Terapevticheskii arkhivTerapevticheskii arkhivТерапевтический архив0040-36602309-5342LLC Obyedinennaya Redaktsiya3264910.17116/terarkh201688682-86Editorial articleПередовая статьяReview ArticleDiabetes mellitus and the central nervous systemСахарный диабет и центральная нервная системаSurkovaE VСурковаЕ ВЭндокринологический научный центр Минздрава России151020168810VOL 88, NO10 (2016)ТОМ 88, №10 (2016)828611042020Copyright ©; 2016, Consilium MedicumCopyright ©; 2016, ООО "Консилиум Медикум"2016Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://ter-arkhiv.ru/0040-3660/article/view/32649

The review considers the current views on the central nervous system (CNS) in diabetes mellitus (DM). It discusses an attitude towards the term «diabetic encephalopathy». The data of investigations of cognitive functions in types 1 and 2 DM and the brain structural imaging results obtained using up-to-date technologies are considered. The results of studies of the factors that induce cerebral changes in DM and their associated cognitive impairments are given. There is evidence that hyperglycemia has a more considerable impact on the above processes than hypoglycemia; other possible factors, apart from blood glucose control, are set out. The current views on the function of insulin in the CNS and the relationship of central insulin resistance to Alzheimer’s disease are outlined. There are current data on intranasal insulin application that is still exploratory, but, as might be judged from the findings, may by a promising method for the treatment and prevention of cognitive decline in both patients with DM and those without this condition.

Аннотация В обзоре рассматриваются современные представления о состоянии центральной нервной системы (ЦНС) при сахарном диабете (СД). Обсуждается отношение к термину «диабетическая энцефалопатия». Рассматриваются данные исследований когнитивных функций при СД 1-го и 2-го типов, а также результаты визуализации мозговых структур, полученные с использованием современных технологий. Приводятся результаты изучения факторов, индуцирующих изменения мозга при СД и связанных с ними когнитивных расстройств. Представлены доказательства более весомого влияния на указанные процессы гипергликемии по сравнению с гипогликемией, перечислены другие возможные факторы воздействия помимо контроля уровня глюкозы в крови. Изложены современные взгляды на функции инсулина в ЦНС и связь центральной инсулинорезистентности с болезнью Альцгеймера. Приведены актуальные данные по применению интраназального инсулина, которое носит пока исследовательский характер, но, как позволяют судить полученные результаты, может в будущем явиться перспективным методом лечения и профилактики снижения когнитивных функций как у больных СД, так и лиц без СД.

diabetes mellitusbraincognitive functionshyperglycemiahypoglycemiainsulininsulin resistanceAlzheimer’s diseaseсахарный диабетмозгкогнитивные функциигипергликемиягипогликемияинсулининсулинорезистентностьболезнь АльцгеймераIDF Diabetes Atlas, 7th Edition, Brussels; 2015.Miles WR, Root HF. Psychologic tests applied to diabetic patients. Arch Int Med. 1922;30:767-777.DeJong RN. The nervous system complications in diabetes mellitus with special reference to cerebrovascular changes. JNervMentDis. 1950;111:181-206.Чугунова Л.А., Семенова И.В., Орлов Ю.Ю., Шестакова М.В. Сахарный диабет 2 типа и когнитивные нарушения. Сахарныйдиабет. 2008;1:61-66.Mijnhout GS, Scheltens P, Diamant M,
