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

<div><p>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.</p> </div

Plasma Olanzapine levels after intragastric (IG) and intracerebroventricular (ICV) infusion of Olanzapine.

<p>(IG: Vehicle group n = 5, Olanzapine group n = 6 and ICV Vehicle group n = 8 and Olanzapine group n = 12) Plasma Olanzapine levels are significantly higher in IG-Olanzapine-treated than in IG-vehicle-infused animals (One-Way ANOVA, p<0.001), or ICV-Olanzapine animals (2-Way ANOVA, <i>Administration route * Treatment</i> p<0.001). Plasma Olanzapine levels of ICV-Olanzapine animals are not significantly different from the ICV-Vehicle animals (One-Way ANOVA, p = 0.2). Vehicle-treated animals  =  white bars; Olanzapine-treated animals  =  black bars; *p<0.001.</p

Effects of ICV infusion of Olanzapine.

<p>(Vehicle group n = 6, Olanzapine group n = 9). 2a: Glucose evolution before (t = 90 to t = 100) and during (t = 120 to t = 260) ICV Olanzapine infusion (30 µg/kg/h). No significant differences between the 2 groups were detected (ANOVA repeated measures; <i>Time,</i> p<0.001; <i>Time * Group,</i> p = 0.59; <i>Group,</i> p = 0.635). 2b: Endogenous glucose production before (t = 90 to t = 100) and during (t = 120 to t = 260) ICV Olanzapine infusion. No significant changes were detected (ANOVA repeated measures; <i>Time,</i> p = 0.731; <i>Time * Group,</i> p = 0.709; <i>Group,</i> p = 0.84). 2c: Corticosterone levels before (t = 90 to t = 100) and during (t = 120 to t = 260) ICV Olanzapine infusion. No significant changes were detected (ANOVA repeated measures; <i>Time,</i> p = 0.971; <i>Time * Group,</i> p = 0.631; <i>Group,</i> p = 0.546). 2d: Plasma insulin levels before (mean of time points t = 90 and t = 100) and at the end (mean of time points t = 220 and t = 260) of the ICV infusion of Olanzapine. No significant changes were detected (ANOVA repeated measures; <i>Time,</i> p = 0.722; <i>Time * Group,</i> p = 0.638; <i>Group,</i> p = 0.274). Vehicle-treated animals  =  white dots; Olanzapine-treated animals  =  black dots.</p

Effects of intragastric infusion of Olanzapine on liver glycogen content in Experiments 1, 2 and 3.

<p>6a: During Experiment-1 hepatic glycogen levels show a non-significant increase in the Olanzapine-treated animals (p = 0.096; T-test). 6b: During the low-level hyperinsulinemic-euglycemic clamp (Experiment-2) hepatic glycogen levels are decreased in the Olanzapine-treated animals (p = 0.007; T-test). 6c: During the high-level hyperinsulinemic-euglycemic clamp (Experiment-3) the Olanzapine-treated animals show significantly less hepatic glycogen storage than the control group (p = 0.043; T-test). Vehicle-treated animals  =  white bars; Olanzapine-treated animals  =  black bars. Abs/mg  =  Absorption measured at 600 nm per mg wet tissue.</p

Effects of intragastric infusion of Olanzapine.

<p>(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; <i>Time,</i> p<0.001; <i>Time * Group,</i> p<0.001; <i>Group,</i> 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; <i>Time,</i> p = 0.426; <i>Time * Group,</i> p = 0.937; <i>Group,</i> 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; <i>Time,</i> p<0.001; <i>Time * Group,</i> p = 0.58; <i>Group,</i> 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; <i>Time,</i> p = 0.601; <i>Time * Group,</i> p = 0.981; <i>Group,</i> p = 0.834). Vehicle-treated animals  =  white dots; Olanzapine-treated animals  =  black dots.</p

Effects of intragastric infusion of Olanzapine on liver insulin sensitivity (Experiment 2).

<p>(Vehicle group n = 8, Olanzapine group n = 7) 4a: Endogenous glucose production at basal (mean of 3 time points: t = 90 to t = 100; white bars) and during the hyperinsulinemic state (mean of 5 time points: t = 250 to t = 290; black bars). EGP significantly decreased during the hyperinsulinemic state for the vehicle group (p = 0.018, One-Way ANOVA) and remained unchanged in the Olanzapine group (p = 0.111, One-Way ANOVA). 4b: Glucose uptake at basal (mean of 3 time points: t = 90 to t = 100; white bars) and during the hyperinsulinemic state (mean of 5 time points: t = 250 to t = 290; black bars). Glucose uptake is significantly increased in both the vehicle (p = 0.002, One-Way ANOVA) and Olanzapine group (p = 0.046, One-Way ANOVA). 4c: Plasma corticosterone levels were significantly elevated by the IG infusion of Olanzapine (ANOVA repeated measures; <i>Time,</i> p<0.001; <i>Time * Group,</i> p<0.001; <i>Group,</i> p = 0.039). Vehicle-treated animals  =  white dots; Olanzapine-treated animals  =  black dots. 4d: Plasma insulin levels were elevated 1.3-fold during the hyperinsulinemic state (mean of 3 time points; black bars) compared to the basal level (mean of 2 time points; white bars) (ANOVA repeated measures; <i>Time,</i> p = 0.062; <i>Time * Group,</i> p = 0.956; <i>Group,</i> p = 0.706). *p<0.05,**p<0.001.</p

Assessment of fitness and vector competence of a New Caledonia <i>wMel Aedes aegypti</i> strain before field-release.

BACKGROUND: Biological control programs involving Wolbachia-infected Aedes aegypti are currently deployed in different epidemiological settings. New Caledonia (NC) is an ideal location for the implementation and evaluation of such a strategy as the only proven vector for dengue virus (DENV) is Ae. aegypti and dengue outbreaks frequency and severity are increasing. We report the generation of a NC Wolbachia-infected Ae. aegypti strain and the results of experiments to assess the vector competence and fitness of this strain for future implementation as a disease control strategy in Noumea, NC. METHODS/PRINCIPAL FINDINGS: The NC Wolbachia strain (NC-wMel) was obtained by backcrossing Australian AUS-wMel females with New Caledonian Wild-Type (NC-WT) males. Blocking of DENV, chikungunya (CHIKV), and Zika (ZIKV) viruses were evaluated via mosquito oral feeding experiments and intrathoracic DENV challenge. Significant reduction in infection rates were observed for NC-wMel Ae. aegypti compared to WT Ae. aegypti. No transmission was observed for NC-wMel Ae. aegypti. Maternal transmission, cytoplasmic incompatibility, fertility, fecundity, wing length, and insecticide resistance were also assessed in laboratory experiments. Ae. aegypti NC-wMel showed complete cytoplasmic incompatibility and a strong maternal transmission. Ae. aegypti NC-wMel fitness seemed to be reduced compared to NC-WT Ae. aegypti and AUS-wMel Ae. aegypti regarding fertility and fecundity. However further experiments are required to assess it accurately. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that the NC-wMel Ae. aegypti strain is a strong inhibitor of DENV, CHIKV, and ZIKV infection and prevents transmission of infectious viral particles in mosquito saliva. Furthermore, our NC-wMel Ae. aegypti strain induces reproductive cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, supporting field-releases in Noumea, NC