Translational Stroke Research

, Volume 10, Issue 1, pp 78–90 | Cite as

Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Diabetic Rats via Enhanced Post-Ischemic Mitochondrial Dysfunction

  • Vibha Shukla
  • Perry Fuchs
  • Allen Liu
  • Charles H. Cohan
  • Chuanhui Dong
  • Clinton B. Wright
  • Miguel A. Perez-Pinzon
  • Kunjan R. DaveEmail author
Original Article


Diabetes significantly increases the risk of stroke and post-stroke mortality. Recurrent hypoglycemia (RH) is common among diabetes patients owing to glucose-lowering therapies. Earlier, we showed that RH in a rat model of insulin-dependent diabetes exacerbates cerebral ischemic damage. Impaired mitochondrial function has been implicated as a central player in the development of cerebral ischemic damage. Hypoglycemia is also known to affect mitochondrial functioning. The present study tested the hypothesis that prior exposure of insulin-treated diabetic (ITD) rats to RH exacerbates brain damage via enhanced post-ischemic mitochondrial dysfunction. In a rat model of streptozotocin-induced diabetes, we evaluated post-ischemic mitochondrial function in RH-exposed ITD rats. Rats were exposed to five episodes of moderate hypoglycemia prior to the induction of cerebral ischemia. We also evaluated the impact of RH, both alone and in combination with cerebral ischemia, on cognitive function using the Barnes circular platform maze test. We observed that RH exposure to ITD rats leads to increased cerebral ischemic damage and decreased mitochondrial complex I activity. Exposure of ITD rats to RH impaired spatial learning and memory. Our results demonstrate that RH exposure to ITD rats potentially increases post-ischemic damage via enhanced post-ischemic mitochondrial dysfunction.


Ischemic damage Mitochondria Hippocampus Barnes maze test Open field Type 1 diabetes 



cornus ammonis


electron transport chain


insulin-treated diabetic


mitochondrial membrane potential


mitochondrial permeability transition pores


recurrent hypoglycemia


reactive oxygen species






type 1 diabetes


type 2 diabetes


tumor necrosis factor α



We would like to thank Dr. Brant Watson for critical reading of this manuscript.

Funding Information

The present study is supported by NIH grant NS073779 and the Evelyn F. McKnight Brain Institute. The funding agency had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the article for publication.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

All animal experiments were carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and were approved by an institutional animal care and use committee.

Supplementary material

12975_2018_622_MOESM1_ESM.pdf (119 kb)
ESM 1 (PDF 119 kb)


