PTP1B deficiency protects against metabolic dysfunction in glucose homeostasisupon Olanzapine intraperitoneal treatment

Abstract

Schizophrenia is a chronic mental disorder that affects approximately 50 million people worldwide. Also, it is associated with psychotic experiences that not allow patients to have a normal life. Fortunately, treatments used can suppress the symptomatology and lead to a productive life and integration in the society. According to the current guidelines, the first line in schizophrenia’s therapy are the second generation antipsychotic drugs (SGA). Besides being D2 receptors antagonists/partial agonists, the SGAs have the ability to interact also with serotonergic, histaminergic and other receptors; minimizing the symptomatology and not resulting in neurological side effects (contrarily to first generation antipsychotic drugs). Nevertheless, recent clinical observations show a variety of metabolic dysfunctions in patients under SGAs treatment, such as abnormal gain weight, hyperglycemia and dyslipidemia. However, the molecular mechanisms behind these alterations are still very poorly understood. Having this in consideration, the objective of this work was to study the effect of Olanzapine administration in wild-type (WT) and PTP1B-deficient (KO) mice on glucose homeostasis and the mechanisms involved. Of interest, PTP1B is the main tyrosine phosphatase of the insulin receptor, and PTP1B KO mice are protected against insulin resistance and development of type 2 diabetes mellitus. After administration of 10 mg/kg/day of Olanzapine for 8 weeks to WT and PTP1B-KO mice, the glucose homeostasis tests suggest that Olanzapine induced insulin resistance only in WT mice. Also, primary hepatocytes from WT mice treated with Olanzapine showed lower glucose uptake than those from non-treated WT mice. In contrast, Olanzapine treatment of PTP1B KO mice significantly increased hepatocyte glucose uptake, suggesting that Olanzapine-induced insulin resistance is at least in part dependent on PTP1B. These results support the relevance of PTP1B in Olanzapine-induced insulin resistance in hepatocytes.