Inside the Diabetic Brain: Role of Different Players Involved in Cognitive Decline
Abstract

Diabetes mellitus is the most common metabolic disease, and its prevalence is increasing. A growing body of evidence, both in animal models and epidemiological studies, has demonstrated that metabolic diseases like obesity, insulin resistance, and diabetes are associated with alterations in the central nervous system (CNS), being linked with development of cognitive and memory impairments and presenting a higher risk for dementia and Alzheimer’s disease. The rising prevalence of diabetes together with its increasing earlier onset suggests that diabetes-related cognitive dysfunction will increase in the near future, causing substantial socioeconomic impact. Decreased insulin secretion or action, dysregulation of glucose homeostasis, impairment in the hypothalamic–pituitary–adrenal axis, obesity, hyperleptinemia, and inflammation may act independently or synergistically to disrupt neuronal homeostasis and cause diabetes-associated cognitive decline. However, the crosstalk between those factors and the mechanisms underlying the diabetes-related CNS complications is still elusive. During the past few years, different strategies (neuroprotective and antioxidant drugs) have emerged as promising therapies for this complication, which still remains to be preventable or treatable. This Review summarizes fundamental past and ongoing research on diabetes-associated cognitive decline, highlighting potential contributors, mechanistic mediators, and new pharmacological approaches to prevent and/or delay this complication.
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- Chun Wang, Juan Li, Shidi Zhao, Li Huang. Diabetic encephalopathy causes the imbalance of neural activities between hippocampal glutamatergic neurons and GABAergic neurons in mice. Brain Research 2020, 1742 , 146863. https://doi.org/10.1016/j.brainres.2020.146863
- Ranyao Yang, Xue Jiang, Xiqian He, Donglou Liang, Shusen Sun, Guangyan Zhou. Ginsenoside Rb1 Improves Cognitive Impairment Induced by Insulin Resistance through Cdk5/p35-NMDAR-IDE Pathway. BioMed Research International 2020, 2020 , 1-9. https://doi.org/10.1155/2020/3905719
- Ari B. Cuperfain, James L. Kennedy, Vanessa F. Gonçalves. Overlapping mechanisms linking insulin resistance with cognition and neuroprogression in bipolar disorder. Neuroscience & Biobehavioral Reviews 2020, 111 , 125-134. https://doi.org/10.1016/j.neubiorev.2020.01.022
- Alba M. Garcia-Serrano, João M. N. Duarte. Brain Metabolism Alterations in Type 2 Diabetes: What Did We Learn From Diet-Induced Diabetes Models?. Frontiers in Neuroscience 2020, 14 https://doi.org/10.3389/fnins.2020.00229
- Si Shi, Hua‐Jing Yin, Jiang Li, Ling Wang, Wei‐Ping Wang, Xiao‐Liang Wang. Studies of pathology and pharmacology of diabetic encephalopathy with KK‐Ay mouse model. CNS Neuroscience & Therapeutics 2020, 26 (3) , 332-342. https://doi.org/10.1111/cns.13201
- Qing-Qing Zhang, Wen-Shan Li, Zhou Liu, Hui-Li Zhang, Ying-Gui Ba, Rui-Xia Zhang. Metformin therapy and cognitive dysfunction in patients with type 2 diabetes. Medicine 2020, 99 (10) , e19378. https://doi.org/10.1097/MD.0000000000019378
