Castellani Laura N, Peppler Willem T, Sutton Charles D, Whitfield Jamie, Charron Maureen J, Wright David C
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
Departments of Biochemistry, Obstetrics and Gynecology and Women's Health and Medicine (Endocrinology), Albert Einstein College of Medicine, Bronx, NY, USA.
Psychoneuroendocrinology. 2017 Aug;82:38-45. doi: 10.1016/j.psyneuen.2017.05.005. Epub 2017 May 3.
To determine if glucagon is involved in mediating the increase in blood glucose levels caused by the second-generation antipsychotic drug olanzapine.
Whole body glucagon receptor deficient mice (Gcgr) or WT littermate controls were injected with olanzapine (5mg/kg BW IP) and changes in blood glucose measured over the following 120min. Separate cohorts of mice were treated with olanzapine and changes in pyruvate tolerance, insulin tolerance and whole body substrate oxidation were determined.
Olanzapine treatment increased serum glucagon and lead to rapid increases in blood glucose concentrations in WT mice. Gcgr mice were protected against olanzapine-induced increases in blood glucose but this was not explained by differences in terminal serum insulin concentrations, enhanced AKT phosphorylation in skeletal muscle, adipose tissue or liver or differences in RER. In both genotypes olanzapine induced an equivalent degree of insulin resistance as measured using an insulin tolerance test. Olanzapine treatment led to an exaggerated glucose response to a pyruvate challenge in WT but not Gcgr mice and this was paralleled by reductions in the protein content of PEPCK and G6Pase in livers from Gcgr mice.
Gcgr mice are protected against olanzapine-induced increases in blood glucose. This is likely a result of reductions in liver glucose output, perhaps secondary to decreases in PEPCK and G6Pase protein content. Our findings highlight the central role of the liver in mediating olanzapine-induced disturbances in glucose homeostasis.
确定胰高血糖素是否参与介导第二代抗精神病药物奥氮平引起的血糖水平升高。
给全身胰高血糖素受体缺陷小鼠（Gcgr）或野生型同窝对照小鼠腹腔注射奥氮平（5mg/kg体重），并在接下来的120分钟内测量血糖变化。对另一组小鼠进行奥氮平处理，测定丙酮酸耐受性、胰岛素耐受性和全身底物氧化的变化。
奥氮平处理可使野生型小鼠血清胰高血糖素升高，并导致血糖浓度迅速升高。Gcgr小鼠对奥氮平诱导的血糖升高具有抵抗力，但这并非由终末血清胰岛素浓度差异、骨骼肌、脂肪组织或肝脏中AKT磷酸化增强或呼吸商差异所解释。在两种基因型小鼠中，通过胰岛素耐受性试验测得奥氮平诱导的胰岛素抵抗程度相当。奥氮平处理导致野生型小鼠而非Gcgr小鼠对丙酮酸刺激的血糖反应过度，且Gcgr小鼠肝脏中磷酸烯醇式丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6Pase）蛋白含量降低与此平行。
Gcgr小鼠对奥氮平诱导的血糖升高具有抵抗力。这可能是肝脏葡萄糖输出减少的结果，可能继发于PEPCK和G6Pase蛋白含量降低。我们的研究结果突出了肝脏在介导奥氮平引起的葡萄糖稳态紊乱中的核心作用。
