Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China.
Biomed Pharmacother. 2021 Jan;133:110912. doi: 10.1016/j.biopha.2020.110912. Epub 2020 Nov 17.
The present study aimed to investigate the possible effects of metformin on the olanzapine-induced insulin resistance in rats.
Rats were randomly divided into three groups: the control (Control) group, the olanzapine (Ola) group and the olanzapine + metformin (Ola + Met) group. Rats in the Ola group received olanzapine (8 mg/kg/day) intraperitoneally while rats in the Ola + Met group received olanzapine (8 mg/kg/day) intraperitoneally and metformin (300 mg/kg/day) orally for 8 weeks. Rats in the Control group received vehicle accordingly. Body weight and fasting blood glucose were recorded routinely. Inflammatory cytokines TNF-α, IL-6 and IL-1β and IL-10 were measured by ELISA. The gene expression of macrophages markers was examined by qPCR. The epididymal white adipose tissue, liver and skeletal muscle were also isolated for immunohistochemical analysis.
Olanzapine significantly induced body weight gain and insulin resistance compared to the control, which was markedly alleviated by metformin. Pro-inflammatory cytokines TNF-α, IL-6 and IL-1β were upregulated while the anti-inflammatory cytokine IL-10 was downregulated by olanzapine in plasma and epididymal white adipose tissue compared to the control, but not the liver and skeletal muscle. However, metformin co-administration significantly decreased the levels of TNF-α, IL-6 and IL-1β while increased the level of IL-10 in epididymal white adipose tissue compared to olanzapine-treated rats. Moreover, olanzapine treatment markedly increased the expression of the CD68 and the M1 macrophage markers while decreased the expression of the M2 macrophage markers in epididymal white adipose tissue in rats compared to the control. However, metformin co-treatment ameliorated the effects of olanzapine.
Our results suggest that metformin alleviated olanzapine-induced insulin resistance possibly by suppressing the inflammatory responses mediated by macrophage infiltration and polarization in epididymal white adipose tissue.
本研究旨在探讨二甲双胍对奥氮平诱导的大鼠胰岛素抵抗的可能作用。
将大鼠随机分为三组：对照组（Control）、奥氮平组（Ola）和奥氮平加二甲双胍组（Ola+Met）。奥氮平组大鼠腹腔内注射奥氮平（8mg/kg/天），奥氮平加二甲双胍组大鼠腹腔内注射奥氮平（8mg/kg/天）和二甲双胍（300mg/kg/天），连续 8 周。对照组大鼠给予相应的载体。常规记录体重和空腹血糖。通过 ELISA 测定炎性细胞因子 TNF-α、IL-6 和 IL-1β以及 IL-10 的表达。通过 qPCR 检测巨噬细胞标志物的基因表达。还分离附睾白色脂肪组织、肝脏和骨骼肌进行免疫组织化学分析。
与对照组相比，奥氮平显著诱导体重增加和胰岛素抵抗，而二甲双胍明显减轻了这种情况。与对照组相比，奥氮平使血浆和附睾白色脂肪组织中的促炎细胞因子 TNF-α、IL-6 和 IL-1β上调，而抗炎细胞因子 IL-10 下调，但在肝脏和骨骼肌中没有。然而，与奥氮平治疗组相比，二甲双胍联合给药显著降低了附睾白色脂肪组织中 TNF-α、IL-6 和 IL-1β的水平，同时增加了 IL-10 的水平。此外，与对照组相比，奥氮平处理显著增加了附睾白色脂肪组织中 CD68 和 M1 巨噬细胞标志物的表达，同时降低了 M2 巨噬细胞标志物的表达。然而，二甲双胍联合治疗改善了奥氮平的作用。
我们的结果表明，二甲双胍通过抑制附睾白色脂肪组织中巨噬细胞浸润和极化介导的炎症反应，缓解了奥氮平诱导的胰岛素抵抗。
