Pathogenetic Role of Disorders of Insulin Signaling Pathways and Diabetes-Associated Hyperglycemia in the Mechanisms of Diabetic Encephalopathy Formation and Hypersensitivity of the Brain to Ischemia-Reperfusion
Abstract
The aim of the study was to analyze the literature data regarding the pathogenetic role of insulin signaling disorders and diabetes-associated hyperglycemia in the mechanisms of diabetic encephalopathy and hypersensitivity of the brain to ischemia-reperfusion.
Conclusion. Analysis of the literature data shows a number of common links between the pathogenesis of diabetic encephalopathy and ischemic-reperfusion brain injury, which may, to some extent, explain the predisposition of diabetics to acute cerebral circulatory disorders and their adverse course. However, it is clear that the severity of such comorbid pathology cannot be explained only by the additive effect of individual links in the pathogenesis, which indicates the necessity for further in-depth study of its molecular-genetic aspects.
References
IDF Diabetes Atlas. 7th ed. [Internet]. Brussels; 2015 [cited 2017 Jul 9]. 144 р. Available from: http://www.oedg.at/pdf/1606_IDF_Atlas_2015_UK.pdf.
Standards of medical care in diabetes-2016: Summary of revisions. Diabetes Care. 2016 Jan;39(1):4-5. Available from: https://doi.org/10.2337/dc16-S003
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006 Nov; 3(11):e442. Available from: https://doi.org/10.1371/journal.pmed.0030442
Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocrinol Metab. 2016 Jul-Aug; 20(4): 546-551. Available from: https://doi.org/10.4103/2230-8210.183480
Yamagishi S, Nakamura N, Suematsu M, Kaseda K, Matsui T. Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes. Mol Med. 2015;21(1):32-40. Available from: https://doi.org/10.2119/molmed.2015.00067
Ji R, Schwamm LH, Pervez MA, Singhal AB. Ischemic stroke and transient ischemic attack in young adults: risk factors, diagnostic yield, neuroimaging, and thrombolysis. JAMA Neurol. 2013 Jan;70(1):51-57. Available from: https://doi.org/10.1001/jamaneurol.2013.575
Lackland DT, Roccella EJ, Deutsch AF, Fornage M, George MG, Howard G, et al. Factors influencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association. Stroke. 2014 Jan;45(1):315-353. Available from: https://doi.org/10.1161/01.str.0000437068.30550.cf
Maiese K. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR. Neural Regen Res. 2016 Mar;11(3):372-385. Available from: https://doi.org/10.4103/1673-5374.179032
Tanaka R, Ueno Y, Miyamoto N, Yamashiro K, Tanaka Y, Shimura H, et al. Impact of diabetes and prediabetes on the short-term prognosis in patients with acute ischemic stroke. J Neurol Sci. 2013 Sep 15;332(1-2):45-50. Available from: https://doi.org/10.1016/j.jns.2013.06.010
Lindley RI, Wardlaw JM, Whiteley WN, Cohen G, Blackwell L, Murray GD, et al. Alteplase for acute ischemic stroke: outcomes by clinically important subgroups in the Third International Stroke Trial. Stroke. 2015 Mar;46(3):746-56. Available from: https://doi.org/10.1161/STROKEAHA.114.006573
Khalid Al-Rubeaan, Fawaz Al-Hussain, Amira M. Youssef, Shazia N. Subhani, Ahmad H. Al-Sharqawi, Heba M. Ibrahim. Ischemic Stroke and Its Risk Factors in a Registry-Based Large Cross-Sectional Diabetic Cohort in a Country Facing a Diabetes Epidemic [Internet]. Journal of Diabetes Research. 2016 [cited 2017 Jul 9];2016. Available from: https://doi.org/10.1155/2016/4132589
Liao CC, Shih CC, Yeh CC, Chang YC, Hu CJ, Lin JG, et al. Impact of Diabetes on Stroke Risk and Outcomes: Two Nationwide Retrospective Cohort Studies. Medicine (Baltimore). 2015 Dec;94(52):e2282. Available from: https://doi.org/10.1097/MD.0000000000002282
Cardoso S, Santos RX, Correia SC, Carvalho C, Santos MS, Baldeiras I, et al. Insulin-induced recurrent hypoglycemia exacerbates diabetic brain mitochondrial dysfunction and oxidative imbalance. Neurobiol Dis. 2013 Jan;49:1-12. Available from: https://doi.org/10.1016/j.nbd.2012.08.008
Price TO, Sheibani N, Shah GN. Regulation of high glucose-induced apoptosis of brain pericytes by mitochondrial CA VA: A specific target for prevention of diabetic cerebrovascular pathology. Biochim Biophys Acta. 2017;1863(4):929-935. Available from: https://doi.org/10.1016/j.bbadis.2017.01.025
Lee SH, Zabolotny JM, Huang H, Lee H, Kim YB. Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood. Mol Metabol. 2016 Aug;5(8):589-601. Available from: https://doi.org/10.1016/j.molmet.2016.06.011
