The Effect Of Insulin Induced Acute Hypoglycemia on Brain Neurotransmitters and Oxidative Stress , Possible Protection by Gabapentin And Olanzapine


  • Hadaf A. ALJunaiyeh Assistant Professor, Department Of Pharmacology, College Of Medicine, University of Thi-Qar, Iraq.
  • Alaa Kadhem Alwan B.Sc. (Pharmacy), Thi-Qar Health Office, Republic of Iraq.
  • Nabeel A. J. Ali Professor , Department Of Pharmacology, College Of Medicine, University of Basrah, Iraq.


Hypoglycemia, Insulin, Gabapentin, Olanzapine, MDA, Dopamine, GABA, Noradrenaline


Background, Diabetes mellitus is one of the most common metabolic diseases in the world and the number of its patients still growing and according to the International Diabetes Federation reach 552 in 2030. Hypoglycemia is dangerous adverse effect of insulin therapy and remains an unsolved problem; During hypoglycemia lack of glucose supply to neurons can lead to confusion, seizures, brain damage which is sometimes irreversible and can even cause death. Aim ,The study designed to test the effect of acute insulin induced hypoglycemia on: 1)the brain oxidative status as measured by Malondialdehyde (MDA). 2)brain neurotransmitters; dopamine, ɣ-Amino butyric acid (GABA)and noradrenaline. And Possible protective effect of gabapentin and olanzapine against hypoglycemia. Method and Materials, 32 male rabbits, randomly divided into four groups, group A (control group) treated with (2.5ml/kg) distilled water orally and (0.1 ml/kg) distilled water subcutaneously. Group B (Hypoglycemic group) treated with (2.5ml/kg) distilled water orally and (1 IU/kg) insulin subcutaneously. Group C (hypoglycemic group + gabapentin) given (25 mg/kg) gabapentin orally and (1 IU/kg) insulin subcutaneously. Group D (hypoglycemic group + olanzapine) treated with(2mg/kg) olanzapine orally and (1 IU /kg) insulin subcutaneously. Blood samples  used to determine glucose level and brain tissue used to estimation neurotransmitters. Statistics, Results are presented as the mean ± Sd. Statistical significance was set at P < 0.05 and determined by the (SPSS) version 22. Data were analyzed by one-way ANOVA and unpaired t-test. Results, Insulin treated group show significantly increased of MDA and noradrenaline in comparison to control group. In (insulin + gabapentin) treated group show significant decreased of dopamine and no significant changes of GABA and noradrenaline in comparison to control group. While (insulin + olanzapine) result was significantly increased of MDA and decreased of both dopamine and GABA in comparison to control group. On other side the use of gabapentin with insulin lead significant decreased of  MDA and dopamine, significantly decreased of noradrenalin and  Significant decreased of  glucose levels at day one 10 AM, in comparison to use insulin only. While addition olanzapine to insulin show the following result no significantly increased of  MDA, Significant decrease of dopamine and GABA and No significant decreased of noradrenaline in comparison to use insulin only. Conclusion, Insulin hypoglycemia lead to oxidative stress and brain neurotransmitters disturbance which are partly reversed by gabapentin and olanzapine, on the other hand both drugs tend to exacerbate insulin induced hypoglycemia. Caution should be excreted when giving any of the two drugs in such situation.


Choudhary P, Rickels MR, Senior PA, Vantyghem, Paola Maffi, Thomas W. Kay, et al. Evidence-Informed Clinical Practice Recommendations for Treatment of Type 1 Diabetes Complicated by Problematic Hypo-glycemia. Diabetes Care. 2015 ;38(6):1016-102.

Dømgaard M, Bagger M, Rhee NA, Burton CM, Thorsteinsson B. Individual and societal consequences of hypoglycemia: A cross-sectional survey. Postgrad Med. 2015; 127(5):438-45.

Desimone ME, Weinstock RS. Hypoglycemia. In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, Koch C, McLachlan R, New M, Rebar R, Singer F, Vinik A, Weickert MO, editors. SourceEndotext [Internet]. South Dartmouth (MA):, Inc.; 2000-.2015 Apr 12.

de Galan BE, Schouwenberg BJ, Tack CJ, P. Smits . Pathophysiology and management of recurrent hypoglycemia and hypoglycemia unawareness in diabetes. Neth J Med. 2006 ;64(8):269-79.

Mohseni S. Neurologic damage in hypoglycemia, Handb Clin Neurol. 2014; 126:513-32.

