Korean Journal of Biological Psychiatry (생물정신의학)

The Korean Society of Biological Psychiatry (대한생물정신의학회)
권호 표지

The Effect of Clozapine on Central Insulin Response in Rats

항정신병약물 클로자핀이 흰쥐 뇌실로 주입한 인슐린의 반응에 미치는 영향

  • Kim, Se Hyun (Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University) ;
  • Yu, Hyun Sook (Biomedical Research Institute, Seoul National University Hospital) ;
  • Park, So Young (Biomedical Research Institute, Seoul National University Hospital) ;
  • Kim, Min Kyung (Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Park, Hong Geun (Biomedical Research Institute, Seoul National University Hospital) ;
  • Kim, Yong Sik (Department of Neuropsychiatry, Dongguk University Ilsan Hospital)
  • 김세현 (서울대학교 의학연구원 인간행동의학연구소) ;
  • 유현숙 (서울대학교병원 의생명연구원) ;
  • 박소영 (서울대학교병원 의생명연구원) ;
  • 김민경 (서울대학교 의과대학 의과학과) ;
  • 박홍근 (서울대학교병원 의생명연구원) ;
  • 김용식 (동국대학교 의과대학 일산병원 정신건강의학과)
  • Received : 2012.07.10
  • Accepted : 2012.07.16
  • Published : 2012.11.30
Download PDF
⟨ Previous Next ⟩

Abstract

Objectives Although antipsychotic drug clozapine has superior efficacy, this is hampered by metabolic side effects such as weight gain and diabetes. Recent studies demonstrate that clozapine induces insulin resistance. However, the identity and location of insulin resistance induced by clozapine has not been clarified. In this study, the effect of clozapine on central insulin response was investigated in rats. Methods Male Sprague-Dawley rats received intraperitoneal injection of clozapine or vehicle, which was followed by intracerebroventricular injection of insulin or its vehicle. The effects of clozapine on insulin-induced changes in blood glucose level and Akt phosphorylation in hypothalamus were investigated. Results Intraperitoneal injection of clozapine (20 mg/kg) increased blood glucose in rats. Intracerebroventricular injection of insulin reduced blood glucose in rats, which was blunted by pretreatment of clozapine. Accompanied with the antagonistic effect of clozapine to central insulin action in terms of blood glucose, clozapine inhibited the insulin-induced phosphorylation of Akt at Ser473 in rat hypothalamus. Conclusion Administration of clozapine inhibited the central insulin-induced changes in blood glucose and Akt phosphorylation in rat hypothalamus. These findings suggest that hypothalamus could be the site of action for the clozapine-induced insulin resistance.

