217. Olanzapine Abolishes the Ability of Central Insulin to Inhibit Hepatic Glucose Production

Abstract

Background: Atypical antipsychotics (AAPs), such as olanzapine (OLA), are widely prescribed but are associated with high rates of type 2 diabetes. Historically, the risk of diabetes was attributed to the weight gain propensity of AAPs; however, recent work shows that AAPs (a) can have immediate effects independent of weight gain and (b) can dysregulate glucose homeostasis via the brain. In addition, links between central insulin pathways and AAP therapeutic efficacy have been proposed. Thus, understanding brain-mediated glucose dysregulation may be critical not only to treating these side-effects, but to maximizing AAP efficacy. We aimed to identify the link between AAPs and brain-mediated glucose dysregulation by examining whether OLA causes insulin resistance by impairing central insulin sensing. Methods: Euglycemic pancreatic clamps were used to measure hepatic glucose production and peripheral glucose disposal. Rats were subcutaneously administered OLA or vehicle (VEH), and an intracerebroventricular (ICV) infusion of insulin or vehicle (VEH) was administered into the 3rd ventricle. The treatment groups were as follows (ICV-peripheral): VEH-VEH; VEH-OLA; INS-OLA; INS-VEH. Results: There were no differences in glucose or insulin levels between any groups during the basal or clamp phase. The glucose infusion rate, a measure of whole body insulin sensitivity, was increased in the INS-VEH and INS-OLA groups relative to VEH-VEH and VEH-OLA groups. Glucose uptake was also increased in the INS-VEH group relative to VEH-VEH, and OLA co-administration did not influence this increase. The INS-VEH group demonstrated significant suppression of hepatic glucose production relative to basal phase, as to be expected, but this suppression effect was no longer observed with OLA coadministration. Conclusion: OLA abolishes the ability of a central insulin infusion to suppress HGP, suggesting OLA induces central insulin resistance. This supports that notion that atypical antipsychotics such as OLA can induce central insulin resistance to result in impaired whole body insulin sensitivity, separate from changes in adiposity or weight gain. Future investigations into the specific mechanisms of AAP-induced central insulin resistance are necessary and suggested to aid in developing pharmaceutical treatments without adverse metabolic effects.