IPMK modulates hepatic glucose production and insulin signaling
IPMK modulates hepatic glucose production and insulin signaling
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DOI：
10.1002/jcp.30827
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发表时间：
2022-07-13
影响因子：
5.6
通讯作者：
Kim, Sangwon F.
中科院分区：
文献类型：
--
作者：
Jung, Ik-Rak;Anokye-Danso, Frederick;Kim, Sangwon F.
肝脏葡萄糖生成（HGP）对于维持正常葡萄糖稳态至关重要。虽然肝脏胰岛素抵抗导致葡萄糖产生过多，但其机制尚不清楚。在这里，我们表明，肌醇多磷酸多激酶（IPMK），肌醇多磷酸生物合成的关键酶，在调节肝脏胰岛素信号转导和肝脏异生在体外和体内的作用。IPMK缺陷肝细胞表现出胰岛素诱导的Akt-FoxO 1信号转导激活降低。磷酸烯醇式丙酮酸羧激酶1（Pck 1）和葡萄糖6-磷酸酶（G6 pc）的信使RNA水平的表达，介导肝细胞生成的关键酶，在IPMK缺陷的肝细胞相比，野生型肝细胞增加。重要的是，重新表达IPMK可以恢复胰岛素敏感性，并增加IPMK缺陷肝细胞中的葡萄糖产量。此外，肝细胞特异性IPMK缺失加剧了高脂饮食小鼠的高血糖症和胰岛素敏感性，伴随着丙酮酸耐量试验期间HGP的增加和IPMK缺陷肝脏中Akt磷酸化的减少。我们的研究结果表明，IPMK介导的胰岛素信号和新生血管，并可能成为潜在的糖尿病治疗的目标。
Hepatic glucose production (HGP) is crucial for the maintenance of normal glucose homeostasis. Although hepatic insulin resistance contributes to excessive glucose production, its mechanism is not well understood. Here, we show that inositol polyphosphate multikinase (IPMK), a key enzyme in inositol polyphosphate biosynthesis, plays a role in regulating hepatic insulin signaling and gluconeogenesis both in vitro and in vivo. IPMK-deficient hepatocytes exhibit decreased insulin-induced activation of Akt-FoxO1 signaling. The expression of messenger RNA levels of phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose 6-phosphatase (G6pc), key enzymes mediating gluconeogenesis, are increased in IPMK-deficient hepatocytes compared to wild type hepatocytes. Importantly, re-expressing IPMK restores insulin sensitivity and alleviates glucose production in IPMK-deficient hepatocytes. Moreover, hepatocyte-specific IPMK deletion exacerbates hyperglycemia and insulin sensitivity in mice fed a high-fat diet, accompanied by an increase in HGP during pyruvate tolerance test and reduction in Akt phosphorylation in IPMK deficient liver. Our results demonstrate that IPMK mediates insulin signaling and gluconeogenesis and may be potentially targeted for treatment of diabetes.