Acute Peripheral but Not Central Administration of Olanzapine Induces Hyperglycemia Associated with Hepatic and Extra-Hepatic Insulin Resistance

Abstract

Atypical antipsychotic drugs such as Olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying the metabolic side-effects of these centrally acting drugs are still unknown to a large extent. We compared the effects of peripheral (intragastric; 3 mg/kg/h) versus central (intracerebroventricular; 30 µg/kg/h) administration of Olanzapine on glucose metabolism using the stable isotope dilution technique (Experiment 1) in combination with low and high hyperinsulinemic-euglycemic clamps (Experiments 2 and 3), in order to evaluate hepatic and extra-hepatic insulin sensitivity, in adult male Wistar rats. Blood glucose, plasma corticosterone and insulin levels were measured alongside endogenous glucose production and glucose disappearance. Livers were harvested to determine glycogen content. Under basal conditions peripheral administration of Olanzapine induced pronounced hyperglycemia without a significant increase in hepatic glucose production (Experiment 1). The clamp experiments revealed a clear insulin resistance both at hepatic (Experiment 2) and extra-hepatic levels (Experiment 3). The induction of insulin resistance in Experiments 2 and 3 was supported by decreased hepatic glycogen stores in Olanzapine-treated rats. Central administration of Olanzapine, however, did not result in any significant changes in blood glucose, plasma insulin or corticosterone concentrations nor in glucose production. In conclusion, acute intragastric administration of Olanzapine leads to hyperglycemia and insulin resistance in male rats. The metabolic side-effects of Olanzapine appear to be mediated primarily via a peripheral mechanism, and not to have a central origin.

In male rats, the ability of central insulin to suppress glucose production is impaired by olanzapine, whereas glucose uptake is left intact

“…To our knowledge, the only 2 published studies that found no effect of olanzapine on hepatic glucose production in rodents used either a pancreatic basal clamp (peripheral infusion of insulin 1 mU/ kg/min) 33 or measured glucose production following a central olanzapine injection under basal conditions (no insulin infusion). 34 These 2 studies used techniques that (in contrast to the hyperinsulinemic euglycemic clamp or an ICV insulin infusion) do not induce elevated central insulin. Furthermore, acute central olanzapine administration in rodents was found to induce hyperglycemia only in a postprandial state (where one would expect elevated physiologic levels of insulin or glucose that reach the brain) in association with increases in key gluconeogenic enzymes in the liver.…”

Olanzapine Activates Hepatic Mammalian Target of Rapamycin: New Mechanistic Insight into Metabolic Dysregulation with Atypical Antipsychotic Drugs

“…To date, very little is understood about the potential effects of OLZ administration on the peripheral organs critical for metabolic homeostasis. The liver is key for overall glucose and lipid homeostasis, and recent studies have suggested that the effect of OLZ on the liver may contribute to its metabolic disturbances (Girault et al, 2012). Therefore, we explored the effects of OLZ on indices of carbohydrate and lipid metabolism in this organ and determined the underlying mechanisms in a mouse model of OLZ exposure.…”

LLY-2707, A Novel Nonsteroidal Glucocorticoid Antagonist That Reduces Atypical Antipsychotic–Associated Weight Gain in Rats

“…The effects of the GRA compounds on glycemic regulation were evaluated using intragastric infusion of olanzapine. Previous studies have demonstrated that this method can increase plasma corticosterone and glucose without affecting plasma insulin concentrations in a time-dependent manner (Girault et al, 2012). We tested the hypothesis that pretreatment with GRAs can prevent this glucose excursion.…”

“…Therefore, we used an short-term intragastric infusion of olanzapine (Girault et al, 2012) to understand the potential direct effects of sGRAs on the hyperglycemia. By use of a similar methodology with an oral bolus administration, it was shown that AAPDs that increase body weight cause an increase in plasma glucose and corticosterone, whereas the APDs that do not increase body weight do not increase these parameters (Assie et al, 2008).…”

“…The studies and analytical work were performed under contract at Covance and Advion (Indianapolis, IN), respectively. (Girault et al, 2012) showing increases in plasma glucose after intragastric infusion of olanzapine. The live phase of the intragastric infusion studies was conducted at Bioanalytical Systems, Inc. (BASi, West Lafayette, IN).…”