  1. 1.
    Amador-Alvarado L, Montiel T, Massieu L. Differential production of reactive oxygen species in distinct brain regions of hypoglycemic mice. Metab Brain Dis. 2014;29:711–9.PubMedGoogle Scholar
  2. 2.
    American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care. 2011;34(Suppl 1):S11–61.PubMedCentralGoogle Scholar
  3. 3.
    Anderson MF, Sims NR. Mitochondrial respiratory function and cell death in focal cerebral ischemia. J Neurochem. 1999;73:1189–99.PubMedGoogle Scholar
  4. 4.
    Baregamian N, Song J, Bailey CE, Papaconstantinou J, Evers BM, Chung DH. Tumor necrosis factor-alpha and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy, and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis. Oxidative Med Cell Longev. 2009;2:297–306.Google Scholar
  5. 5.
    Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, et al. Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke. 1997;28:1233–44.PubMedGoogle Scholar
  6. 6.
    Barrientos A, Moraes CT. Titrating the effects of mitochondrial complex I impairment in the cell physiology. J Biol Chem. 1999;274:16188–97.PubMedGoogle Scholar
  7. 7.
    Beckman, J., Libby, P., Creager, M., Diabetes mellitus, the metabolic syndrome, and atherosclerotic vascular disease, 2008.Google Scholar
  8. 8.
    Boland E, Monsod T, Delucia M, Brandt CA, Fernando S, Tamborlane WV. Limitations of conventional methods of self-monitoring of blood glucose: lessons learned from 3 days of continuous glucose sensing in pediatric patients with type 1 diabetes. Diabetes Care. 2001;24:1858–62.PubMedGoogle Scholar
  9. 9.
    Borutaite V, Morkuniene R, Brown GC. Release of cytochrome c from heart mitochondria is induced by high Ca2+ and peroxynitrite and is responsible for Ca(2+)-induced inhibition of substrate oxidation. Biochim Biophys Acta. 1999;1453:41–8.PubMedGoogle Scholar
  10. 10.
    Brainin M, Tuomilehto J, Heiss WD, Bornstein NM, Bath PM, Teuschl Y, et al. Post-stroke cognitive decline: an update and perspectives for clinical research. Eur J Neurol. 2015;22(229–238):e213–26.Google Scholar
  11. 11.
    Canevari L, Kuroda S, Bates TE, Clark JB, Siesjo BK. Activity of mitochondrial respiratory chain enzymes after transient focal ischemia in the rat. J Cereb Blood Flow Metab. 1997;17:1166–9.PubMedGoogle Scholar
  12. 12.
    Cardoso S, Correia SC, Santos RX, Carvalho C, Candeias E, Duarte AI, et al. Hyperglycemia, hypoglycemia and dementia: role of mitochondria and uncoupling proteins. Curr Mol Med. 2013;13:586–601.PubMedGoogle Scholar
  13. 13.
    Center for Disease Control and Prevention 2016 (Retrieved on September 25th, 2016).
  14. 14.
    Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab. 2001;21:2–14.PubMedGoogle Scholar
  15. 15.
    Chauvin C, De Oliveira F, Ronot X, Mousseau M, Leverve X, Fontaine E. Rotenone inhibits the mitochondrial permeability transition-induced cell death in U937 and KB cells. J Biol Chem. 2001;276:41394–8.PubMedGoogle Scholar
  16. 16.
    Choi BY, Kim JH, Kim HJ, Yoo JH, Song HK, Sohn M, et al. Pyruvate administration reduces recurrent/moderate hypoglycemia-induced cortical neuron death in diabetic rats. PLoS One. 2013;8:e81523.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Cohan CH, Neumann JT, Dave KR, Alekseyenko A, Binkert M, Stransky K, et al. Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats. PLoS One. 2015;10:e0124918.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Corda S, Laplace C, Vicaut E, Duranteau J. Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide. Am J Respir Cell Mol Biol. 2001;24:762–8.Google Scholar
  19. 19.
    Cryer PE. Hypoglycemia-associated autonomic failure in diabetes. Am J Physiol Endocrinol Metab. 2001;281:E1115–21.PubMedGoogle Scholar
