Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

cDNA array reveals increased expression of glucose-dependent insulinotropic polypeptide following chronic clozapine treatment: role in atypical antipsychotic drug-induced adverse metabolic effects

The Pharmacogenomics Journal volume 6, pages 131–140 (2006)Cite this article

Abstract

Clozapine is an atypical antipsychotic drug with unique pharmacological and therapeutic properties. Unlike the typical antipsychotic drug, haloperidol, clozapine does not cause extrapyramidal side effects; however, weight gain, dyslipidemia, and type II diabetes are commonly associated with the use of this drug in subjects with schizophrenia. The aim of this study was to profile gene expression in the rat striatum following clozapine treatment. Chronic treatment with clozapine revealed upregulation of several genes including the glucose-dependent insulinotropic polypeptide (GIP) gene by over 200% in the rat striatum. The cDNA array results for the GIP gene were confirmed by real-time RT-PCR as well as by radioimmunoassay. Expression of the GIP gene in the central nervous system is consistent with the results of retinal GIP gene expression as reported by other investigators. Taken together, these findings implicate the possible role of GIP as a neuromodulator in the central nervous system. GIP is an insulinotropic agent with stimulatory effects on insulin synthesis and release from the pancreas. However, changes in brain GIP levels are most likely unrelated to the metabolic adverse effects (dyslipidemia, type II diabetes, weight gain) associated with clozapine treatment. Therefore, we also measured GIP gene expression in the K-cell-rich regions, duodenum and jejunum (small intestine), and plasma GIP levels using radioimmunoassay following chronic treatment with clozapine. GIP mRNA levels in the small intestine and the plasma GIP at the protein level were significantly elevated in clozapine-treated subjects. Furthermore, as observed in humans, chronic clozapine treatment also caused weight gain, and increased levels of insulin, triglycerides and leptin in the plasma. These results suggest that adverse metabolic effects associated with clozapine treatment may be related to its ability to increase intestinal gene expression for GIP.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

5-HT :

serotonin

cAMP :

cyclic adenosine monophosphate

CRE :

cAMP response element

CREB :

cAMP response element-binding protein

GIP :

glucose-dependent insulinotropic polypeptide

GLUT4 :

glucose transporter-4

MMLV :

Moloney Murine Leukemia Virus

PKA :

protein kinase A

RT-PCR :

reverse transcriptase-polymerase chain reaction

References

  1. Cho GJ, Ryu S, Kim YH, Kim YS, Cheon EW, Park JM et al. Upregulation of glucose-dependent insulinotropic polypeptide and its receptor in the retina of streptozotocin-induced diabetic rats. Curr Eye Res 2002; 25: 381–388.

    Article  Google Scholar 

  2. Leucht S, Pitschel-Walz G, Abraham D, Kissling W . Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res 1999; 35: 51–68.

    Article  CAS  Google Scholar 

  3. Pickar D . Prospects for pharmacotherapy of schizophrenia. Lancet 1995; 345: 557–562.

    Article  CAS  Google Scholar 

  4. Pilowsky LS, Costa DC, Ell PJ, Murray RM, Verhoeff NP, Kerwin RW . Clozapine, single photon emission tomography, and the D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet 1992; 340: 199–202.

    Article  CAS  Google Scholar 

  5. Richelson E, Nelson A . Antagonism by neuroleptics of neurotransmitter receptors of normal human brain in vitro. Eur J Pharmacol 1984; 103: 197–204.

    Article  CAS  Google Scholar 

  6. Tauscher J, Hussain T, Agid O, Verhoeff NP, Wilson AA, Houle S et al. Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics. Am J Psychiatry 2004; 161: 1620–1625.

    Article  Google Scholar 

  7. Newcomer JW . Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J Clin Psychiatry 2004; 65: Suppl 18: 36-46.

    Google Scholar 

  8. Buchanan RW . Clozapine: efficacy and safety. Schizophr Bull 1995; 21: 579–591.

    Article  CAS  Google Scholar 

  9. McGurk SR . The effects of clozapine on cognitive functioning in schizophrenia. J Clin Psychiatry 1999; 60 (Suppl 12): 24–29.

    CAS  Google Scholar 

  10. Meltzer HY, Okayli G . Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. Am J Psychiatry 1995; 152: 183–190.

    Article  CAS  Google Scholar 

  11. Gianfrancesco F, White R, Wang RH, Nasrallah HA . Antipsychotic-induced type 2 diabetes: evidence from a large health plan database. J Clin Psychopharmacol 2003; 23: 328–335.

