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

et al. (2012) Acute Peripheral but Not Central Administration of Olanzapine Induces Hyperglycemia Associated with Hepatic and Extra-Hepatic Insulin Resistance. PLoS ONE 7(8): e43244. doi:10.1371/journal.pone.0043244 Acute Peripheral but Not Central Administration of Olanzapine Induces Hyperglycemia Associated with Hepatic and Extra-Hepatic Insulin Resistance Elodie M. Girault 0 Anneke Alkemade 0 Ewout Foppen 0 Marie tte T. Ackermans 0 Eric Fliers 0 Andries Kalsbeek 0 Michael Bader, Max-Delbru ck Center for Molecular Medicine (MDC), Germany 0 1 Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Science , Amsterdam , The Netherlands , 2 Department of Endocrinology and Metabolism, Academic Medical Center (AMC), University of Amsterdam , Amsterdam , The Netherlands , 3 Laboratory of Endocrinology, Department of Clinical Chemistry, Academic Medical Center (AMC), University of Amsterdam , Amsterdam , The Netherlands 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 mg/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 Olanzapinetreated 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. - Funding: This work was supported in part by a grant from Top Institute Pharma (project T2-105). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. Competing Interests: The authors have declared that no competing interests exist. Atypical antipsychotic drugs (AAPDs) are increasingly replacing the use of typical antipsychotics due to their decreased risk for extrapyramidal side-effects [1] and their higher efficacy in the treatment of negative symptoms of schizophrenia [24]. However, some AAPDs are associated with unfavorable metabolic sideeffects such as weight gain and insulin resistance [3,5]. Epidemiologic studies showed that Olanzapine is one of the AAPDs that causes the most pronounced weight gain [6]. Also clinically, Olanzapine represents one of the atypical antipsychotics with the greatest risk of inducing weight gain and/or metabolic disturbances [7]. These metabolic side-effects, especially weight gain, decrease patients compliance [8] even though Olanzapine is a very effective drug in terms of symptom reduction [4,9]. Moreover, weight gain and insulin resistance are risk factors for type 2 diabetes and cardiovascular diseases [10]. The mechanisms underlying Olanzapine-induced metabolic disturbances are still unclear. Olanzapine is known to bind to a great number of receptors, such as the histamine H1 receptor [11,12], the serotonin 5-HT2c receptor [1315], the adrenergic a2 and b3 receptors, the acetylcholine m3 receptor (high affinity) and the dopamine 2 (D2) receptor (low affinity) [16,17]. In addition, it is not obvious whether the metabolic side-effects are mediated by central or peripheral effects of the drug. The principal mechanism of action of AAPDs is clearly based on their actions in the central nervous system (CNS), but the receptors they bind to are also widely expressed in peripheral tissues such as the liver [1822]. In rat models, it has been shown that an acute subcutaneous administration of Olanzapine induces insulin resistance by increasing hepatic glucose production and decreasing glucose uptake [23]. These findings indicate that the Olanzapine-induced metabolic changes can occur rapidly, and even before the weight gain occurs, indicating that these effects are not secondary to the weight gain. Two studies investigated possible central effects of Olanzapine using acute intracerebroventricular (ICV) infusions of the drug, however, whilst one study reported Olanzapine to induce metabolic changes [24] the other study found no metabolic changes after the central administration [25]. Neither of these two studies published plasma levels of Olanzapine post-infusion, Figure 1. Effects of intragastric infusion of Olanzapine. (Vehicle group n = 5, Olanzapine group n = 6). 1a: Glucose evolution before (t = 90 to t = 100) and during (t = 120 to t = 240) the intragastric infusion of Olanzapine infusion (3 mg/kg/h). Glycemia significantly increased after 60 min of Olanzapine infusion (*p,0.05, **p,0.001; ANOVA repeated measures; Time, p,0.001; Time * Group, p,0.001; Group, p = 0.001). 1b: Endogenous glucose production before (t = 90 to t = 100) and during (t = 120 to t = 240) intragastric Olanzapine infusion. No significant changes were observed (ANOVA repeated measures; Time, p = 0.426; Time * Group, p = 0.937; Group, p = 0.356). 1c: Corticosterone levels before (t = 90 to t = 100) and during (t = 120 to t = 240) intragastric Olanzapine infusion. Corticosterone levels are significantly higher in the Olanzapine group only at t = 220 (*p,0.05; ANOVA repeated measures; Time, p,0.001; Time * Group, p = 0.58; Group, p = 0.039). 1d: Plasma insulin levels before (mean of time points t = 90 and t = 100) and at the end (mean of time points t = 180 and t = 220) of the intragastric infusion of Olanzapine. No significant differences were detected (ANOVA repeated measures; Time, p = 0.601; Time * Group, p = 0.981; Group, p = 0.834). Vehicle-treated animals = white dots; Olanzapine-treated animals = black dots. doi:10.1371/journal.pone.0043244.g001 therefore a possible peripheral effect due to leakage cannot be excluded. In ord (...truncated)