In male rats, the ability of central insulin to suppress glucose production is impaired by olanzapine, whereas glucose uptake is left intact

In male rats, the ability of central insulin to suppress glucose production is impaired by olanzapine, whereas glucose uptake is left intact

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J Psychiatry Neurosci 2017;42(6):424-431

Chantel Kowalchuk, BSc*; Celine Teo, BHSc*; Virginia Wilson, MSc; Araba Chintoh, PhD; Loretta Lam, BSc; Sri Mahavir Agarwal, MBBS, MD; Adria Giacca, MD; Gary J. Remington, MD, PhD; Margaret K. Hahn, MD, PhD

Abstract

Background: Insulin receptors are widely expressed in the brain and may represent a crossroad between metabolic and cognitive disorders. Although antipsychotics, such as olanzapine, are the cornerstone treatment for schizophrenia, they are associated with high rates of type 2 diabetes and lack efficacy for illness-related cognitive deficits. Historically, this risk of diabetes was attributed to the weight gain propensity of antipsychotics, but recent work suggests antipsychotics can have weight-independent diabetogenic effects involving unknown brain-mediated mechanisms. Here, we examined whether antipsychotics disrupt central insulin action, hypothesizing that olanzapine would impair the well-established ability of central insulin to supress hepatic glucose production.

Methods: Pancreatic euglycemic clamps were used to measure glucose kinetics alongside a central infusion of insulin or vehicle into the third ventricle. Male rats were pretreated with olanzapine or vehicle per our established model of acute olanzapine-induced peripheral insulin resistance. Groups included (central–peripheral) vehicle–vehicle (n = 11), insulin–vehicle (n = 10), insulin–olanzapine (n = 10) and vehicle–olanzapine (n = 8).

Results: There were no differences in peripheral glucose or insulin levels. Unexpectedly, we showed that central insulin increased glucose uptake, and this effect was not perturbed by olanzapine. We replicated suppression of glucose production by insulin (clamp relative to basal: 77.9% ± 13.1%, all p < 0.05), an effect abolished by olanzapine (insulin–olanzapine: 7.7% ± 14%).

Limitations: This study used only male rats and an acute dose of olanzapine.

Conclusion: To our knowledge, this is the first study suggesting olanzapine may impair central insulin sensing, elucidating a potential mechanism of antipsychotic-induced diabetes and opening avenues of investigation related to domains of schizophrenia psychopathology.


Submitted May 7, 2017; Revised June 20, 2017; Revised July 13, 2017; Accepted July 14, 2017; Early-released Oct. 17, 2017

*These authors contributed equally to this work.

Acknowledgements: The authors thank Dr. Tony Lam from the University of Toronto for his advice on the pancreatic euglycemic clamp protocol, Dr. Alan Wilson from the Centre for Addiction and Mental Health (CAMH) for helping with experiments, and Marcos Sanchez from CAMH for his assistance in statistical analysis.

Affiliations: From the Centre for Addiction and Mental Health, Toronto, Ont., Canada (Kowalchuk, Teo, Wilson, Chintoh, Agarwal, Remington, Hahn); the Institute of Medical Sciences, University of Toronto, Toronto, Ont., Canada (Kowalchuk, Giacca, Remington, Hahn); the Department of Psychiatry, University of Toronto, Toronto, Ont., Canada (Chintoh, Remington, Hahn); and the Department of Physiology, University of Toronto, Toronto, Ont., Canada (Lam, Giacca).

Funding: This research was funded by the Banting and Best Diabetes Centre, the Department of Psychiatry University of Toronto Excellence Fund, and the Banting Research Foundation Discovery Award.

Competing interests. G. Remington has received consultant fees from Neurocrine Biosciences and Synchroneuron, as well as research support from Novartis. No other competing interests declared.

Contributors: A. Chintoh, G. Remington and M. Hahn designed the study. C. Kowalchuk, C. Teo, V. Wilson and L. Lam acquired the data, which C. Kowalchuk, S. Agarwal, A. Giacca, G. Remington and M. Hahn analyzed. C. Kowalchuk and M. Hahn wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.170092

Correspondence to: M.K. Hahn, Centre for Addiction and Mental Health, 250 College St, Toronto ON M5T 1R8; margaret.hahn@camh.ca