Sanjay Kalra , Basal insulin analogues in the treatment of diabetes mellitus: What progress have we made? Indian J EndocrinolMetab. 2015; 19( 1): S71–S73.

Mazen Alsahli and John E. Gerich , Hypoglycemia in Patients with Diabetes and Renal Disease J.: Clin. Med. 2015, 4(5), 948-964.

Bonaventura A , Montecucco F, Dallegri F , Update on strategies limiting iatrogenic hypoglycemia. Endocr Connect. 2015. pii: EC-15-0044.

Michael J. Thompson and John P. Mordes . Hypoglycemia in Pancreatic Disease. American pancreatic Association. 2015; Version 1.0

Willis WD, Diago-Cabezudo JI, Madec-Hily A, and Aftab Aslam .Medical resource use, disturbance of daily life and burden of hypoglycemia in insulin-treated patients with diabetes: results from a European online survey, Expert Rev Pharmacoecon Outcomes Res.2013 ; 13(1):123-30.

Sämann A, Lehmann T, Heller T, Nicolle Müller, Petra Hartmann, Gunter B Wolf , and Ulrich A Müller. A retrospective study on the incidence and risk factors of severe hypoglycemia in primary care., FamPract. 2013 ;30(3):290-3.

Oyer DS, The science of hypoglycemia in patients with diabetes. Curr Diabetes Rev. 2013 ;9(3):195-208

Cryer PE. Hypoglycemia in diabetes: pathophysiology, prevalence, and prevention. American Diabetes Association, Alexandria, VA 2009. de Galan BE, Schouwenberg BJ, Tack CJ, P. Smits . Pathophysiology and management of recurrent hypoglycemia and hypoglycemia unawareness in diabetes. Neth J Med. 2006 ;64(8):269-79.

Ghasemi R , Haeri A, Dargahi L, Mohamed Z, Ahmadiani A , Insulin in the brain: sources, localization and functions .Mol Neurobiol. 2013 ; 47(1):145-71.

Zargar AH, Type 1 diabetes guidelines: Are they enough?, Indian J EndocrinolMetab. 2015 ;19(Suppl 1):S18-21.

Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. PharmacolTher. 2012; 136:82–93.

Vaváková M, Ďuračková Z, Trebatická J, Markers of Oxidative Stress and Neuroprogression in Depression Disorder. Oxid Med Cell Longev. 2015;2015:898393.

Halliwell B. The antioxidant paradox: less paradoxical now? British Journal of Clinical Pharmacology. 2013;75(3):637–644.

Patocková J, Marhol P, Tůmová E , Oxidative stress in the brain tissue of laboratory mice with acute post insulin hypoglycemia. Physiol Res. 2003;52(1):131-5.

Sandilyan MB, Dening T, Brain function, disease and dementia Nurs Stand. 2015 27;29(39):36-42.

Kim TH, Choi J, Kim HG , Quantification of neurotransmitters in mouse brain tissue by using liquid chromatography coupled electrospray tandem mass spectrometry. J Anal Methods Chem. 2014;2014:506870.

Fitzgerald PJ, Elevated Norepinephrine may be a Unifying Etiological Factor in the Abuse of a Broad Range of Substances: Alcohol, Nicotine, Marijuana, Heroin, Cocaine, and Caffeine. Subst Abuse. 2013 ;7:171-83

PertovaaraA,The noradrenergic pain regulation system:a potential target for pain therapy. Eur J Pharmacol. 2013 ;716(1-3):2-7.

Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H. "GABA and GABA receptors in the central nervous system and other organs, International Review of Cytology .2002 ;213. pp. 1–47.

Anju P, Moothedath I, Rema Shree AB, Gamma amino butyric acid accumulation in medicinal plants without stress. AncSci Life. 2014 ; 34(2):68-72.

Chang CY, Challa CK, Shah J, and Jean Daniel Eloy , Gabapentin in acute postoperative pain management. Biomed Res Int. 2014;2014:631756.

Kukkar A, Bali A, Singh N, Jaggi AS. Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res. 2013 ;36(3):237-51.

Boroujerdi A, Zeng J, Sharp K, Calcium channel alpha-2-delta-1 protein up regulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states Pain. 2011;152:649–655.

Chudek J, Olszanecka-Glinianowicz M, Almgren-Rachtan A, Tomasz Gabryelewicz . Evaluation of the safety profile of zolafren(®), a generic olanzapine formulation, in patients with bipolar disorder: a post-authorization safety study. AdvTher. 2015 ;32(5):418-28.

