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首页> 外文期刊>Cell metabolism >APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice.
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APPL1 potentiates insulin-mediated inhibition of hepatic glucose production and alleviates diabetes via Akt activation in mice.

机译：APPL1增强胰岛素介导的肝葡萄糖生成的抑制作用，并通过Akt激活小鼠减轻糖尿病。

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Hepatic insulin resistance is the major contributor to fasting hyperglycemia in type 2 diabetes. Here we report that the endosomal adaptor protein APPL1 increases hepatic insulin sensitivity by potentiating insulin-mediated suppression of the gluconeogenic program. Insulin-stimulated activation of Akt and suppression of gluconeogenesis in hepatocytes are enhanced by APPL1 overexpression, but are attenuated by APPL1 knockdown. APPL1 interacts with Akt and blocks the association of Akt with its endogenous inhibitor tribble 3 (TRB3) through direct competition, thereby promoting Akt translocation to the plasma membrane and the endosomes for further activation. In db/db diabetic mice, the blockage of the augmented interaction between Akt and TRB3 by hepatic overexpression of APPL1 is accompanied by a marked attenuation of hyperglycemia and insulin resistance. These results suggest that the potentiating effects of APPL1 on insulin-stimulated suppression of hepatic glucose production are attributed to its ability in counteracting the inhibition of Akt activation by TRB3.
机译：肝胰岛素抵抗是2型糖尿病空腹高血糖的主要因素。在这里我们报告说，内体衔接蛋白APPL1通过增强胰岛素介导的糖异生程序的抑制作用来增加肝胰岛素敏感性。胰岛素刺激的Akt激活和肝细胞糖异生的抑制通过APPL1过表达增强，但通过APPL1敲低减弱。 APPL1与Akt相互作用，并通过直接竞争阻止Akt与其内源性抑制剂tribble 3（TRB3）的缔合，从而促进Akt易位至质膜和内体以进一步激活。在db / db糖尿病小鼠中，APPL1的肝过表达会阻断Akt和TRB3之间增强的相互作用，并伴有高血糖和胰岛素抵抗的明显减弱。这些结果表明APPL1对胰岛素刺激的肝葡萄糖生成抑制的增强作用归因于其抵消TRB3对Akt激活的抑制作用的能力。

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