  20. 20.
    Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2004;350:2272–9.PubMedGoogle Scholar
  21. 21.
    Cuzzocrea S, Riley DP, Caputi AP, Salvemini D. Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev. 2001;53:135–59.PubMedGoogle Scholar
  22. 22.
    Dave KR, Lange-Asschenfeldt C, Raval AP, Prado R, Busto R, Saul I, et al. Ischemic preconditioning ameliorates excitotoxicity by shifting glutamate/gamma-aminobutyric acid release and biosynthesis. J Neurosci Res. 2005;82:665–73.PubMedGoogle Scholar
  23. 23.
    Dave KR, Saul I, Busto R, Ginsberg MD, Sick TJ, Perez-Pinzon MA. Ischemic preconditioning preserves mitochondrial function after global cerebral ischemia in rat hippocampus. J Cereb Blood Flow Metab. 2001;21:1401–10.PubMedGoogle Scholar
  24. 24.
    Dave KR, Tamariz J, Desai KM, Brand FJ, Liu A, Saul I, et al. Recurrent hypoglycemia exacerbates cerebral ischemic damage in streptozotocin-induced diabetic rats. Stroke. 2011;42:1404–11.PubMedGoogle Scholar
  25. 25.
    Davis EA, Jones TW. Hypoglycemia in children with diabetes: incidence, counterregulation and cognitive dysfunction. J Pediatr Endocrinol Metab. 1998;11:177–82.PubMedGoogle Scholar
  26. 26.
    Davis SN, Fowler S, Costa F. Hypoglycemic counterregulatory responses differ between men and women with type 1 diabetes. Diabetes. 2000a;49:65–72.PubMedGoogle Scholar
  27. 27.
    Davis SN, Shavers C, Costa F. Gender-related differences in counterregulatory responses to antecedent hypoglycemia in normal humans. J Clin Endocrinol Metab. 2000b;85:2148–57.PubMedGoogle Scholar
  28. 28.
    DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977–86.Google Scholar
  29. 29.
    Doll DN, Engler-Chiurazzi EB, Lewis SE, Hu H, Kerr AE, Ren X, et al. Lipopolysaccharide exacerbates infarct size and results in worsened post-stroke behavioral outcomes. Behav Brain Funct. 2015a;11:32.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Doll DN, Rellick SL, Barr TL, Ren X, Simpkins JW. Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity. J Neurochem. 2015b;132:443–51.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, et al. Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study. Diabet Med. 2005;22:749–55.PubMedGoogle Scholar
  32. 32.
    EDIC group. Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial Cohort. Diabetes Care. 1999;22:99–111.Google Scholar
  33. 33.
    Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA. Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab. 1997;17:1143–51.PubMedGoogle Scholar
  34. 34.
    Feng ZC, Sick TJ, Rosenthal M. Oxygen sensitivity of mitochondrial redox status and evoked potential recovery early during reperfusion in post-ischemic rat brain. Resuscitation. 1998;37:33–41.PubMedGoogle Scholar
  35. 35.
    Fiskum G, Murphy AN, Beal MF. Mitochondria in neurodegeneration: acute ischemia and chronic neurodegenerative diseases. J Cereb Blood Flow Metab. 1999;19:351–69.PubMedGoogle Scholar
  36. 36.
    Geddes J, Schopman JE, Zammitt NN, Frier BM. Prevalence of impaired awareness of hypoglycaemia in adults with type 1 diabetes. Diabet Med. 2008;25:501–4.PubMedGoogle Scholar
  37. 37.
    Gehlaut RR, Dogbey GY, Schwartz FL, Marling CR, Shubrook JH. Hypoglycemia in type 2 diabetes—more common than you think: a continuous glucose monitoring study. J Diabetes Sci Technol. 2015;9:999–1005.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Giachin G, Bouverot R, Acajjaoui S, Pantalone S, Soler-Lopez M. Dynamics of human mitochondrial complex I assembly: implications for neurodegenerative diseases. Front Mol Biosci. 2016;3:43.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Goossens V, Grooten J, De Vos K, Fiers W. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci U S A. 1995;92:8115–9.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Goossens V, Stange G, Moens K, Pipeleers D, Grooten J. Regulation of tumor necrosis factor-induced, mitochondria- and reactive oxygen species-dependent cell death by the electron flux through the electron transport chain complex I. Antioxid Redox Signal. 1999;1:285–95.PubMedGoogle Scholar