DjordjevićFilijović N, Antonijević MD, Pavlović A, Ivan Vuckovic , Katarina Nikolic , and Danica Agbaba .The stress stability of olanzapine: studies of interactions with excipients in solid state pharmaceutical formulations. Drug DevInd Pharm. 2015 ;41(3):502-14.

Manjeet Mapara, Betsy Sara Thomas, and K. M. Bhat, Rabbit as an animal model for experimental research. Dent Res J (Isfahan). 2012 ; 9(1): 111–118.

Jiang ZL, Sato T. Rise in plasma oxidized glutathione by experimental hypoglycemia. Tohoku J Exp Med. 1999 ;187(1):59-64 .

Pietrzak B, Czarnecka E.The effect of combined administration of ethanol and gabapentin on rabbit electroencephalographic activity. Basic ClinPharmacolToxicol. 2006 ;99(5):383-90 (A)

Pietrzak B, Czarnecka E. Effect of the administration of tiagabine and gabapentin on rabbit electroencephalogramactivity. J Pharm Pharmacol. 2006 ;58(10):1367-72.( B)

Kapur S, VanderSpek SC, Brownlee BA, Nobrega JN..Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy. J PharmacolExpTher. 2003;305(2):625-31.

Jiang Zl, Kohzuki M, Harada T, Sato T.Glutathione suppresses increase of serum creatine kinase in experimental hypoglycemia. Diabetes Res ClinPract. 2007 ;77(3):357-62.

Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979 ;95(2):351-8 .

V. F. H. Jensen, I. B. Bøgh and J. Lykkesfeldt . Effect of Insulin-Induced Hypoglycemia on the Central Nervous System: Evidence from Experimental Studies. Journal of Neuroendocrinology . 2014; 26, 123–150.

Kale A, Börcek AÖ, Emmez H, Yildirim Z, Durdağ E, Lortlar N,et al . Neuroprotective effects of gabapentin on spinal cord ischemia-reperfusion injury in rabbits . J Neurosurg Spine .2011 ; 15:228–237.

Kim YS, Chang HK, Lee JW, Sung YH, Kim SE, Shin MS, et al . Protective effect of gabapentin on N-methyl-D-aspartate-induced excitotoxicity in rat hippocampal CA1 neurons. J Pharmacol Sci. 2009 ;109(1):144-7.

Patel M, Bapu C, Padh H, Nivsarkar M. Olanzapine induced thrombocythemia in Sprague-Dawley rats. Drug Chem Toxicol. 2004 ; 27(4):379-87.

Guzman DC, Garcia EH, Mejia GB, Olguin HJ, Gonzalez JA, Labra Ruiz NA. Effect of morphine and lacosamide on levels of dopamine and 5-HIAA in brain regions of rats with induced hypoglycemia. Pakistan journal of biological sciences.2014; 17(2):292-296)

Vinish M, Elnabawi A, Milstein JA, Burke JS, Kallevang JK, Turek KC,et al . Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function. Int J Neuropsychopharmacol. 2013 ;16(7):1599-609.

Errante LD , Petroff OA. Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations . Seizure. 2003 ;12(5):300-6.

Xu S, Gullapalli RP, Frost DO. Olanzapine antipsychotic treatment of adolescent rats causes long term changes in glutamate and GABA levels in the nucleus accumbens. Schizophr Res. 201 ;161(2-3):452-7

Dooley DJ, Donovan CM, Pugsley TA. Stimulus-dependent modulation of [(3)H]norepinephrine release from rat neocortical slices by gabapentin and pregabalin. J Pharmacol Exp Ther. 2000 ;295(3):1086-93 .

Haruta I, Asakawa A, Inui A. Olanzapine-induced hypoglycemia in anorexia nervosa. Endocrine. 2014 ;46(3):672-3 .

H. Jeong Kim, Dong Wook Kim, Dong Joo Yun, Gun-Sei Oh, and Sang Hyun Jang. Olanzapine-Induced Hypoglycemic Encephalopathy: A Case Report. J Neurocrit Care 2012;5:30-32.

Nagamine T, Hypoglycemia associated with insulin hypersecretion following the addition of olanzapine to conventional antipsychotics. Neuropsychiatr Dis Treat. 2006 ;2(4):583-5 .

Scholl JH, van Eekeren R, van Puijenbroek EP. Six cases of (severe) hypoglycaemia associated with gabapentin use in both diabetic and non-diabetic patients. Br J Clin Pharmacol. 2015 May;79(5):870-1