Biessels GJ, Wessels AM, Simsek S, Snoek FJ, Heine RJ. Diabetic encephalopathy: a concept in need of a definition. Diabetologia. 2006;49:1447-1448.Sima AAF. Encephalopaties: the emerging diabetic complications. Acta Diabetol. 2010;47(4):279-293. doi:10.1007/s00592-010-0218-0Строков И.А., Захаров В.В., Строков К.И. Диабетическая энцефалопатия. Неврология, нейропсихиатрия, психосоматика. 2012; 4(2S):30-40.Котов С.В., Рудакова И.Г., Исакова Е.В. Энцефалопатия у больных сахарным диабетом II типа. Клиникаилечение. Неврологическийжурнал. 2001;3:35-37.Seaquist ER. The Final Frontier: How Does Diabetes Affect the Brain? Diabetes. 2010;59:4-5. doi:10.2337/db09-1600Brands AMA, Biessels GJ, de Haan EHF, Kappelle LJ, Kessels RPC The effects of type 1 diabetes on cognitive performance. Diabetes Care. 2005;28:726-735.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.Naguib JM, Kulinskaya E, Lomax Cl, Garralda ME. Neuro-cognitive performance in children with type 1 diabetes: a meta analysis. J Pediatr Psychol. 2009;34:271-282. doi:10.1093/jpepsy/jsn074Dahlquist G, Källén B. Swedish Childhood Diabetes Study Group. School performance in children with type 1 diabetes — a population-based register study. Diabetologia. 2007;50:957-964.Northam EA, Lin A, Finch S, Werther GA, Cameron FJ. Psychosocial wellbeing and functional outcomes in youth with type 1 diabetes 12 years after disease onset. Diabetes Care. 2010;33:1430-1437. doi:10.2337/dc09-2232Ly TT, Anderson M, Mcnamara K, Davis EA, Jones TW. Neurocognitive Outcomes in Young Adults With Early-Onset Type 1 Diabetes. Diabetes Care. 2011;34:2192-2197. doi:10.2337/dc11-0697Biessels GJ, Reijmer YD. Brain Changes Underlying Cognitive Dysfunction in Diabetes: What Can We Learn From MRI? Diabetes. 2014; 63:2244-2252. doi:10.2337/db14-0348Mauras N, Mazaika P, Buckingham B, Weinzimer S, White NH, Tsalikian E, Hershey T, Cato A, Cheng P, Kollman C, Beck RW, Ruedy K, Aye T, Fox L, Arbelaez AM, Wilson D, Tansey M, Tamborlane W, Peng D, Marzelli M, Winer KK, and Reissfor AL, for the Diabetes Research in Children Network (DirecNet). Longitudinal Assessment of Neuroanatomical and Cognitive Differences in Young Children With Type 1 Diabetes: Association With Hyperglycemia. Diabetes. 2015; 64:1770-1779. doi:10.2337/db14-1445Ferguson SC, Blane A, Wardlaw J, Frier BM, Perros P, McCrimmon RJ, Ian J, Deary IJ. Influence of an early-onset age of type 1 diabetes on cerebral structure and cognitive function. Diabetes Care. 2005;28:1431-1437.Marzelli MJ, Mazaika PK, Barnea-Goraly N, Hershey T, Tsalikian E, Tamborlane W, Mauras N, Reiss AL, for the Diabetes Research in Children Network (DirecNet). Neuroanatomical correlates of dysglycemia in young children with type 1 diabetes. Diabetes 2014;63:343-353. doi:10.2337/db13-0179Barnea-Goraly N, Raman M, Mazaika P, Marzelli M, Hershey T, Weinzimer SA, Aye T, Buckingham B, Mauras N, White NH, Fox LA, Tansey M, Beck RW, Ruedy KJ, Kollman C, Cheng P, Reiss AL. Diabetes Research in Children Network (DirecNet). Alterations in white matter structure in young children with type 1 diabetes. Diabetes Care. 2014;37:332-340. doi:10.2337/dc13-1388Jacobson AM, Ryan CM, Cleary PA, Waberski BH, Weinger K, Musen G, Dahms W and the DCCT/EDIC Research Group. Biomedical risk factors for decreased cognitive functioning in type 1 diabetes: an 18 year follow-up of the Diabetes Control and Complications Trial (DCCT) cohort. Diabetologia. 