- Fengwei Nan, Guibo Sun, Weijie Xie, Tianyuan Ye, Xiao Sun, Ping Zhou, Xi Dong, Jiafu Sun, Xiaobo Sun, Mengren Zhang. Ginsenoside Rb1 mitigates oxidative stress and apoptosis induced by methylglyoxal in SH-SY5Y cells via the PI3K/Akt pathway. Molecular and Cellular Probes 2019, 48 , 101469. https://doi.org/10.1016/j.mcp.2019.101469
- Wenhui Yan, Meng Zhang, Ye Yu, Xinyao Yi, Tingli Guo, Hao Hu, Qiang Sun, Mingxia Chen, Huangui Xiong, Lina Chen. Blockade of voltage-gated potassium channels ameliorates diabetes-associated cognitive dysfunction in vivo and in vitro. Experimental Neurology 2019, 320 , 112988. https://doi.org/10.1016/j.expneurol.2019.112988
- Hongyan Lin, Yang Yuan, Sai Tian, Jing Han, Rong Huang, Dan Guo, Jiaqi Wang, Ke An, Shaohua Wang. In Addition to Poor Glycemic Control, a High Level of Irisin in the Plasma Portends Early Cognitive Deficits Clinically in Chinese Patients With Type 2 Diabetes Mellitus. Frontiers in Endocrinology 2019, 10 https://doi.org/10.3389/fendo.2019.00634
- Wenhui Yan, Miao Pang, Ye Yu, Xilan Gou, Peiru Si, Alina Zhawatibai, Yutong Zhang, Meng Zhang, Tingli Guo, Xinyao Yi, Lina Chen. The neuroprotection of liraglutide on diabetic cognitive deficits is associated with improved hippocampal synapses and inhibited neuronal apoptosis. Life Sciences 2019, 231 , 116566. https://doi.org/10.1016/j.lfs.2019.116566
- Silvia Giatti, Silvia Diviccaro, Roberto Cosimo Melcangi. Neuroactive Steroids and Sex-Dimorphic Nervous Damage Induced by Diabetes Mellitus. Cellular and Molecular Neurobiology 2019, 39 (4) , 493-502. https://doi.org/10.1007/s10571-018-0613-6
- Douglas A. Formolo, Joana M. Gaspar, Hiago M. Melo, Tuany Eichwald, Ramiro Javier Zepeda, Alexandra Latini, Michael S. Okun, Roger Walz. Deep Brain Stimulation for Obesity: A Review and Future Directions. Frontiers in Neuroscience 2019, 13 https://doi.org/10.3389/fnins.2019.00323
- Alejandra Aketzalli Flores-Gómez, Ma. de Jesús Gomez-Villalobos, Gonzalo Flores. Consequences of diabetes mellitus on neuronal connectivity in limbic regions. Synapse 2019, 73 (3) , e22082. https://doi.org/10.1002/syn.22082
- Amanda Nunes Santiago, Marco Aurélio Mori, Francisco Silveira Guimarães, Humberto Milani, Rúbia Maria Weffort de Oliveira. Effects of Cannabidiol on Diabetes Outcomes and Chronic Cerebral Hypoperfusion Comorbidities in Middle-Aged Rats. Neurotoxicity Research 2019, 35 (2) , 463-474. https://doi.org/10.1007/s12640-018-9972-5
- Anup Bhusal, Md Habibur Rahman, In-Kyu Lee, Kyoungho Suk. Role of Hippocampal Lipocalin-2 in Experimental Diabetic Encephalopathy. Frontiers in Endocrinology 2019, 10 https://doi.org/10.3389/fendo.2019.00025
- Suzanne M. de la Monte. The Full Spectrum of Alzheimer’s Disease Is Rooted in Metabolic Derangements That Drive Type 3 Diabetes. 2019,,, 45-83. https://doi.org/10.1007/978-981-13-3540-2_4
- Cristobal L. Miranda, Lance A. Johnson, Oriane de Montgolfier, Valerie D. Elias, Lea S. Ullrich, Joshua J. Hay, Ines L. Paraiso, Jaewoo Choi, Ralph L. Reed, Johana S. Revel, Chrissa Kioussi, Gerd Bobe, Urszula T. Iwaniec, Russell T. Turner, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Paul R. Blakemore, Adrian F. Gombart, Claudia S. Maier, Jacob Raber, Jan F. Stevens. Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice. Scientific Reports 2018, 8 (1) https://doi.org/10.1038/s41598-017-18992-6
