A growing body of literature has linked atypical antipsychotics (AAPs) to an increased propensity for weight gain and metabolic disturbances, including type 2 diabetes. While weight gain is a leading risk factor for diabetes, evidence suggests that AAPs may influence glucose homeostasis independently of changes in adiposity. These ‘direct’ drug effects have been consistently supported by animal models, where following even a single dose of certain AAPs immediate effects are observed with noted perturbations on insulin sensitivity, and insulin secretion. However, the mechanisms underlying these effects remain poorly understood. Also, the translational value of the acute dosing rodent model has not been established in humans. As such, we set out to first elucidate mechanisms of these ‘direct’ effects by deconstructing antipsychotic receptor binding profiles using selective antagonists and gold standard clamping techniques to examine effects on glucose metabolism. We also investigated antipsychotic administration directly into the brain in rodents to tease out central vs. peripheral effects on glucose metabolism. Finally, we examined whether the effects of a single dose of olanzapine on glucose metabolism could be replicated in healthy humans, independently of adiposity or the confounding effects of the illness of schizophrenia. Our findings suggest that cholinergic, serotonergic, and dopaminergic pathways may be involved in antipsychotic-induced glucose dysregulation. We also suggest that such effects may be mediated in part through the central nervous system. Our results in humans suggest that acute drug effects may be less pronounced than in rodents, failing to note an effect on insulin sensitivity or secretion, but observing other early perturbations in lipid and glucose metabolism. Taken together, the work here begins to elucidate mechanisms underlying the diabetogenic risk associated with AAPs, findings which have important implications given the widespread use of these drugs, as well as the increased mortality attributable to cardiovascular disease that defines those with schizophrenia.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/35834 |
| Date | 07 August 2013 |
| Creators | Hahn, Margaret |
| Contributors | Remington, Gary |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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