2011;54:245-255. doi:10.1007/s00125-010-1883-9Antenor-Dorsey JAV, Meyer E, Rutlin J, Perantie DC, White NH, Arbelaez AM, Shimony JS, Hershey T. White matter microstructural integrity in youth with type 1 diabetes. Diabetes. 2013;62:581-589. doi:10.2337/db12-0696Perantie DC, Koller JM, Weaver PM, Lugar HM, Black KJ, White NH, Hershey T. Prospectively determined impact of type 1 diabetes on brain volume during development. Diabetes. 2011;60:3006-3014. doi:10.2337/db11-0589Perantie DC, Wu J, Koller JM, Lim A, Warren SL, Black KJ, Sadler M, White NH, Hershey T. Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth with type 1 diabetes. DiabetesCare. 2007;30:2331-2337.Янишевский С.Н. Поражение головного мозга при сахарном диабете 2 типа (клинико-морфологическое исследование): Автореф. дисс. ... д-ра мед. наук.СПб.; 2014.Камчатнов П.Р., Мартынов М.Ю., Чугунова Л.А., Умарова Х.Я., Ясманова А.Н., Чугунов А.В. Расстройства мозгового кровообращения у больных сахарным диабетом. Лечебное дело. 2005;3:67-73.Семенова И.В. Клинико-диагностические особенности ранних когнитивных расстройств у больных сахарным диабетом 2 типа с хронической ишемией головного мозга: Автореф. дисс. ... канд. мед. наук. М.; 2009.Erus G, Battapady H, Zhang T, Lovato J, Miller ME, Williamson JD, Launer LJ, Bryan RN, Davatzikos Ch. Spatial Patterns of Structural Brain Changes in Type 2 Diabetic Patients and Their Longitudinal Progression With Intensive Control of Blood Glucose. Diabetes Care. 2015;38:97-104. doi:10.2337/dc14-1196Tong J, Geng H, Zhang Z, Zhu X, Meng Q, Sun X, Zhang M., Qian R, Sun L, Liang Q. Brain metabolite alterations demonstrated by proton magnetic resonance spectroscopy in diabetic patients with retinopathy. Magn Reson Imaging. 2014;32:1037-1042. doi:10.1016/j.mri.2014.04.020Mazaika PK, Weinzimer SA, Mauras N, Buckingham B, White NH, Tsalikian E, Hershey T, Cato A, Aye T, Fox L, Wilson DM, Tansey M, Tamborlane W, Peng D, Raman M, Marzelli M, Reiss AL. Diabetes Research in Children Network (DirecNet). Variations in brain volume and growth in young children with type 1 diabetes. Diabetes. 2016;65:476-485. doi:10.2337/db15-1242Malone JI, Hanna S, Saporta S, Mervis RF, Park CR, Chong L, Diamond DM. Hyperglycemia not hypoglycemia alters neuronal dendrites and impairs spatial memory. Pediatric Diabetes. 2008;9:531-539.McLaurin J, Franklin T, Chakrabartty A, Fraser PE. Phosphatidylinositol and inositol involvement in Alzheimer amyloid-beta fibril growth and arrest. J Mol Biol. 1998;278:183-194.Malone JI. Diabetic Central Neuropathy: CNS Damage Related to Hyperglycemia. Diabetes. 2016;65:355-357. doi:10.2337/dbi15-0034Malone JI, Hanna S, Saporta S, Mervis RF, Park CR, Chong L, Diamond DM. Hyperglycemia NOT hypoglycemia alters neuronal dendrites and impairs spatial memory. Pediatric Diabetes. 2008;9:531-539.Zhang Z, Lovato J, Battapady H, Davatzikos Ch, Gerstein HC, Ismail-Beigi F, Launer LJ, Murray A, Punthakee Z, Tirado AA, Williamson J, Bryan RN, Miller ME. Effect of Hypoglycemia on Brain Structure in People With Type 2 Diabetes: Epidemiological Analysis of the ACCORD-MIND MRI Trial Diabetes Care. 2014;37:3279-3285. doi:10.2337/dc14-0973Northamand E, Cameron FJ. Understanding the diabetes brain: New Technologies but Old Challenges. Diabetes. 