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首页> 外文期刊>Molecular and Cellular Biology >The Combined Deletion of S6K1 and Akt2 Deteriorates Glycemic Control in a High-Fat Diet
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The Combined Deletion of S6K1 and Akt2 Deteriorates Glycemic Control in a High-Fat Diet

机译：S6K1和Akt2的联合删除恶化了高脂饮食中的血糖控制

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Signaling downstream of mechanistic target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) controls specific and distinct aspects of insulin action and nutrient homeostasis in an interconnected and as yet unclear way. Mice lacking the mTORC1 substrate S6 kinase 1 (S6K1) maintain proper glycemic control with a high-fat diet. This phenotype is accompanied by insulin hypersensitivity, Akt- and AMP-activated kinase upregulation, and increased lipolysis in adipose tissue and skeletal muscle. Here, we show that, when S6K1 inactivation is combined with the deletion of the mTORC2 substrate Akt2, glucose homeostasis is compromised due to defects in both insulin action and β-cell function. After a high-fat diet, the S6K1?/? Akt2?/? double-mutant mice do not become obese, though they are severely hyperglycemic. Our data demonstrate that S6K1 is required for pancreatic β-cell growth and function during adaptation to insulin resistance states. Strikingly, the inactivation of two targets of mTOR and phosphatidylinositol 3-kinase signaling is sufficient to reproduce major hallmarks of type 2 diabetes.
机译：雷帕霉素复合物1和2（mTORC1和mTORC2）的机械靶标下游信号传递以相互联系且尚不清楚的方式控制胰岛素作用和营养稳态的特定和不同方面。缺少mTORC1底物S6激酶1（S6K1）的小鼠可通过高脂饮食维持适当的血糖控制。该表型伴有胰岛素超敏反应，Akt和AMP激活的激酶上调，以及脂肪组织和骨骼肌中脂解的增加。在这里，我们表明，当S6K1失活与mTORC2底物Akt2的缺失结合在一起时，由于胰岛素作用和β细胞功能的缺陷，葡萄糖稳态受到损害。高脂饮食后， S6K1 ？/？ Akt2 ？/？双突变小鼠不变得肥胖，尽管他们严重高血糖。我们的数据表明，在适应胰岛素抵抗状态期间，胰岛β细胞生长和功能需要S6K1。令人惊讶的是，mTOR和磷脂酰肌醇3激酶信号转导的两个目标的失活足以重现2型糖尿病的主要特征。

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