Magistretti PJ, Allaman I. A cellular perspective on brain energy metabolism and functional imaging. Neuron. 2015 May 20;86(4):883-901. Available from: https://doi.org/10.1016/j.neuron.2015.03.035
Soltesova D, Vesela A, Mravec B, Herichova I. Daily profile of glut1 and glut4 expression in tissues inside and outside the blood-Brain barrier in control and streptozotocin-treated rats. Physiol Res. 2013;62(1):115-124. Available from: https://doi.org/10.33549/physiolres.932596
Shah K, Desilva S, Abbruscato T. The role of glucose transporters in brain disease: diabetes and Alzheimer's Disease. Int J Mol Sci. 2012 Oct;13(10):12629-12655. Available from: https://doi.org/10.3390/ijms131012629
Andersen JV, Christensen SK, Nissen JD, Waagepetersen HS. Improved cerebral energetics and ketone body metabolism in db/db mice. J Cereb Blood Flow Metab. 2017 Mar;37(3):1137-1147. Available from: https://doi.org/10.1177/0271678X16684154
Newsholme P, Gaudel C, Krause M. Mitochondria and diabetes. An intriguing pathogenetic role. Adv Exp Med Biol. 2012; 942:235-247. Available from:
https://doi.org/10.1007/978-94-007-2869-1_10
Rehni AK, Nautiyal N, Perez-Pinzon MA, Dave KR. Hyperglycemia / hypoglycemia-induced mitochondrial dysfunction and cerebral ischemic damage in diabetics. Metab Brain Dis. 2015 Apr;30(2):437-447. Available from: https://doi.org/10.1007/s11011-014-9538-z
Cardoso S, Santos MS, Seiça R, Moreira PI. Cortical and hippocampal mitochondria bioenergetics and oxidative status during hyperglycemia and/or insulin-induced hypoglycemia. Biochim Biophys Acta. 2010 Nov;1802(11):942-951. Available from: https://doi.org/10.1016/j.bbadis.2010.07.001
Park J, Min JS, Kim B, Chae UB, Yun JW, Choi MS, et al. Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways. Neurosci Lett. 2015 Jan 1;584:191-196. Available from: https://doi.org/10.1016/j.neulet.2014.10.016
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010 Oct;107(9):1058-1070. Available from: https://doi.org/10.1161/CIRCRESAHA.110.223545
Moreira PI, Rolo AP, Sena C, Seiça R, Oliveira CR, Santos MS. Insulin attenuates diabetes-related mitochondrial alterations: a comparative study. Med Chem. 2006;2(3):299-308. Available from: https://doi.org/10.2174/157340606776930754
Crofts AR, Hong S, Wilson C, Burton R, Victoria D, Harrison C, et al. The mechanism of ubihydroquinone oxidation at the Qo-site of the cytochrome bc1 complex. Biochim Biophys Acta. 2013 Nov-Dec;1827(11-12):1362-377. Available from: https://doi.org/10.1016/j.bbabio.2013.01.009
Perez-Gallardo RV, Noriega-Cisneros R, Esquivel-Gutierrez E, Calderon-Cortes E, Cortes-Rojo C, Manzo-Avalos S, et al. Effects of diabetes on oxidative and nitrosative stress in kidney mitochondria from aged rats. J Bioenerg Biomembr. 2014 Dec;46(6):511-518. Available from: https://doi.org/10.1007/s10863-014-9594-4
Wu J, Jin Z, Zheng H, Yan LJ. Sources and implications of NADH/NAD+ redox imbalance in diabetes and its complications. Diabetes Metab Syndr Obes. 2016 May 10;9:145-153. Available from: https://doi.org/10.2147/DMSO.S106087
Prakash R, Somanath PR, El-Remessy AB, Kelly-Cobbs A, Stern JE, Dore-Duffy P, et al. Enhanced cerebral but not peripheral angiogenesis in the Goto-Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling. Diabetes. 2012 Jun;61:1533-1542. Available from: https://doi.org/10.2337/db11-1528
Ceretta LB, Réus GZ, Abelaira HM, Ribeiro KF, Zappellini G, Felisbino FF, et al. Increased oxidative stress and imbalance in antioxidant enzymes in the brains of alloxan-induced diabetic rats. Exp Diabetes Res. 2012;2012:302682. Available from: https://doi.org/10.1155/2012/302682
Zheng H, Wu J, Jin Z, Yan LJ. Protein Modifications as Manifestations of Hyperglycemic Glucotoxicity in Diabetes and Its Complications. Biochem Insights. 2016 Mar:9:1-9. Available from: https://doi.org/10.4137/BCI.S36141
Chilelli NC, Burlina S, Lapolla A. AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: a "glycoxidation-centric" point of view. Nutr Metab Cardiovasc Dis. 2013 Oct;23(10):913-919. Available from: https://doi.org/10.1016/j.numecd.2013.04.004
Luo X, Wu J, Jing S, Yan LJ. Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity. Aging Dis. 2016 Jan;7(1):90-110. Available from: https://doi.org/10.14336/AD.2015.0702
Vahabzadeh G, Ebrahimi SA, Rahbar-Roshandel N, Mahmoudian M. The Effect of Noscapine on Oxygen-Glucose Deprivation on Primary Murine Cortical Neurons in High Glucose Condition. Iran J Pharm Res. 2016;15(2):501-512.