2013;62:341-342. doi:10.2337/db12-1181Russo VC, Higgins S, Werther GA, Cameron FJ. Effects of fluctuating glucose levels on neuronal cells in vitro. Neurochem Res. 2012;37:1768-1782. doi:10.1007/s11064-012-0789-yBenedict C, Frey WH 2nd, Schiöth HB, Schultes B, Born J, Hallschmid M. Intranasal insulin as a therapeutic option in the treatment of cognitive impairments. Exp Gerontol. 2011;46:112-115. doi:10.1016/j.exgerVincent A. Stiff, twitchy or wobbly: are GAD antibodies pathogenic? Brain 2008;131:2536-2537. doi:10.1093/brain/awn221Dahlquist G, Källén B. School marks for Swedish children whose mothers had diabetes during pregnancy: a population-based study. Diabetologia. 2007;50:1826-1831.De Felice FG, Benedict Ch. A Key Role of Insulin Receptors in Memory. Diabetes. 2015;64:3653-3655. doi:10.2337/dbi15-0011Porte D Jr, Baskin DG, Schwartz MW. Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes. 2005;54:1264-1276.Freiherr J, Hallschmid M, Frey WH 2nd, Brünner YF, Chapman CD, Hölscher C, Craft S, De Felice FG, Benedict C. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs. 2013;27:505-514. doi:10.1007/s40263-013-0076-8Hallschmid M., Shultes B. Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders? Diabetologia. 2009;52:2264-2269. doi:10.1007/s00125-009-1501-xGray SM, Meijer RI, Barrett EJ. Insulin Regulates Brain Function, but How Does It Get There? Diabetes. 2014;63:3992-3997. doi:10.2337/db14-0340Hoyer S, Nitsch R. Cerebral excess release of neurotransmitter amino acids subsequent to reduced cere- bral glucose metabolism in early-onset dementia of Alzheimer type. J. Neural Transm. 1989;75:227-232.Hoyer S. Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update. Exp Gerontol. 2000;35:1363-1372.Hoyer S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol. 2004;490:115-125.Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease — is this type 3 diabetes? J Alzheimers Dis. 2005;7:63-80.Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis. 2005;8:247-268.Benedict C, Dodt C, Hallschmid M, Lepiorz M, Fehm HL, Born J, Kern W. Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings. Metabolism. 2005;54:1356-1361.Benedict C, Kern W, Schultes B, Born J, Hallschmid M. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab. 2008;93:1339-1344. doi:10.1210/jc.2007-2606Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012;69:29-38. doi:10.1001/archneurol.2011.233Hallschmid M, Benedict C, Schultes B, Perras B, Fehm HL, Kern W, Born J. Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders. Regul Pept. 2008;149:79-83. doi:10.1016/j.regpep.2007.06.012Thorne RG, Pronk GJ, Padmanabhan V, Frey WH 2nd. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience. 2004;127:481-496.Hanson LR, Frey WH 2nd. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2008;9(3):S5. doi:10.1186/1471-2202-9-S3-S5Novak V, Milberg W,Hao Y, Munshi M, Novak P,Galica A,Manor B, Roberson P, Craft S,Abduljalil A.Enhancement of Vasoreactivity and Cognition by Intranasal Insulin in Type 2 Diabetes. Diabetes Care. 2014;37:751-759. doi:10.2337/dc13-1672Zhang H,Hao Y,Manor B,Novak P,Milberg W,Zhang J,Fang J,Novak V.Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes. Diabetes. 2015;64:1025-1034. doi:10.2337/db14-1000Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey Ii WH, Craft S. Intranasal Insulin Administration Dose-Dependently Modulates Verbal Memory and Plasma Amyloid-beta in Memory-Impaired Older Adults. J Alzheimer Dis. 2008;13:323-331.