    Article  CAS  Google Scholar 

  12. Hagg S, Joelsson L, Mjorndal T, Spigset O, Oja G, Dahlqvist R . Prevalence of diabetes and impaired glucose tolerance in patients treated with clozapine compared with patients treated with conventional depot neuroleptic medications. J Clin Psychiatry 1998; 59: 294–299.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. Henderson DC . Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002; 16: 77–89.

    Article  CAS  Google Scholar 

  15. Melkersson KI, Hulting AL, Brismar KE . Different influences of classical antipsychotics and clozapine on glucose-insulin homeostasis in patients with schizophrenia or related psychoses. J Clin Psychiatry 1999; 60: 783–791.

    Article  CAS  Google Scholar 

  16. Popli AP, Konicki PE, Jurjus GJ, Fuller MA, Jaskiw GE . Clozapine and associated diabetes mellitus. J Clin Psychiatry 1997; 58: 108–111.

    Article  CAS  Google Scholar 

  17. Wirshing DA, Spellberg BJ, Erhart SM, Marder SR, Wirshing WC . Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998; 44: 778–783.

    Article  CAS  Google Scholar 

  18. Yazici KM, Erbas T, Yazici AH . The effect of clozapine on glucose metabolism. Exp Clin Endocrinol Diabetes 1998; 106: 475–477.

    Article  CAS  Google Scholar 

  19. 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.

    Article  Google Scholar 

  20. Casey DE . Dyslipidemia and atypical antipsychotic drugs. J Clin Psychiatry 2004; 65 (Suppl 18): 27–35.

    CAS  PubMed  Google Scholar 

  21. Howes OD, Bhatnagar A, Gaughran FP, Amiel SA, Murray RM, Pilowsky LS . A prospective study of impairment in glucose control caused by clozapine without changes in insulin resistance. Am J Psychiatry 2004; 161: 361–363.

    Article  Google Scholar 

  22. Henderson DC, Cagliero E, Copeland PM, Borba CP, Evins E, Hayden D et al. Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry 2005; 62: 19–28.

    Article  CAS  Google Scholar 

  23. Henderson DC . Clozapine: diabetes mellitus, weight gain, and lipid abnormalities. J Clin Psychiatry 2001; 62 (Suppl 23): 39–44.

    CAS  PubMed  Google Scholar 

  24. Dwyer DS, Donohoe D . Induction of hyperglycemia in mice with atypical antipsychotic drugs that inhibit glucose uptake. Pharmacol Biochem Behav 2003; 75: 255–260.

    Article  CAS  Google Scholar 

  25. Bridler R, Umbricht D . Atypical antipsychotics in the treatment of schizophrenia. Swiss Med Wkly 2003; 133: 63–76.

    CAS  PubMed  Google Scholar 

  26. Centorrino F, Fogarty KV, Cimbolli P, Salvatore P, Thompson TA, Sani G et al. Aripiprazole: initial clinical experience with 142 hospitalized psychiatric patients. J Psychiatr Pract 2005; 11: 241–247.

    PubMed  Google Scholar 

  27. Naber D, Lambert M . Aripiprazole: a new atypical antipsychotic with a different pharmacological mechanism. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 1213–1219.

    Article  CAS  Google Scholar 

  28. Sondhi S, Thomas N, Chong VZ, N-Marandi S, Castellano JM, Gabriele J et al. Glucose-Dependent Insulinotropic polypeptide (GIP) and its receptors: gene expression in discrete human brain regions. Abstract: Society for Neuroscience 2003.

  29. Sondhi S, Thomas N, Castellano J, N-Marandi S, Gabriele J, Chong V et al. Glucose-dependent insulinotropic polypeptide and its receptors: gene expression in discrete human brain regions. FASEB J 2004; 19: 3011.

    Google Scholar 

  30. Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI . Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology 1993; 133: 2861–2870.

    Article  CAS  Google Scholar 

  31. Kaplan AM, Vigna SR . Gastric inhibitory polypeptide (GIP) binding sites in rat brain. Peptides 1994; 15: 297–302.

    Article  CAS  Google Scholar 

  32. Alvarez E, Martinez MD, Roncero I, Chowen JA, Garcia-Cuartero B, Gispert JD et al. The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J Neurochem 2005; 92: 798–806.