Keywords

References

  1. Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry 2007;68 Suppl 1:20-27. https://doi.org/10.4088/JCP.0807e20
  2. Henderson DC, Cagliero E, Gray C, Nasrallah RA, Hayden DL, Schoenfeld DA, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry 2000;157:975-981. https://doi.org/10.1176/appi.ajp.157.6.975
  3. Henderson DC, Copeland PM, Borba CP, Daley TB, Nguyen DD, Cagliero E, et al. Glucose metabolism in patients with schizophrenia treated with olanzapine or quetiapine: a frequently sampled intravenous glucose tolerance test and minimal model analysis. J Clin Psychiatry 2006;67:789-797. https://doi.org/10.4088/JCP.v67n0513
  4. Henderson DC, Nguyen DD, Copeland PM, Hayden DL, Borba CP, Louie PM, et al. Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry 2005;66:1116-1121. https://doi.org/10.4088/JCP.v66n0905
  5. Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159:561-566. https://doi.org/10.1176/appi.ajp.159.4.561
  6. Houseknecht KL, Robertson AS, Zavadoski W, Gibbs EM, Johnson DE, Rollema H. Acute effects of atypical antipsychotics on wholebody insulin resistance in rats: implications for adverse metabolic effects. Neuropsychopharmacology 2007;32:289-297. https://doi.org/10.1038/sj.npp.1301209
  7. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008;13:27-35. https://doi.org/10.1038/sj.mp.4002066
  8. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004;27:596-601. https://doi.org/10.2337/diacare.27.2.596
  9. Kim SH, Nikolics L, Abbasi F, Lamendola C, Link J, Reaven GM, et al. Relationship between body mass index and insulin resistance in patients treated with second generation antipsychotic agents. J Psychiatr Res 2010;44:493-498. https://doi.org/10.1016/j.jpsychires.2009.11.007
  10. Hou JC, Pessin JE. Ins (endocytosis) and outs (exocytosis) of GLUT4 trafficking. Curr Opin Cell Biol 2007;19:466-473. https://doi.org/10.1016/j.ceb.2007.04.018
  11. Ardizzone TD, Bradley RJ, Freeman AM 3rd, Dwyer DS. Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine. Brain Res 2001;923:82-90. https://doi.org/10.1016/S0006-8993(01)03026-8
  12. Panariello F, Perruolo G, Cassese A, Giacco F, Botta G, Barbagallo AP, et al. Clozapine impairs insulin action by up-regulating Akt phosphorylation and Ped/Pea-15 protein abundance. J Cell Physiol 2012;227:1485-1492. https://doi.org/10.1002/jcp.22864
  13. Dwyer DS, Pinkofsky HB, Liu Y, Bradley RJ. Antipsychotic drugs affect glucose uptake and the expression of glucose transporters in PC12 cells. Prog Neuropsychopharmacol Biol Psychiatry 1999;23:69-80. https://doi.org/10.1016/S0278-5846(98)00092-X
  14. Hill JW, Elmquist JK, Elias CF. Hypothalamic pathways linking energy balance and reproduction. Am J Physiol Endocrinol Metab 2008;294:E827-E832. https://doi.org/10.1152/ajpendo.00670.2007
  15. Levin BE, Magnan C, Dunn-Meynell A, Le Foll C. Metabolic sensing and the brain: who, what, where, and how? Endocrinology 2011;152:2552-2557. https://doi.org/10.1210/en.2011-0194
  16. Routh VH. Glucose sensing neurons in the ventromedial hypothalamus. Sensors (Basel) 2010;10:9002-9025. https://doi.org/10.3390/s101009002
  17. Tulipano G, Rizzetti C, Bianchi I, Fanzani A, Spano P, Cocchi D. Clozapine-induced alteration of glucose homeostasis in the rat: the contribution of hypothalamic-pituitary-adrenal axis activation. Neuroendocrinology 2007;85:61-70. https://doi.org/10.1159/000100981
  18. Martins PJ, Haas M, Obici S. Central nervous system delivery of the antipsychotic olanzapine induces hepatic insulin resistance. Diabetes 2010;59:2418-2425. https://doi.org/10.2337/db10-0449
  19. Garcia-San Frutos M, Fernandez-Agullo T, De Solis AJ, Andres A, Arribas C, Carrascosa JM, et al. Impaired central insulin response in aged Wistar rats: role of adiposity. Endocrinology 2007;148:5238-5247. https://doi.org/10.1210/en.2007-0543
  20. Kim SH, Yu HS, Park HG, Jeon WJ, Song JY, Kang UG, et al. Dose-dependent effect of intracerebroventricular injection of ouabain on the phosphorylation of the MEK1/2-ERK1/2-p90RSK pathway in the rat brain related to locomotor activity. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:1637-1642. https://doi.org/10.1016/j.pnpbp.2008.05.027