  41. 41.
    Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013;8:2003–14.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Harrison FE, Reiserer RS, Tomarken AJ, McDonald MP. Spatial and nonspatial escape strategies in the Barnes maze. Learn Mem. 2006;13:809–19.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Hattori K, Lee H, Hurn PD, Crain BJ, Traystman RJ, DeVries AC. Cognitive deficits after focal cerebral ischemia in mice. Stroke. 2000;31:1939–44.PubMedGoogle Scholar
  44. 44.
    Hershey T, Perantie DC, Warren SL, Zimmerman EC, Sadler M, White NH. Frequency and timing of severe hypoglycemia affects spatial memory in children with type 1 diabetes. Diabetes Care. 2005;28:2372–7.PubMedGoogle Scholar
  45. 45.
    Herzog RI, Chan O, Yu S, Dziura J, McNay EC, Sherwin RS. Effect of acute and recurrent hypoglycemia on changes in brain glycogen concentration. Endocrinology. 2008;149:1499–504.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Higuchi M, Proske RJ, Yeh ET. Inhibition of mitochondrial respiratory chain complex I by TNF results in cytochrome c release, membrane permeability transition, and apoptosis. Oncogene. 1998;17:2515–24.PubMedGoogle Scholar
  47. 47.
    Hodges H, Nelson A, Virley D, Kershaw TR, Sinden JD. Cognitive deficits induced by global cerebral ischaemia: prospects for transplant therapy. Pharmacol Biochem Behav. 1997;56:763–80.PubMedGoogle Scholar
  48. 48.
    Iijima T. Mitochondrial membrane potential and ischemic neuronal death. Neurosci Res. 2006;55:234–43.PubMedGoogle Scholar
  49. 49.
    Iijima T, Mishima T, Tohyama M, Akagawa K, Iwao Y. Mitochondrial membrane potential and intracellular ATP content after transient experimental ischemia in the cultured hippocampal neuron. Neurochem Int. 2003;43:263–9.PubMedGoogle Scholar
  50. 50.
    International Diabetes Federation, IDF diabetes atlas. 2015.Google Scholar
  51. 51.
    Isaev NK, Stelmashook EV, Dirnagl U, Plotnikov EY, Kuvshinova EA, Zorov DB. Mitochondrial free radical production induced by glucose deprivation in cerebellar granule neurons. Biochemistry (Mosc). 2008;73:149–55.Google Scholar
  52. 52.
    Isenberg JS, Klaunig JE. Role of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cells. Toxicol Sci. 2000;53:340–51.PubMedGoogle Scholar
  53. 53.
    Janssen MM, Snoek FJ, de Jongh RT, Casteleijn S, Deville W, Heine RJ. Biological and behavioural determinants of the frequency of mild, biochemical hypoglycaemia in patients with type 1 diabetes on multiple insulin injection therapy. Diabetes Metab Res Rev. 2000;16:157–63.PubMedGoogle Scholar
  54. 54.
    Jing L, Mai L, Zhang JZ, Wang JG, Chang Y, Dong JD, et al. Diabetes inhibits cerebral ischemia-induced astrocyte activation—an observation in the cingulate cortex. Int J Biol Sci. 2013;9:980–8.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Jing L, Wang JG, Zhang JZ, Cao CX, Chang Y, Dong JD, et al. Upregulation of ICAM-1 in diabetic rats after transient forebrain ischemia and reperfusion injury. J Inflamm (Lond). 2014;11:35.Google Scholar
  56. 56.
    Kauppinen RA, Nicholls DG. Synaptosomal bioenergetics. The role of glycolysis, pyruvate oxidation and responses to hypoglycaemia. Eur J Biochem. 1986;158:159–65.PubMedGoogle Scholar
  57. 57.
    Kiprianova I, Sandkuhler J, Schwab S, Hoyer S, Spranger M. Brain-derived neurotrophic factor improves long-term potentiation and cognitive functions after transient forebrain ischemia in the rat. Exp Neurol. 1999;159:511–9.PubMedGoogle Scholar
  58. 58.
    Kissela B, Air E. Diabetes: impact on stroke risk and poststroke recovery. Semin Neurol. 2006;26:100–7.PubMedGoogle Scholar
  59. 59.
    Kowaltowski AJ, Vercesi AE, Fiskum G. Bcl-2 prevents mitochondrial permeability transition and cytochrome c release via maintenance of reduced pyridine nucleotides. Cell Death Differ. 2000;7:903–10.PubMedGoogle Scholar
  60. 60.
    Lee C, Sciamanna M, Peterson P. Intact rat brain mitochondria from a single animal: preparation and properties. Methods Toxicology. 1993;2:41–50.Google Scholar
  61. 61.
    Levine DA, Galecki AT, Langa KM, Unverzagt FW, Kabeto MU, Giordani B, et al. Trajectory of cognitive decline after incident stroke. JAMA. 2015;314:41–51.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Lincoln NB, Faleiro RM, Kelly C, Kirk BA, Jeffcoate WJ. Effect of long-term glycemic control on cognitive function. Diabetes Care. 1996;19:656–8.PubMedGoogle Scholar
  63. 63.
    Liu P, Yang X, Hei C, Meli Y, Niu J, Sun T, et al. Rapamycin reduced ischemic brain damage in diabetic animals is associated with suppressions of mTOR and ERK1/2 signaling. Int J Biol Sci. 2016;12:1032–40.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Liu Y, Rosenthal RE, Haywood Y, Miljkovic-Lolic M, Vanderhoek JY, Fiskum G. Normoxic ventilation after cardiac arrest reduces oxidation of brain lipids and improves neurological outcome. Stroke. 1998;29:1679–86.PubMedGoogle Scholar
  65. 65.
    McCrimmon RJ, Frier BM. Hypoglycaemia, the most feared complication of insulin therapy. Diabete Metab. 1994;20:503–12.PubMedGoogle Scholar
  66. 66.
    McGowan JE, Chen L, Gao D, Trush M, Wei C. Increased mitochondrial reactive oxygen species production in newborn brain during hypoglycemia. Neurosci Lett. 2006;399:111–4.PubMedGoogle Scholar
  67. 67.
    McNally PG, Dean JD, Morris AD, Wilkinson PD, Compion G, Heller SR. Using continuous glucose monitoring to measure the frequency of low glucose values when using biphasic insulin aspart 30 compared with biphasic human insulin 30: a double-blind crossover study in individuals with type 2 diabetes. Diabetes Care. 2007;30:1044–8.PubMedGoogle Scholar
  68. 68.
    McNay E. Recurrent hypoglycemia increases anxiety and amygdala norepinephrine release during subsequent hypoglycemia. Front Endocrinol (Lausanne). 2015;6:175.Google Scholar
  69. 69.
    McNay EC, Sherwin RS. Effect of recurrent hypoglycemia on spatial cognition and cognitive metabolism in normal and diabetic rats. Diabetes. 2004;53:418–25.PubMedGoogle Scholar
  70. 70.
    McNay EC, Williamson A, McCrimmon RJ, Sherwin RS. Cognitive and neural hippocampal effects of long-term moderate recurrent hypoglycemia. Diabetes. 2006;55:1088–95.PubMedGoogle Scholar
  71. 71.
    McNeilly AD, Gallagher JR, Dinkova-Kostova AT, Hayes JD, Sharkey J, Ashford ML, et al. Nrf2-mediated neuroprotection against recurrent hypoglycemia is insufficient to prevent cognitive impairment in a rodent model of type 1 diabetes. Diabetes. 2016;65:3151–60.PubMedGoogle Scholar
  72. 72.
    Moro MA, Almeida A, Bolanos JP, Lizasoain I. Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med. 2005;39:1291–304.PubMedGoogle Scholar
  73. 73.
    Moulaert VR, Verbunt JA, van Heugten CM, Wade DT. Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review. Resuscitation. 2009;80:297–305.PubMedGoogle Scholar
  74. 74.
    Murakami K, Kondo T, Kawase M, Li Y, Sato S, Chen SF, et al. Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci. 1998;18:205–13.PubMedGoogle Scholar
  75. 75.
    Myers KM, Fiskum G, Liu Y, Simmens SJ, Bredesen DE, Murphy AN. Bcl-2 protects neural cells from cyanide/aglycemia-induced lipid oxidation, mitochondrial injury, and loss of viability. J Neurochem. 1995;65:2432–40.PubMedGoogle Scholar
  76. 76.
    Nathan DM. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014;37:9–16.PubMedGoogle Scholar
  77. 77.
    Nawashiro H, Tasaki K, Ruetzler CA, Hallenbeck JM. TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 1997;17:483–90.PubMedGoogle Scholar
  78. 78.
    Niatsetskaya ZV, Sosunov SA, Matsiukevich D, Utkina-Sosunova IV, Ratner VI, Starkov AA, et al. The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice. J Neurosci. 2012;32:3235–44.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Nicholls DG, Budd SL. Mitochondria and neuronal survival. Physiol Rev. 2000;80:315–60.PubMedGoogle Scholar
  80. 80.
    Okada M, Tamura A, Urae A, Nakagomi T, Kirino T, Mine K, et al. Long-term spatial cognitive impairment following middle cerebral artery occlusion in rats. A behavioral study. J Cereb Blood Flow Metab. 1995;15:505–12.PubMedGoogle Scholar
  81. 81.
    Ormstad H, Aass HC, Amthor KF, Lund-Sorensen N, Sandvik L. Serum cytokine and glucose levels as predictors of poststroke fatigue in acute ischemic stroke patients. J Neurol. 2011;258:670–6.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Pastorino JG, Simbula G, Yamamoto K, Glascott PA Jr, Rothman RJ, Farber JL. The cytotoxicity of tumor necrosis factor depends on induction of the mitochondrial permeability transition. J Biol Chem. 1996;271:29792–8.PubMedGoogle Scholar
  83. 83.
    Patockova J, Marhol P, Tumova E, Krsiak M, Rokyta R, Stipek S, et al. Oxidative stress in the brain tissue of laboratory mice with acute post insulin hypoglycemia. Physiol Res. 2003;52:131–5.PubMedGoogle Scholar
  84. 84.
    Pedersen-Bjergaard U, Pramming S, Heller SR, Wallace TM, Rasmussen AK, Jorgensen HV, et al. Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes Metab Res Rev. 2004;20:479–86.PubMedGoogle Scholar
  85. 85.
    Perez CA, Samudra N, Aiyagari V. Cognitive and functional consequence of cardiac arrest. Curr Neurol Neurosci Rep. 2016;16:70.PubMedGoogle Scholar
  86. 86.
    Piantadosi CA, Zhang J. Mitochondrial generation of reactive oxygen species after brain ischemia in the rat. Stroke. 1996;27:327–31.PubMedGoogle Scholar
  87. 87.
    Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol. 2003;463:3–33.PubMedGoogle Scholar
  88. 88.
    Puente EC, Silverstein J, Bree AJ, Musikantow DR, Wozniak DF, Maloney S, et al. Recurrent moderate hypoglycemia ameliorates brain damage and cognitive dysfunction induced by severe hypoglycemia. Diabetes. 2010;59:1055–62.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Rath PC, Aggarwal BB. TNF-induced signaling in apoptosis. J Clin Immunol. 1999;19:350–64.PubMedGoogle Scholar
  90. 90.
    Rovet J, Alvarez M. Attentional functioning in children and adolescents with IDDM. Diabetes Care. 1997;20:803–10.PubMedGoogle Scholar
  91. 91.
    Schopman JE, Geddes J, Frier BM. Frequency of symptomatic and asymptomatic hypoglycaemia in type 1 diabetes: effect of impaired awareness of hypoglycaemia. Diabet Med. 2011;28:352–5.PubMedGoogle Scholar
  92. 92.