Stanika RI, Villanueva I, Kazanina G, Andrews SB, Pivovarova NB. Comparative impact of voltage-gated calcium channels and NMDA receptors on mitochondria-mediated neuronal injury. J Neurosci. 2012 May 9;32(19):6642-6650. Available from: https://doi.org/10.1523/JNEUROSCI.6008-11.2012
Chen J, Li Z, Hatcher JT, Chen QH, Chen L, Wurster RD, et al. Deletion of TRPC6 Attenuates NMDA Receptor-Mediated Ca2+ Entry and Ca2+-Induced Neurotoxicity Following Cerebral Ischemia and Oxygen-Glucose Deprivation. Front Neurosci. 2017 Mar 28;11:138. Available from: https://doi.org/10.3389/fnins.2017.00138
Hou J, Chong ZZ, Shang YC, Maiese K. FoxO3a governs early and late apoptotic endothelial programs during elevated glucose through mitochondrial and caspase signaling. Mol Cell Endocrinol. 2010 Jun;321(2):194-206. Available from: https://doi.org/10.1016/j.mce.2010.02.037
Rizzuto R, De Stefani D, Raffaello A, Mammucari C. Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol. 2012 Sept;13(9):566-578. Available from: https://doi.org/10.1038/nrm3412
MacAskill AF, Atkin TA, Kittler JT. Mitochondrial trafficking and the provision of energy and calcium buffering at excitatory synapses. Eur J Neurosci. 2010 Jul;32(2):231-240. Available from: https://doi.org/10.1111/j.1460-9568.2010.07345.x
Pekun TG, Lemeshchenko VV, Lyskova TI, Waseem TV, Fedorovich SV. Influence of intra- and extracellular acidification on free radical formation and mitochondria membrane potential in rat brain synaptosomes. J Mol Neurosci. 2013 Jan;49(1):211-222. Available from: https://doi.org/10.1007/s12031-012-9913-3
Chassagnon IR, McCarthy CA, Chin YK, Pineda SS, Keramidas A, Mobli M, et al. Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a. Proc Natl Acad Sci U S A. 2017 Apr;114(14):3750-3755. Available from: https://doi.org/10.1073/pnas.1614728114
Wang YZ, Zeng WZ, Xiao X, Huang Y, Song XL, Yu Z, et al. Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death. Cell Death Differ. 2013 Oct;20(10):1359-1369. Available from: https://doi.org/10.1038/cdd.2013.90
Gao S, Yu Y, Ma ZY, Sun H, Zhang YL, Wang XT, et al. NMDAR-Mediated Hippocampal Neuronal Death is Exacerbated by Activities of ASIC1a. Neurotox Res. 2015 Aug;28(2):122-137. Available from: https://doi.org/10.1007/s12640-015-9530-3
Rose KL, Watson AJ, Drysdale TA, Cepinskas G, Chan M, Rupar CA, et al. Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport. Am J Physiol Endocrinol Metab. 2015 Aug;309(4):370-379. Available from: https://doi.org/10.1152/ajpendo.00107.2015
Zeng WZ, Liu DS, Duan B, Song XL, Wang X, Wei D, et al. Molecular mechanism of constitutive endocytosis of Acid-sensing ion channel 1a and its protective function in acidosis-induced neuronal death. J Neurosci. 2013 Apr;33(16):7066-7078. Available from: https://doi.org/10.1523/JNEUROSCI.5206-12.2013
Yin F, Boveris A, Cadenas E. Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid Redox Signal. 2014 Jan;20(2):353-371. Available from: https://doi.org/10.1089/ars.2012.4774
Rasola A, Bernardi P. Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. Cell Calcium. 2011 Sep;50(3):222-233. Available from: https://doi.org/10.1016/j.ceca.2011.04.007
Lee GH, Lee HY, Li B, Kim HR, Chae HJ. Bax inhibitor-1-mediated inhibition of mitochondrial Ca2+ intake regulates mitochondrial permeability transition pore opening and cell death. Sci Rep. 2014 Jun;4:5194. Available from: https://doi.org/10.1038/srep05194