- Joana M. Gaspar, Lício A. Velloso. Hypoxia Inducible Factor as a Central Regulator of Metabolism – Implications for the Development of Obesity. Frontiers in Neuroscience 2018, 12 https://doi.org/10.3389/fnins.2018.00813
- Jens Bohlken, Louis Jacob, Karel Kostev. Association Between the Use of Antihyperglycemic Drugs and Dementia Risk: A Case-Control Study. Journal of Alzheimer's Disease 2018, 66 (2) , 725-732. https://doi.org/10.3233/JAD-180808
- Tanya J. W. McDonald, Mackenzie C. Cervenka. Ketogenic Diets for Adult Neurological Disorders. Neurotherapeutics 2018, 15 (4) , 1018-1031. https://doi.org/10.1007/s13311-018-0666-8
- Rashad Hussain, Hira Zubair, Sarah Pursell, Muhammad Shahab. Neurodegenerative Diseases: Regenerative Mechanisms and Novel Therapeutic Approaches. Brain Sciences 2018, 8 (9) , 177. https://doi.org/10.3390/brainsci8090177
- Tanya McDonald, Mackenzie Cervenka. The Expanding Role of Ketogenic Diets in Adult Neurological Disorders. Brain Sciences 2018, 8 (8) , 148. https://doi.org/10.3390/brainsci8080148
- Yonghao Feng, Aiqun Chu, Qiong Luo, Men Wu, Xiaohong Shi, Yinghui Chen. The Protective Effect of Astaxanthin on Cognitive Function via Inhibition of Oxidative Stress and Inflammation in the Brains of Chronic T2DM Rats. Frontiers in Pharmacology 2018, 9 https://doi.org/10.3389/fphar.2018.00748
- Shreyasi Chatterjee, Amritpal Mudher. Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits. Frontiers in Neuroscience 2018, 12 https://doi.org/10.3389/fnins.2018.00383
- S. Giatti, R. Mastrangelo, M. D'Antonio, M. Pesaresi, S. Romano, S. Diviccaro, D. Caruso, N. Mitro, R.C. Melcangi. Neuroactive steroids and diabetic complications in the nervous system. Frontiers in Neuroendocrinology 2018, 48 , 58-69. https://doi.org/10.1016/j.yfrne.2017.07.006
- Wei Yu, Wenliang Zha, Jun Ren. Exendin-4 and Liraglutide Attenuate Glucose Toxicity-Induced Cardiac Injury through mTOR/ULK1-Dependent Autophagy. Oxidative Medicine and Cellular Longevity 2018, 2018 , 1-14. https://doi.org/10.1155/2018/5396806
- Hee Jae Lee, Hye In Seo, Hee Yun Cha, Yun Jung Yang, Soo Hyun Kwon, Soo Jin Yang. Diabetes and Alzheimer's Disease: Mechanisms and Nutritional Aspects. Clinical Nutrition Research 2018, 7 (4) , 229. https://doi.org/10.7762/cnr.2018.7.4.229
- M.R.P. Markus, T. Ittermann, K. Wittfeld, S. Schipf, U. Siewert-Markus, M. Bahls, R. Bülow, N. Werner, D. Janowitz, S.E. Baumeister, S.B. Felix, M. Dörr, W. Rathmann, H. Völzke, H.J. Grabe. Prediabetes is associated with lower brain gray matter volume in the general population. The Study of Health in Pomerania (SHIP). Nutrition, Metabolism and Cardiovascular Diseases 2017, 27 (12) , 1114-1122. https://doi.org/10.1016/j.numecd.2017.10.007
- Anne Fink, Britta Haenisch. Oral antidiabetic drugs and dementia risk. Neurology 2017, 89 (18) , 1848-1849. https://doi.org/10.1212/WNL.0000000000004613
- Ariela R. Orkaby, Kelly Cho, Jean Cormack, David R. Gagnon, Jane A. Driver. Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes. Neurology 2017, 89 (18) , 1877-1885. https://doi.org/10.1212/WNL.0000000000004586
