Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats

Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats

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J Psychiatry Neurosci 2012;37(6):407-15

Heidi N. Boyda, BSc; Ric M. Procyshyn, PharmD, PhD; Lurdes Tse, MSc; Erin Hawkes, MSc; Chen Helen Jin, MD; Catherine C.Y. Pang, PhD; William G. Honer, MD; Alasdair M. Barr, PhD

Boyda, Tse, Hawkes, Jin, Pang, Barr — Department of Anesthesiology and Pharmacology, University of British Columbia; Procyshyn, Honer — Department of Psychiatry, University of British Columbia; Procyshyn, Honer, Barr — British Columbia Mental Health & Addictions Research Institute, Vancouver, BC

Abstract

Background: The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents.

Methods: We compared the effects of 3 distinct classes of anti dia betic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapineinduced metab olic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assessment of insulin resist ance equation.

Results: Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels.

Limitations: We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by anti diabetic treatments.

Conclusion: The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.


Submitted Sept. 30, 2011; Revised Feb. 2, Mar. 12, 20, 2012; Accepted Mar. 22, 2012.

Acknowledgements: The current research was supported by grants from the British Columbia Provincial Health Services Authority and National Sciences and Engineering Research Council of Canada (NSERC) grant 356069-09 to A.M. Barr, and NSERC grant 355912-11 to C.C.Y. Pang. A.M. Barr is a Canadian Institutes of Health Research (CIHR) New Investigator, and H.N. Boyda is a CIHR Banting scholar.

Competing interests: None declared for H.N. Boyda, L. Tse, E. Hawkes and C.C.Y. Pang. R.M. Procyshyn declares having consulted for AstraZeneca, Bristol-Myers Squibb, Janssen, Sunovion and Pfizer; received lecture fees from AstraZeneca, Bristol-Myers Squibb, Otsuka and Pfizer; and developed educational presentations for Bristol- Myers Squibb and Pfizer. C.H. Jin declares having received a student award from the NSERC to fund a summer research project. W.G.Honer declares advisory board membership with Roche Canada and In Silico Biosciences; having received consultant fees from Novartis and the Canadian Agency for Drugs and Technology in Health; receiving royalties from antibody manufacturers for licenses held by his university; and having received travel support from multiple academic and health authorities for presentations. A.M. Barr declares advisory board membership with Roche Canada; having acted as legal consultant for Eli Lilly Canada; and having a grant pending with BMS Canada through his institution.

Contributors: H.N. Boyda, R.M. Procyshyn, C.C.Y. Pang and A.M. Barr designed the study. H.N. Boyda, L. Tse, E. Hawkes, C.H. Jin and A.M. Barr acquired the data, which H.N. Boyda, W.G. Honer and A.M. Barr analyzed. H.N. Boyda, R.M. Procyshyn, C.C.Y. Pang and A.M. Barr wrote the article, which H.N. Boyda, L. Tse, E. Hawkes, C.H. Jin, W.G. Honer and A.M. Barr reviewed. All authors approved the article’s publication.

DOI: 10.1503/jpn.110140

Correspondence to: A.M. Barr, Department of Anesthesiology and Pharmacology, University of British Columbia, 2176 Health Sciences Mall,
Vancouver BC V6T 1Z3; albarr@interchange.ubc.ca