Chen Q, Xu H, Xu A, Ross T, Bowler E, Hu Y, et al. Inhibition of Bcl-2 sensitizes mitochondrial permeability transition pore (MPTP) opening in ischemia-damaged mitochondria. PLoS One. 2015 Mar;10(3):0118834. https://doi.org/10.1371/journal.pone.0118834
Weinberg E, Maymon T, Weinreb M. AGEs induce caspase-mediated apoptosis of rat BMSCs via TNFalpha production and oxidative stress. J Mol Endocrinol. 2014 Jan;52(1):67-76. Available from: https://doi.org/10.1530/JME-13-0229
Hu S, Wang D, Zhang J, Du M, Cheng Y, Liu Y, et al. Mitochondria Related Pathway Is Essential for Polysaccharides Purified from Sparassis crispa Mediated Neuro-Protection against Glutamate-Induced Toxicity in Differentiated PC12 Cells. Int J Mol Sci. 2016 Jan;17(2):133. Available from: https://doi.org/10.3390/ijms17020133
Shukla V, Shakya AK, Perez-Pinzon MA, Dave KR. Cerebral ischemic damage in diabetes: an inflammatory perspective. J Neuroinflammation. 2017 Jan 23;14(1):21. Available from: https://doi.org/10.1186/s12974-016-0774-5
Zhou XY, Luo Y, Zhu YM, Liu ZH, Kent TA, Rong JG, et al. Inhibition of autophagy blocks cathepsins-tBid-mitochondrial apoptotic signaling pathway via stabilization of lysosomal membrane in ischemic astrocytes. Cell Death Dis. 2017 Feb;8(2):2618. Available from: https://doi.org/10.1038/cddis.2017.34
Chen J, Jing J, Yu S, Song M, Tan H, Cui B, et al. Advanced glycation endproducts induce apoptosis of endothelial progenitor cells by activating receptor RAGE and NADPH oxidase/JNK signaling axis. Am J Transl Res. 2016 May;8(5):2169-2178.
Tai TY, Warner LN, Jones TD, Jung S, Concepcion FA, Skyrud DW, et al. Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition in an animal model of temporal lobe epilepsy. Neuroscience. 2017 May 4;349:35-47. Available from: https://doi.org/10.1016/j.neuroscience.2017.02.024
Li L, Xiao L, Hou Y, He Q, Zhu J, Li Y, et al. Sestrin2 Silencing Exacerbates Cerebral Ischemia/Reperfusion Injury by Decreasing Mitochondrial Biogenesis through the AMPK/PGC-1α Pathway in Rats. Sci Rep. 2016 Jul;6:30272. Available from: https://doi.org/10.1038/srep30272
Rehni AK, Liu A, Perez-Pinzon MA, Dave KR. Diabetic aggravation of stroke and animal models. Exp Neurol. 2017 Jun;292:63-79. Available from: https://doi.org/10.1016/j.expneurol.2017.03.004
Hei C, Liu P, Yang X, Niu J, Li PA. Inhibition of mTOR signaling Confers Protection against Cerebral Ischemic Injury in Acute Hyperglycemic Rats. Int J Biol Sci. 2017 Jul;13(7):878-887. Available from: https://doi.org/10.7150/ijbs.18976
Correia SC, Santos RX, Carvalho C, Cardoso S, Candeias E, Santos MS, et al. Insulin signaling, glucose metabolism and mitochondria: major players in Alzheimer's disease and diabetes interrelation. Brain Res. 2012 Mar 2;1441:64-78. Available from: https://doi.org/10.1016/j.brainres.2011.12.063
Hong S, Agresta L, Guo C, Wiley JW. The TRPV1 receptor is associated with preferential stress in large dorsal root ganglion neurons in early diabetic sensory neuropathy. J Neurochem. 2008 May;105(4):1212-1222. Available from: https://doi.org/10.1111/j.1471-4159.2008.05220.x
Brooks C, Cho SG, Wang CY, Yang T, Dong Z. Fragmented mitochondria are sensitized to Bax insertion and activation during apoptosis. Am J Physiol Cell Physiol. 2011 Mar;300(3):447-455. Available from: https://doi.org/10.1152/ajpcell.00402.2010
Copyright (c) 2022 Svitlana Tkachuk, Oleksiy Tkachuk, Olha Nika, Yuliya Hodovanets

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).