A preclinical evaluation of antipsychotic drug-induced metabolic side-effects : a focus on glucose dysregulation and insulin resistance

Second generation antipsychotic (SGA) drugs represent the pharmacotherapeutic drug treatment of choice for patients affected by psychosis. Despite their clinical benefits, some SGA drugs are associated with significant metabolic side-effects including weight gain, glucose intolerance, insulin resistance and hypertriglyceridemia that ultimately increases patient risk for the development of cardiometabolic disorders. Although abundant, preclinical literature on SGA drug-induced metabolic side-effects has failed to characterize an underlying mechanism to glucose derangements. We therefore completed seven studies to validate the use of a rat model of SGA drug-induced glucose dysregulation that will establish a consistent approach for future mechanistic studies of insight. We employed the intraperitoneal glucose tolerance test, the hyperinsulinemic-euglycemic clamp, as well as surrogate measures of metabolic indices to ascertain the pharmacological effects of SGA drugs specifically on hyperglycemia, glucose intolerance and insulin resistance. Antipsychotic drugs of higher metabolic liability (olanzapine and clozapine) parallel what is observed in humans and induced substantial glucose intolerance and insulin resistance that was both dose and time dependent. Antipsychotic drugs of lower metabolic liability (risperidone and haloperidol) were associated with modest effects on metabolic indices, compared to controls. The newer SGA drugs also demonstrated drug-dependent effects: iloperidone was associated with profound glucose intolerance and insulin resistance, while asenapine-induced effects were minimal, compared to controls. As for antipsychotic polypharmacy (the practice of when two antipsychotic drugs are administered together), either administrations of clozapine and haloperidol or clozapine and risperidone were found to cause substantially greater glucose intolerance, relative to the administration of a single drug. Chronic treatment with olanzapine produced sustained glucose intolerance and insulin resistance; whereas intermittent olanzapine treatment led to a first-ever report of the sensitization of glucose metabolism. Lastly, different classes of antidiabetic drug treatments or daily exercise intervention was found to partially ameliorate the metabolic side-effects of olanzapine. These data confirm that our current rodent paradigm parallels clinical literature. Our studies have provided insight into the metabolic influence of SGA drugs on peripheral target tissues such as hepatic, pancreatic and skeletal muscle. Ultimately, these results will further understanding of the underlying mechanisms by which SGA drugs cause glucose dysregulation and insulin resistance.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat