The Role of Insulin Deficiency in Cognitive Dysfunction in Patients with Type 1 Diabetes Mellitus
https://doi.org/10.23946/2500-0764-2024-9-2-94-102
Abstract
Type 1 diabetes mellitus is a chronic autoimmune disease with a onset in childhood and adolescence. Neurological disorders are among the most frequent complications of type 1 diabetes mellitus and might lead to cognitive impairment termed as diabetic encephalopathy. Besides regulating blood glucose, insulin have neuroprotective and pro-cognitive effects through its action on insulin receptors in the brain, promoting the production of neurotransmitters, long-term potentiation, synaptic plasticity, and neuronal differentiation. By enhancing abovementioned processes responsible for learning and memory, insulin improves cognitive functioning. Insulin deficiency triggers cognitive dysfunction and diabetic encephalopathy via mitochondrial dysfunction, oxidative stress, and disorganisation of glucose metabolism which alter functioning of glucose transporter proteins and induce pericyte loss, ultimately compromising integrity of the blood-brain barrier. Intranasal delivery of exogenous insulin, which bypasses the bloodbrain barrier, may serve as an efficient therapeutic strategy for correcting cognitive impairment in patients with diabetic encephalopathy. Further research is needed to uncover and understand the effects of exogenous insulin on cognitive functions in patients with type 1 diabetes mellitus.
About the Author
Yu. V. BykovRussian Federation
Dr. Yuri V. Bykov, MD, PhD, Associate Professor, Department of Anesthesiology and Critical Care Medicine
310, Mira Street, Stavropol, 355017
References
1. Ab-Hamid N, Omar N, Ismail CA, Long I. Diabetes and cognitive decline: Challenges and future direction. World J Diabetes. 2023;14(6):795-807. https://doi.org/10.4239/wjd.v14.i6.795
2. Bednarik P, Moheet AA, Grohn H, Kumar AF, Eberly LE, Seaquist ER, Mangia S. Type 1 Diabetes and Impaired Awareness of Hypoglycemia Are Associated with Reduced Brain Gray Matter Volumes. Front Neurosci. 2017;11:529. https://doi.org/10.3389/fnins.2017.00529
3. Rodrigues Oliveira SM, Rebocho A, Ahmadpour E, Nissapatorn V, de Lourdes Pereira M. Type 1 Diabetes Mellitus: A Review on Advances and Challenges in Creating Insulin Producing Devices. Micromachines (Basel). 2023;14(1):151. https://doi.org/10.3390/mi14010151
4. Rosengren A, Dikaiou P. Cardiovascular outcomes in type 1 and type 2 diabetes. Diabetologia. 2023;66(3):425-437. https://doi.org/10.1007/s00125-022-05857-5.
5. Bykov YuV. Type I diabetes mellitus in pediatric practice and lesions of the central nervous system. Tauride medico-biological Bulletin. 2020;4(23):91-97. (In Russ). https://doi.org/10.37279/2070-8092-2020-23-4-91-97
6. Bykov YuV, Baturin VA. Diabetic encephalopathy in diabetes mellitus in childhood: pathophysiology and clinical manifestations (review). Saratov Scientific and Medical Journal. 2022;18(1):46-49. (In Russ).
7. van Duinkerken E, Snoek FJ, de Wit M. The cognitive and psychological effects of living with type 1 diabetes: a narrative review. Diabet Med. 2020;37(4):555-563. https://doi.org/10.1111/dme.14216
8. Zilliox LA, Chadrasekaran K, Kwan JY, Russell JW. Diabetes and cognitive impairment. Curr Diab Rep. 2016;16:87. https://doi.org/10.1007/s11892-016-0775-x
9. Bykov YuV, Baturin VA. Cognitive impairment in type 1 diabetes mellitus. Siberian Scientific Medical Journal. 2023;43(1):4-12. (In Russ). https://doi.org/10.18699/SSMJ20230101
10. Zhang J, Liao H, Wang M, Xiong Y, Cao F. An updated metaanalysis of cohort studies: diabetes and risk of Alzheimer’s disease. Diabetes Res Clin Pract. 2017;124:41-47. https://doi.org/10.1016/j.diabres.2016.10.024
11. Cato A, Hershey T. Cognition and type 1 diabetes in children and adolescents. Diabetes Spectr. 2016;29(4):197-202. https://doi.org/10.2337/ds16-0036
12. Biessels GJ, Whitmer RA. Cognitive dysfunction in diabetes: how to implement emerging guidelines. Diabetologia. 2020;63(1):3-9. https://doi.org/10.1007/s00125-019-04977-9