  21. Yu HS, Kim SH, Park HG, Kim YS, Ahn YM. Intracerebroventricular administration of ouabain, a Na/K-ATPase inhibitor, activates tyrosine hydroxylase through extracellular signal-regulated kinase in rat striatum. Neurochem Int 2011;59:779-786. https://doi.org/10.1016/j.neuint.2011.08.011
  22. Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG Jr, et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 2003;52:227-231. https://doi.org/10.2337/diabetes.52.2.227
  23. Gerozissis K. Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 2008;585:38-49. https://doi.org/10.1016/j.ejphar.2008.01.050
  24. Kalra SP. Pivotal role of leptin-hypothalamus signaling in the etiology of diabetes uncovered by gene therapy: a new therapeutic intervention? Gene Ther 2011;18:319-325. https://doi.org/10.1038/gt.2010.164
  25. Prodi E, Obici S. Minireview: the brain as a molecular target for diabetic therapy. Endocrinology 2006;147:2664-2669. https://doi.org/10.1210/en.2006-0143
  26. Sanchez-Lasheras C, Konner AC, Bruning JC. Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators. Front Neuroendocrinol 2010;31:14-15.
  27. Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ. The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord 2001;25 Suppl 5:S63-S67.
  28. Lin JY, Li CS, Pan JT. Effects of various neuroactive substances on single-unit activities of hypothalamic arcuate neurons in brain slices. Brain Res Bull 1993;31:587-594. https://doi.org/10.1016/0361-9230(93)90127-W
  29. Boura-Halfon S, Zick Y. Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab 2009;296:E581-E591. https://doi.org/10.1152/ajpendo.90437.2008
  30. Aubry JM, Schwald M, Ballmann E, Karege F. Early effects of mood stabilizers on the Akt/GSK-3beta signaling pathway and on cell survival and proliferation. Psychopharmacology (Berl) 2009;205:419-429. https://doi.org/10.1007/s00213-009-1551-2
  31. Kang UG, Seo MS, Roh MS, Kim Y, Yoon SC, Kim YS. The effects of clozapine on the GSK-3-mediated signaling pathway. FEBS Lett 2004;560:115-119. https://doi.org/10.1016/S0014-5793(04)00082-1
  32. Lu XH, Dwyer DS. Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J Mol Neurosci 2005;27:43-64. https://doi.org/10.1385/JMN:27:1:043
  33. Olianas MC, Dedoni S, Onali P. Regulation of PI3K/Akt signaling by N-desmethylclozapine through activation of ${\delta}$-opioid receptor. Eur J Pharmacol 2011;660:341-350. https://doi.org/10.1016/j.ejphar.2011.04.012
  34. Roh MS, Seo MS, Kim Y, Kim SH, Jeon WJ, Ahn YM, et al. Haloperidol and clozapine differentially regulate signals upstream of glycogen synthase kinase 3 in the rat frontal cortex. Exp Mol Med 2007;39:353-360. https://doi.org/10.1038/emm.2007.39
  35. Kim SF, Huang AS, Snowman AM, Teuscher C, Snyder SH. From the Cover: Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proc Natl Acad Sci U S A 2007;104:3456-3459. https://doi.org/10.1073/pnas.0611417104
  36. Boyda HN, Tse L, Procyshyn RM, Honer WG, Barr AM. Preclinical models of antipsychotic drug-induced metabolic side effects. Trends Pharmacol Sci 2010;31:484-497. https://doi.org/10.1016/j.tips.2010.07.002
  37. Boyda HN, Tse L, Procyshyn RM, Wong D, Wu TK, Pang CC, et al. A parametric study of the acute effects of antipsychotic drugs on glucose sensitivity in an animal model. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:945-954. https://doi.org/10.1016/j.pnpbp.2010.04.024
  38. Murashita M, Kusumi I, Hosoda H, Kangawa K, Koyama T. Acute administration of clozapine concurrently increases blood glucose and circulating plasma ghrelin levels in rats. Psychoneuroendocrinology 2007;32:777-784. https://doi.org/10.1016/j.psyneuen.2007.05.007
  39. Girgis RR, Javitch JA, Lieberman JA. Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway. Mol Psychiatry 2008;13:918-929. https://doi.org/10.1038/mp.2008.40
  40. Citrome L, Volavka J. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. Diabetes Care 2004;27:2087-2088; author reply 2089-2090. https://doi.org/10.2337/diacare.27.8.2087
  41. Jin H, Meyer JM, Jeste DV. Atypical antipsychotics and glucose dysregulation: a systematic review. Schizophr Res 2004;71:195-212. https://doi.org/10.1016/j.schres.2004.03.024
  42. Mukherjee S, Schnur DB, Reddy R. Family history of type 2 diabetes in schizophrenic patients. Lancet 1989;1:495.