RT Journal Article
SR Electronic
T1 In male rats, the ability of central insulin to suppress glucose production is impaired by olanzapine, whereas glucose uptake is left intact
JF Journal of Psychiatry and Neuroscience
JO J Psychiatry Neurosci
FD Canadian Medical Association
SP 424
OP 431
DO 10.1503/jpn.170092
VO 42
IS 6
A1 Chantel Kowalchuk
A1 Celine Teo
A1 Virginia Wilson
A1 Araba Chintoh
A1 Loretta Lam
A1 Sri Mahavir Agarwal
A1 Adria Giacca
A1 Gary J. Remington
A1 Margaret K. Hahn
YR 2017
UL http://jpn.ca/content/42/6/424.abstract
AB 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.