    Article  CAS  Google Scholar 

  33. Creutzfeldt W . The incretin concept today. Diabetologia 1979; 16: 75–85.

    Article  CAS  Google Scholar 

  34. Fehmann HC, Goke R, Goke B . Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr Rev 1995; 16: 390–410.

    Article  CAS  Google Scholar 

  35. Higashimoto Y, Opara EC, Liddle RA . Dietary regulation of glucose-dependent insulinotropic peptide (GIP) gene expression in rat small intestine. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1995; 110: 207–214.

    Article  CAS  Google Scholar 

  36. Meier JJ, Nauck MA, Schmidt WE, Gallwitz B . Gastric inhibitory polypeptide: the neglected incretin revisited. Regul Pept 2002; 107: 1–13.

    Article  CAS  Google Scholar 

  37. Morgan LM . The metabolic role of GIP: physiology and pathology. Biochem Soc Trans 1996; 24: 585–591.

    Article  CAS  Google Scholar 

  38. Yip RG, Wolfe MM . GIP biology and fat metabolism. Life Sci 2000; 66: 91–103.

    Article  CAS  Google Scholar 

  39. Cataland S, Crockett SE, Brown JC, Mazzaferri EL . Gastric inhibitory polypeptide (GIP) stimulation by oral glucose in man. J Clin Endocrinol Metab 1974; 39: 223–228.

    Article  CAS  Google Scholar 

  40. Pederson RA, Schubert HE, Brown JC . Gastric inhibitory polypeptide. Its physiologic release and insulinotropic action in the dog. Diabetes 1975; 24: 1050–1056.

    Article  CAS  Google Scholar 

  41. Buchan AM, Polak JM, Capella C, Solcia E, Pearse AG . Electronimmunocytochemical evidence for the K cell localization of gastric inhibitory polypeptide (GIP) in man. Histochemistry 1978; 56: 37–44.

    Article  CAS  Google Scholar 

  42. Gremlich S, Porret A, Hani EH, Cherif D, Vionnet N, Froguel P et al. Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes 1995; 44: 1202–1208.

    Article  CAS  Google Scholar 

  43. Thomas FB, Shook DF, O'Dorisio TM, Cataland S, Mekhjian HS, Caldwell JH et al. Localization of gastric inhibitory polypeptide release by intestinal glucose perfusion in man. Gastroenterology 1977; 72: 49–54.

    CAS  PubMed  Google Scholar 

  44. Volz A, Goke R, Lankat-Buttgereit B, Fehmann HC, Bode HP, Goke B . Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. FEBS Lett 1995; 373: 23–29.

    Article  CAS  Google Scholar 

  45. Wheeler MB, Gelling RW, McIntosh CH, Georgiou J, Brown JC, Pederson RA . Functional expression of the rat pancreatic islet glucose-dependent insulinotropic polypeptide receptor: ligand binding and intracellular signaling properties. Endocrinology 1995; 136: 4629–4639.

    Article  CAS  Google Scholar 

  46. Ding WG, Gromada J . Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide. Diabetes 1997; 46: 615–621.

    Article  CAS  Google Scholar 

  47. Lu M, Wheeler MB, Leng XH, Boyd III AE . The role of the free cytosolic calcium level in beta-cell signal transduction by gastric inhibitory polypeptide and glucagon-like peptide I(7-37). Endocrinology 1993; 132: 94–100.

    Article  CAS  Google Scholar 

  48. Jones IR, Owens DR, Luzio S, Hayes TM . Glucose dependent insulinotropic polypeptide (GIP) infused intravenously is insulinotropic in the fasting state in type 2 (non-insulin dependent) diabetes mellitus. Horm Metab Res 1989; 21: 23–26.

    Article  CAS  Google Scholar 

  49. Ross SA, Brown JC, Dupre J . Hypersecretion of gastric inhibitory polypeptide following oral glucose in diabetes mellitus. Diabetes 1977; 26: 525–529.

    Article  CAS  Google Scholar 

  50. Theodorakis MJ, Carlson O, Muller DC, Egan JM . Elevated plasma glucose-dependent insulinotropic polypeptide associates with hyperinsulinemia in impaired glucose tolerance. Diabetes Care 2004; 27: 1692–1698.

    Article  CAS  Google Scholar 

  51. Atmaca M, Kuloglu M, Tezcan E, Ustundag B . Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. J Clin Psychiatry 2003; 64: 598–604.