13. Moheet A, Mangia S, Seaquist ER. 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
14. Duarte JMN. Metabolic Alterations Associated to Brain Dysfunction in Diabetes. Aging Dis. 2015;6(5):304-321. https://doi.org/10.14336/AD.2014.1104
15. Falvo E, Giatti S, Diviccaro S, Cioffi L, Herian M, Brivio P, Calabrese F, Caruso D, Melcangi RC. Diabetic Encephalopathy in a Preclinical Experimental Model of Type 1 Diabetes Mellitus: Observations in Adult Female Rat. Int J Mol Sci. 2023;24(2):1196. https://doi.org/10.3390/ijms24021196
16. Smolina K, Wotton CJ, Goldacre MJ. Risk of dementia in patients hospitalised with type 1 and type 2 diabetes in England, 1998-2011: A retrospective national record linkage cohort study. Diabetologia. 2015;58:942-950. https://doi.org/10.1007/s00125-015-3515-x
17. Sharma S, Brown CE. Microvascular basis of cognitive impairment in type 1 diabetes. Pharmacol Ther. 2022;229:107929. https://doi.org/10.1016/j.pharmthera.2021.107929
18. Gaudieri PA, Chen R, Greer TF, Holmes CS. Cognitive function in children with type 1 diabetes: a meta‐analysis. Diabetes Care. 2008;31:1892-1897. https://doi.org/10.2337/dc07-2132
19. Galizzi G, Di Carlo M. Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration. Biology (Basel). 2022;11(6):943. https://doi.org/10.3390/biology11060943
20. Surkova EV, Derkach KV, Bespalov AI, Shpakov AO. Prospects of intranasal insulin for the correction of cognitive disorders, in particular those associated with diabetes mellitus. Problems of endocrinology. 2019;65(1):5765. (In Russ.). https://doi.org/10.14341/probl9755
21. Spinelli M, Fusco S, Grassi C. Brain insulin resistance and hippocampal plasticity: mechanisms and biomarkers of cognitive decline. Front Neurosci. 2019;13:1-13. https://doi.org/10.3389/fnins.2019.00788
22. Kim HG. Cognitive dysfunctions in individuals with diabetes mellitus. Yeungnam Univ J Med. 2019;36(3):183-191. https://doi.org/10.12701/yujm.2019.00255
23. Tyagi A, Pugazhenthi S. Targeting Insulin Resistance to Treat Cognitive Dysfunction. Mol Neurobiol. 2021;58(6):2672-2691. https://doi.org/10.1007/s12035-021-02283-3
24. Ly H, Verma N, Wu F, Liu M, Liu M, Saatman KE, Nelson PT, Slevin JT, Goldstein LB, Biessels GB, Despa F. Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia. Ann Neurol. 2017;82:208-222. https://doi.org/10.1002/ana.24992
25. Banks WA. The Blood-Brain Barrier Interface in Diabetes Mellitus: Dysfunctions, Mechanisms and Approaches to Treatment. Curr Pharm Des. 2020;26(13):1438-1447. https://doi.org/10.2174/1381612826666200325110014
26. Falsetti L, Viticchi G, Zaccone V, Guerrieri E, Moroncini G, Luzzi S, Silvestrini M. Shared Molecular Mechanisms among Alzheimer’s Disease, Neurovascular Unit Dysfunction and Vascular Risk Factors: A Narrative Review. Biomedicines. 2022;10(2):439. https://doi.org/10.3390/biomedicines10020439
27. Blázquez E, Hurtado-Carneiro V, LeBaut-Ayuso Y, Velázquez E, García-García L, Gómez-Oliver F, Ruiz-Albusac JM, Ávila J, Pozo MA. Significance of Brain Glucose Hypometabolism, Altered Insulin Signal Transduction, and Insulin Resistance in Several Neurological Diseases. Front Endocrinol. (Lausanne). 2022;13:873301. https://doi.org/10.3389/fendo.2022.873301
28. de Cristóbal J, García-García L, Delgado M, Pérez M, Pozo MA, Medina M. Longitudinal Assessment of a Transgenic Animal Model of Tauopathy by FDG-PET Imaging. J Alzheimers Dis JAD. 2014;40:S79- 89. https://doi.org/10.3233/JAD-132276
29. Reno CM, Puente EC, Sheng Z, Daphna-Iken D, Bree AJ, Routh VH, Kahn B, Fisher SJ. Brain GLUT4 knockout mice have impaired glucose tolerance, decreased insulin sensitivity, and impaired hypoglycemic counterregulation. Diabetes. 2017;66(3):587-597. https://doi.org/10.2337/db16-0917
30. Fernandez AM, Hernandez-Garzón E, Perez-Domper P, Perez-Alvarez A, Mederos S, Matsui T, Santi A, Trueba-Saiz A, García-Guerra L, Pose-Utrilla J, Fielitz J, Olson EN, de la Rosa RF, Garcia LG, Pozo MA, Iglesias T, Araque A, Soya H, Perea G, Martin ED, Aleman IT. Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I. Diabetes. 2017;66:64-74. https://doi.org/10.2337/db16-0861
