Insulin exerts its potent effects on hepatic glucose fluxes via direct and indirect mechanisms. Whereas a liver-specific insulin receptor (IR) knockout (LIRKO) mouse exhibits glucose intolerance as well as insulin resistance, it is unclear whether a more acute decrease in the expression of hepatic IR would be sufficient to induce hepatic insulin resistance. Here we report that the downregulation of hepatic IR expression by up to 95 does not modify hepatic insulin action. The i.p. administration (2 injections over 1 week) of an antisense oligodeoxynucleotide (ASO) directed to reduce insulin expression downregulated hepatic IR expression in C57BL6J mice. A high dose of IR-ASO decreased IR protein approximately 95, while a control-ASO failed to modify IR expression. At this dose, the IR-ASO also decreased IR expression in adipose tissue but did not significantly decrease IR expression in hypothalamus or skeletal muscle. Insulin action was assessed with insulin clamp studies in conscious mice. The rate of glucose infusion during the clamp studies was comparable in control-ASO- and IR-ASO-treated mice. Importantly, the depletion of liver IR protein markedly impaired downstream insulin signaling in the liver, but it failed to modify the rate of glucose production. Thus, near ablation of liver IR does not alter insulin action on glucose production.
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机译：胰岛素通过直接和间接机制对肝葡萄糖通量发挥其有效作用。虽然肝脏特异性胰岛素受体 （IR） 敲除 （LIRKO） 小鼠表现出葡萄糖耐受不良和胰岛素抵抗，但尚不清楚肝脏 IR 表达的更急剧下降是否足以诱导肝胰岛素抵抗。在这里，我们报告说，肝脏 IR 表达下调高达 95% 不会改变肝脏胰岛素作用。 腹腔注射（1周内2次注射）反义寡脱氧核苷酸（ASO）旨在降低胰岛素表达，下调C57BL6J小鼠的肝IR表达。高剂量的 IR-ASO 使 IR 蛋白减少约 95%，而对照 ASO 未能改变 IR 表达。在该剂量下，IR-ASO 还降低了脂肪组织中的 IR 表达，但没有显着降低下丘脑或骨骼肌中的 IR 表达。通过胰岛素钳夹研究评估有意识的小鼠的胰岛素作用。钳夹研究期间的葡萄糖输注速率在对照ASO和IR-ASO治疗的小鼠中具有可比性。重要的是，肝脏IR蛋白的消耗显着损害了肝脏中下游胰岛素信号传导，但未能改变葡萄糖的产生速率。因此，肝脏 IR 的近消融不会改变胰岛素对葡萄糖生成的作用。
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