    Article  CAS  Google Scholar 

  52. Melkersson KI, Dahl ML . Relationship between levels of insulin or triglycerides and serum concentrations of the atypical antipsychotics clozapine and olanzapine in patients on treatment with therapeutic doses. Psychopharmacology 2003; 170: 157–166.

    Article  CAS  Google Scholar 

  53. Salera M, Ebert R, Giacomoni P, Pironi L, Venturi S, Corinaldesi R et al. Adrenergic modulation of gastric inhibitory polypeptide secretion in man. Dig Dis Sci 1982; 27: 794–800.

    Article  CAS  Google Scholar 

  54. Aantaa R, Marjamaki A, Scheinin M . Molecular pharmacology of alpha 2-adrenoceptor subtypes. Ann Med 1995; 27: 439–449.

    Article  CAS  Google Scholar 

  55. Inagaki N, Seino Y, Takeda J, Yano H, Yamada Y, Bell GI et al. Gastric inhibitory polypeptide: structure and chromosomal localization of the human gene. Mol Endocrinol 1989; 3: 1014–1021.

    Article  CAS  Google Scholar 

  56. Someya Y, Inagaki N, Maekawa T, Seino Y, Ishii S . Two 3′,5′-cyclic-adenosine monophosphate response elements in the promoter region of the human gastric inhibitory polypeptide gene. FEBS Lett 1993; 317: 67–73.

    Article  CAS  Google Scholar 

  57. Leucht S, Wahlbeck K, Hamann J, Kissling W . New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 2003; 361: 1581–1589.

    Article  CAS  Google Scholar 

  58. 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 Pharmacol Exp Ther 2003; 305: 625–631.

    Article  CAS  Google Scholar 

  59. Chong VZ, Young LT, Mishra RK . cDNA array reveals differential gene expression following chronic neuroleptic administration: implications of synapsin II in haloperidol treatment. J Neurochem 2002; 82: 1533–1539.

    Article  CAS  Google Scholar 

  60. Goto A, Doering L, Nair VD, Mishra RK . Immunohistochemical localization of a 40-kDa catecholamine regulated protein in the nigrostriatal pathway. Brain Res 2001; 900: 314–319.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ontario Mental Health Foundation and National Institute of Health Grant NS20035 and the Canadian Institute of Health Research Grant MT2637.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario, Canada

    S Sondhi, J M Castellano, V Z Chong, R M Rogoza, K J Skoblenick, B A Dyck, J Gabriele, N Thomas, K Ki, Z B Pristupa, D MacCrimmon, P Voruganti, J Foster & R K Mishra

  2. Department of Psychiatry, Queens University, Kingston, Ontario, Canada

    A N Singh

Authors
  1. S Sondhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J M Castellano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V Z Chong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R M Rogoza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K J Skoblenick
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B A Dyck
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Gabriele
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K Ki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Z B Pristupa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A N Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D MacCrimmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P Voruganti
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. R K Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R K Mishra.

Additional information

Contacts: S Sondhi – shireen_sondhi@hotmail.com; JM Castellano – castej@mcmaster.ca; VZ Chong – chongv@mcmaster.ca; RM Rogoza – rainar@hotmail.com; KJ Skoblenick – skoblek@mcmaster.ca; BA Dyck – dyckba@mcmaster.ca; J Gabriele – gabriejp@mcmaster.ca; N Thomas – nthomas@mcmaster.ca; ZB Pristupa – z.pristupa@utoronto.ca; AN Singh – singha@post.queensu.ca; D MacCrimmon – maccrim@mcmaster.ca; P Voruganti – vorugl@mcmaster.ca; J Foster – jfoster@mcmaster.ca.

Preliminary results of this study were reported at the annual meeting of the Society for Neuroscience, 2003, San Diego CA, USA and at the Federation for American Societies of Experimental Biology Meeting in 2004, Washington, DC.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sondhi, S., Castellano, J., Chong, V. et al. cDNA array reveals increased expression of glucose-dependent insulinotropic polypeptide following chronic clozapine treatment: role in atypical antipsychotic drug-induced adverse metabolic effects. Pharmacogenomics J 6, 131–140 (2006). https://doi.org/10.1038/sj.tpj.6500346

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500346

Keywords

This article is cited by

Search

Advanced search

Quick links