31. Banks WA, Owen JB, Erickson MA. Insulin in the Brain: There and Back Again. Pharmacol Ther. 2012;136(1):82-93. https://doi.org/10.1016/j.pharmthera.2012.07.006
32. Duarte J.M., Nogueira C., Mackie K., Oliveira C.R., Cunha R.A., Köfalvi A. Increase of cannabinoid CB1 receptor density in the hippocampus of streptozotocin-induced diabetic rats. Experimental Neurology. 2007;204:479-484. https://doi.org/10.1016/j.expneurol.2006.11.013
33. Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10):1326-1334. https://doi.org/10.1016/j.psyneuen.2004.04.003
34. Agrawal R, Reno CM, Sharma S, Christensen C, Huang Y, Fisher SJ. Insulin action in the brain regulates both central and peripheral functions. Am J Physiol Endocrinol Metab. 2021;321(1):E156-E163. https://doi.org/10.1152/ajpendo.00642.2020
35. Rönnemaa E, Zethelius B, Sundelöf J, Sundström J, DegermanGunnarsson M, Berne C, Lannfelt L, Kilander L. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology. 2008;71:1065-1071. https://doi.org/10.1212/01.wnl.0000310646.32212.3a
36. Wardelmann K, Blümel S, Rath M, Alfine E, Chudoba C, Schell M, Cai W, Hauffe R, Warnke K, Flore T, Ritter K, Weiß J, Kahn CR, Kleinridders A. Insulin action in the brain regulates mitochondrial stress responses and reduces diet-induced weight gain. Mol Metab. 2019;21:68-81. https://doi.org/10.1016/j.molmet.2019.01.001
37. Ruegsegger GN, Manjunatha S, Summer P, Gopala S, Zabeilski P, Dasari S, Vanderboom PM, Lanza IR, Klaus KA, Nair KS. Insulin deficiency and intranasal insulin alter brain mitochondrial function: A potential factor for dementia in diabetes. FASEB J. 2018;33:4458- 4472. https://doi.org/10.1096/fj.201802043R
38. Banks WA, Rhea EM. The Blood-Brain Barrier, Oxidative Stress, and Insulin Resistance. Antioxidants (Basel). 2021;10(11):1695. https://doi.org/10.3390/antiox10111695
39. Paneni F, Costantino S, Cosentino F. Role of oxidative stress in endothelial insulin resistance. World J. Diabetes. 2015;6:326-332. https://doi.org/10.4239/wjd.v6.i2.326
40. Maciejczyk M, Żebrowska E, Chabowski A. Insulin Resistance and Oxidative Stress in the Brain: What’s New? Int J Mol Sci. 2019;20(4):874. https://doi.org/10.3390/ijms20040874
41. Ruegsegger GN, Manjunatha S, Summer P, Gopala S, Zabeilski P, Dasari S, Vanderboom PM, Lanza IR, Klaus KA, Nair KS. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes. FASEB J. 2019;33(3):4458- 4472. https://doi.org/10.1096/fj.201802043R
42. Lanzillotta C, Tramutola A, Di Giacomo G, Marini F, Butterfield DA, Di Domenico F, Perluigi M, Barone E. Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in down syndrome. Free Radic. Biol. Med. 2021;165:152-170. https://doi.org/10.1016/j.freeradbiomed.2021.01.042
43. Gonzalez M, Rojas S, Avila P, Cabrera L, Villalobos R, Palma C, Aguayo C, Peña E, Gallardo V, Guzmán-Gutiérrez E, Sáez T, Salsoso R, Sanhueza C, Pardo F, Leiva A, Sobrevia L. Insulin reverses D-glucoseincreased nitric oxide and reactive oxygen species generation in human umbilical vein endothelial cells. PLoS ONE. 2015;10:e0122398. https://doi.org/10.1371/journal.pone.0122398
44. Takechi R, Lam V, Brook E, Giles C, Fimognari N, Mooranian A, Al-Salami H, Coulson SH, Nesbit M, Mamo JC. Blood-Brain Barrier Dysfunction Precedes Cognitive Decline and Neurodegeneration in Diabetic Insulin Resistant Mouse Model: An Implication for Causal Link. Front Aging Neurosci. 2017;9:399. https://doi.org/10.3389/fnagi.2017.00399
45. Gray SM, Barrett EJ. Insulin transport into the brain. Am J Physiol Cell Physiol. 2018;315:C125-C136. https://doi.org/10.1152/ajpcell.00240.2017
46. Nguyen V, Thomas P, Pemberton S, Babin A, Noonan C, Weaver R, Banks WA, Rhea EM. Central nervous system insulin signaling can influence the rate of insulin influx into brain. Fluids Barriers CNS. 2023;20(1):28. https://doi.org/10.1186/s12987-023-00431-6.
Review
For citations:
Bykov Yu.V. The Role of Insulin Deficiency in Cognitive Dysfunction in Patients with Type 1 Diabetes Mellitus. Fundamental and Clinical Medicine. 2024;9(2):94-102. (In Russ.) https://doi.org/10.23946/2500-0764-2024-9-2-94-102