Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • Olanzapine has been reported to

    2021-10-19

    Olanzapine has been reported to attenuate insulin secretion, cause insulin resistance (Chintoh et al., 2008) and reduce whole body carbohydrate oxidation (Klingerman et al., 2014). However, a blunting of these effects in Gcgr−/− mice would not appear to explain the protection against olanzapine-induced increases in blood glucose. First, terminal serum insulin concentrations were similar in WT and Gcgr−/− mice following olanzapine treatment. Although we did not directly measure insulin secretion per se, equivalent circulating insulin levels would suggest that increases in insulin secretion do not explain the protection against olanzapine-induced hyperglycemia in Gcgr−/− mice. Second, AKT phosphorylation was not increased in liver, triceps muscle and gonadal adipose tissue from Gcgr−/− compared to WT mice following olanzapine treatment providing evidence that the response to endogenous insulin was similar between genotypes (though it should be noted that the threonine AKT phosphorylation was actually reduced in gonadal adipose tissue from Gcgr−/− mice). Consistent with these findings olanzapine treatment essentially prevented insulin-induced reductions in blood glucose in both genotypes during an insulin tolerance test. Lastly, olanzapine-induced reductions in RER, which are indicative of increases in fat and reductions in carbohydrate oxidation, were similar between genotypes providing evidence that differences in fuel oxidation do not explain the protection against hyperglycemia. In Mexiletine HCl to these findings we provide evidence that Gcgr−/− mice are protected against olanzapine-induced perturbations in liver glucose output. As reported in the current investigation, and by others (Girault et al., 2012), under basal, non-hyperinsulinemic conditions, acute olanzapine treatment did not reduce liver glycogen levels suggesting the involvement of olanzapine induced increases in gluconeogenesis. Prior work has shown that olanzapine treatment exacerbates the glucose response to a pyruvate challenge (Ikegami et al., 2013), a finding that was replicated in WT, but not Gcgr−/− mice, in the current study. These findings demonstrate that despite profound insulin resistance and alterations in fuel oxidation that Gcgr−/− mice are likely protected from olanzapine-induced hyperglycemia through reductions in liver glucose output. The blunted increase in blood glucose during a pyruvate tolerance test in Gcgr−/− mice suggests that gluconeogenesis is reduced in these animals. In keeping with this we found that the protein content of key gluconeogenic enzymes such as PEPCK and G6Pase were decreased in livers from Gcgr−/− mice, a finding that is supported by previous work demonstrating glucagon-mediated increases in the expression of G6Pase and PEPCK in hepatocytes (Budick-Harmelin et al., 2012) and reductions in PEPCK mRNA expression in livers from Gcgr−/− mice (Lee et al., 2012). These results provide evidence that the blunted increase in blood glucose with a pyruvate challenge in olanzapine treated Gcgr−/− mice could be secondary to reductions in the liver gluconeogenic machinery. Although Gcgr−/− were protected against olanzapine-induced increases in blood glucose, this dose of olanzapine only modestly increased glucagon levels in olanzapine treated C57BL6/J mice. These findings are in contrast to recent work demonstrating that serum glucagon levels were not elevated in rats following an intravenous infusion of olanzapine (Nagata et al., 2016). This discrepancy could be due to species related differences and/or the route of drug administration. Here, the complete protection against olanzapine-induced increases in blood glucose in Gcgr−/− mice in the face of only modest increases in serum glucagon with this treatment would likely suggest that a portion of the protective effect against olanzapine-induced hyperglycemia could be secondary to reductions in the glucagon mediated regulation of gluconeogenic enzymes such as PEPCK and G6Pase. In accordance with this, we found that epinephrine stimulated increases in blood glucose were also reduced in Gcgr−/− mice. While the current manuscript was in preparation, a recent report demonstrated an attenuation of olanzapine-induced increases in blood glucose in rats treated with the beta-adrenergic agonist propranolol (Nagata et al., 2016). These findings provide evidence that Gcgr−/− mice could be protected against olanzapine-induced increases in blood glucose secondary to reductions in catecholamine-mediated increases in liver glucose output.