- N.A. Mohamed, H.S. Abdel Gawad. Taurine dietary supplementation attenuates brain, thyroid, testicular disturbances and oxidative stress in streptozotocin-induced diabetes mellitus in male rats. Beni-Suef University Journal of Basic and Applied Sciences 2017, 6 (3) , 247-252. https://doi.org/10.1016/j.bjbas.2017.04.006
- Peng-Fei Zhao, Zai-Qun Liu. 2-Isocyano glucose used in Ugi four-component reaction: An approach to enhance inhibitory effect against DNA oxidation. European Journal of Medicinal Chemistry 2017, 135 , 458-466. https://doi.org/10.1016/j.ejmech.2017.04.041
- Wei-Sheng Lin, Jung-Hsin Lo, Jo-Hsuan Yang, Hao-Wei Wang, Shou-Zen Fan, Jui-Hung Yen, Pei-Yu Wang. Ludwigia octovalvis extract improves glycemic control and memory performance in diabetic mice. Journal of Ethnopharmacology 2017, 207 , 211-219. https://doi.org/10.1016/j.jep.2017.06.044
- Shun-Chang Fang, Hang Xie, Fang Chen, Mei Hu, Yan Long, Hong-Bin Sun, Ling-Yi Kong, Hao Hong, Su-Su Tang. Simvastatin ameliorates memory impairment and neurotoxicity in streptozotocin-induced diabetic mice. Neuroscience 2017, 355 , 200-211. https://doi.org/10.1016/j.neuroscience.2017.05.001
- Fahim Atif, Megan C. Prunty, Nefize Turan, Donald G. Stein, Seema Yousuf. Progesterone modulates diabetes/hyperglycemia-induced changes in the central nervous system and sciatic nerve. Neuroscience 2017, 350 , 1-12. https://doi.org/10.1016/j.neuroscience.2017.03.007
- Xiaoxu Sun, Shanshan Li, Lixing Xu, Hao Wang, Zhanqiang Ma, Qiang Fu, Rong Qu, Shiping Ma. Paeoniflorin ameliorates cognitive dysfunction via regulating SOCS2/IRS-1 pathway in diabetic rats. Physiology & Behavior 2017, 174 , 162-169. https://doi.org/10.1016/j.physbeh.2017.03.020
- ZhongJie Liu, ChangQing Ma, Wei Zhao, QingGuo Zhang, Rui Xu, HongFei Zhang, HongYi Lei, ShiYuan Xu. High Glucose Enhances Isoflurane-Induced Neurotoxicity by Regulating TRPC-Dependent Calcium Influx. Neurochemical Research 2017, 42 (4) , 1165-1178. https://doi.org/10.1007/s11064-016-2152-1
- Ming-Min Chung, Christopher J. Nicol, Yi-Chuan Cheng, Kuan-Hung Lin, Yen-Lin Chen, Dee Pei, Chien-Hung Lin, Yi-Nuo Shih, Chia-Hui Yen, Shiang-Jiuun Chen, Rong-Nan Huang, Ming-Chang Chiang. Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs. Experimental Cell Research 2017, 352 (1) , 75-83. https://doi.org/10.1016/j.yexcr.2017.01.017
- Suzanne M. de la Monte. Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease. Drugs 2017, 77 (1) , 47-65. https://doi.org/10.1007/s40265-016-0674-0
- Mariia Matveeva, Julia Samoylova, Natalia Zhukova, Oxana Oleynik, Mariya Rotkank. Perspectives for cognitive rehabilitation of patients with diabetes mellitus. Obesity and metabolism 2016, 13 (4) , 3-7. https://doi.org/10.14341/omet201643-7
- Siamak Ahshin-Majd, Samira Zamani, Taktom Kiamari, Zahra Kiasalari, Tourandokht Baluchnejadmojarad, Mehrdad Roghani. Carnosine ameliorates cognitive deficits in streptozotocin-induced diabetic rats: Possible involved mechanisms. Peptides 2016, 86 , 102-111. https://doi.org/10.1016/j.peptides.2016.10.008
- Dajue Wang. Global Action against Dementia Call for Innovations. Translational Neuroscience and Clinics 2016, 2 (4) , 260-274. https://doi.org/10.18679/CN11-6030_R.2016.037
- Lindsay A. Zilliox, Krish Chadrasekaran, Justin Y. Kwan, James W. Russell. Diabetes and Cognitive Impairment. Current Diabetes Reports 2016, 16 (9) https://doi.org/10.1007/s11892-016-0775-x



