7.893.

42. Gejl M, Gjedde A, Brock B et al. Effects of hypoglycaemia on working memory and regional cerebral blood flow in type 1 diabetes: a randomised, crossover trial. Diabetologia 2018; 61 (3): 551–561. doi: 10.1007/s00125-017-4502-1.

43. Simon A, Skinner S, Ziegler D. Training working memory: anatomy matters. J Neurosci 2016; 36 (30): 7805–7806. doi: 10.1523/JNEUROSCI.1513-16.2016.

44. Landau S, Lal R, O‘Neil J et al. Striatal dopamine and working memory. Cereb Cortex 2009; 19 (2): 445–454. doi: 10.1093/cercor/bhn095.

45. Graveling A, Deary I, Frier B. Acute hypoglycemia impairs executive cognitive function in adults with and without type 1 diabetes. Diabetes Care 2013; 36 (10): 3240–3246. doi: 10.2337/dc13-0194.

46. Punthakee Z, Miller M, Launer L et al. Poor cognitive function and risk of severe hypoglycemia in type 2 diabetes. Diabetes Care 2012; 35 (4): 787–793. doi: 10.2337/dc11-1855.

47. Bolo N, Musen G, Jacobson A et al. Brain activation during working memory is altered in patients with type 1 diabetes during hypoglycemia. Diabetes 2011; 60 (12): 3256–3264. doi: 10.2337/db11-0506.

48. Jonides J, Schumacher E, Smith E et al. The role of parietal cortex in verbal working memory. J Neurosci 1998; 18 (13): 5026–5034. doi: 10.1523/JNEUROSCI.18-13-05026.1998.

49. Schmahmann J. The cerebellar cognitive affective syndrome. Brain 1998; 121 (4): 561–579. doi: 10.1093/brain/121.4.561.

50. Ma Z, Zhang N. Brain-wide connectivity architecture. In: Factors Affecting Neurodevelopment. USA: Elsevier 2021: 247–257. doi: 10.1016/B978-0-12-817986-4.00022-5.

51. Rosenthal J, Amiel S, Yaguez L et al. The effect of acute hypoglycemia on brain function and activation: a functional magnetic resonance imaging study. Diabetes 2001; 50 (7): 1618–1626. doi: 10.2337/diabetes.50.7.1618.

52. Ward T, Bernier R, Mukerji C et al. Finger-tapping test. In: Volkmar FR (ed.) Encyclopedia of autism spectrum disorders. Springer 2013: 1296. doi: 10.1007/978-1-4419-1698-3_343.

53. Stebbins G. Neuropsychological testing. In: Textbook of clinical neurology. USA: Elsevier 2007: 539–557. doi: 10.1016/B978-141603618-0.10027-X.

54. Strachan M, Ewing F, Frier B et al. Effects of acute hypoglycaemia on auditory information processing in adults with type I diabetes. Diabetologia 2003; 46 (1): 97–105. doi: 10.1007/s00125-002-0950-2.

55. Wright R, Frier B, Deary I. Effects of acute insulin-induced hypoglycemia on spatial abilities in adults with type 1 diabetes. Diabetes Care 2009; 32 (8): 1503–1506. doi: 10.2337/dc09-0212.

56. Phillips AA, Chan FHN, Zheng MMZ et al. Neurovascular coupling in humans: physiology, methodological advances and clinical implications. J Cereb Blood Flow Metab 2016; 36 (4): 647–664. doi: 10.1177/0271678X15617954.

57. Kaplan L, Chow BW, Gu C. Neuronal regulation of the blood-brain barrier and neurovascular coupling. Nat Rev Neurosci 2020; 21 (8): 416–432. doi: 10.1038/s41583-020-0322-2.

58. Nippert AR, Chiang PP, Del Franco AP et al. Astrocyte regulation of cerebral blood flow during hypoglycemia. J Cereb Blood Flow Metab 2020; 42 (8): 1534–1546. doi: 10.1177/0271678X221089091.

59. Brož J, Piťhová P, Janíčková Žďárská D. Syndrom porušeného vnímání hypoglykemie u diabetes mellitus. Vnitr Lek 2016; 62 (7–8): 547–550.