    Schulze-Osthoff K, Beyaert R, Vandevoorde V, Haegeman G, Fiers W. Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. EMBO J. 1993;12:3095–104.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Shafiee G, Mohajeri-Tehrani M, Pajouhi M, Larijani B. The importance of hypoglycemia in diabetic patients. J Diabetes Metab Disord. 2012;11:17.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Shoji Y, Uedono Y, Ishikura H, Takeyama N, Tanaka T. DNA damage induced by tumour necrosis factor-alpha in L929 cells is mediated by mitochondrial oxygen radical formation. Immunology. 1995;84:543–8.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Shukla, V., Rehni, A., Dave, K., Dysregulated cytokine released by activated microglia in the hippocampus of diabetes associated recurrent hypoglycemic rat brain exacerbate ischemic damage, Society for Neuroscience, 45th Annual Meeting, Chicago. 2015. 499.419.Google Scholar
  96. 96.
    Sims NR, Anderson MF. Mitochondrial contributions to tissue damage in stroke. Neurochem Int. 2002;40:511–26.PubMedGoogle Scholar
  97. 97.
    Singh P, Jain A, Kaur G. Impact of hypoglycemia and diabetes on CNS: correlation of mitochondrial oxidative stress with DNA damage. Mol Cell Biochem. 2004;260:153–9.PubMedGoogle Scholar
  98. 98.
    Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest. 2007;117:910–8.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Tamborlane WV, Beck RW, Bode BW, Buckingham B, Chase HP, Clemons R, et al. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008;359:1464–76.PubMedGoogle Scholar
  100. 100.
    UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia. 2007;50:1140–7.Google Scholar
  101. 101.
    Unachukwu C, Ofori S. Diabetes mellitus and cardiovascular risk. the internet. J Endocrinol. 2012;7:1–10.Google Scholar
  102. 102.
    Weber KK, Lohmann T, Busch K, Donati-Hirsch I, Riel R. High frequency of unrecognized hypoglycaemias in patients with type 2 diabetes is discovered by continuous glucose monitoring. Exp Clin Endocrinol Diabetes. 2007;115:491–4.PubMedGoogle Scholar
  103. 103.
    Won SJ, Yoo BH, Kauppinen TM, Choi BY, Kim JH, Jang BG, et al. Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats. J Neuroinflammation. 2012;9:182.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Yamada KA, Rensing N, Izumi Y, De Erausquin GA, Gazit V, Dorsey DA, et al. Repetitive hypoglycemia in young rats impairs hippocampal long-term potentiation. Pediatr Res. 2004;55:372–9.PubMedGoogle Scholar
  105. 105.
    Yeoh E, Choudhary P, Nwokolo M, Ayis S, Amiel SA. Interventions that restore awareness of hypoglycemia in adults with type 1 diabetes: a systematic review and meta-analysis. Diabetes Care. 2015;38:1592–609.PubMedGoogle Scholar
  106. 106.
    Ying W, Wei G, Wang D, Wang Q, Tang X, Shi J, et al. Intranasal administration with NAD+ profoundly decreases brain injury in a rat model of transient focal ischemia. Front Biosci. 2007;12:2728–34.PubMedGoogle Scholar
  107. 107.
    Zaidan E, Sims NR. Reduced activity of the pyruvate dehydrogenase complex but not cytochrome c oxidase is associated with neuronal loss in the striatum following short-term forebrain ischemia. Brain Res. 1997;772:23–8.PubMedGoogle Scholar
  108. 108.
    Zoratti M, Szabo I. The mitochondrial permeability transition. Biochim Biophys Acta. 1995;1241:139–76.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Vibha Shukla
    • 1
    • 2
  • Perry Fuchs
    • 1
    • 2
  • Allen Liu
    • 1
    • 2
  • Charles H. Cohan
    • 1
    • 2
    • 3
  • Chuanhui Dong
    • 2
    • 3
  • Clinton B. Wright
    • 2
    • 3
    • 4
  • Miguel A. Perez-Pinzon
    • 1
    • 2
    • 3
    • 4
  • Kunjan R. Dave
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Cerebral Vascular Disease Research LaboratoriesUniversity of Miami School of MedicineMiamiUSA
  2. 2.Department of NeurologyUniversity of Miami School of MedicineMiamiUSA
  3. 3.Evelyn F. McKnight Brain InstituteUniversity of Miami School of MedicineMiamiUSA
  4. 4.Neuroscience ProgramUniversity of Miami School of MedicineMiamiUSA

Personalised recommendations