Tissue-Specific Splicing and Dietary Interaction of a Mutant As160 Allele Determine Muscle Metabolic Fitness in Rodents-猫眼课题宝

DOI：

10.2337/db21-0039

发表时间：

2021-05

期刊：

Diabetes

影响因子：

7.7

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Xinyu Yang;Qiaoli Chen;Q. Ouyang;Ping Rong;Weikuan Feng;Chao Quan;Min Li;Q. Jiang;H. Liang;Tong-Jin Zhao;H. Wang;Shuai Chen

族裔群体在生理和遗传上适应其饮食。因纽特人携带一种常见的AS160R684X突变，导致2型糖尿病。由于人类研究的局限性，这种突变是否在进化上赋予因纽特人适应能力，以及它如何在饮食变化后导致代谢紊乱，都是未知的。在这里，我们开发了一个基因修饰的大鼠模型轴承orthopathy AS160R693X突变，模仿人类患者表现出餐后高血糖症和高胰岛素血症。重要的是，高糖饮食会加重AS160R693X大鼠的代谢异常。AS160R693X突变减少了骨骼肌中的显性长变体AS160，而不影响次要短变体AS160，其抑制肌肉葡萄糖利用但诱导脂肪酸氧化。这种燃料转换表明因纽特人可能适应了传统上富含脂质的低血糖饮食。最后，短变异体AS160的诱导恢复了大鼠心肌细胞和小鼠模型中的葡萄糖利用。我们的研究结果对开发携带AS160R684X突变的患者的精确治疗具有意义。

Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160R684X mutation that causes type 2 diabetes. Whether this mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies. Here, we develop a genetically modified rat model bearing an orthologous AS160R693X mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160R693X rats. The AS160R693X mutation diminishes a dominant long-variant AS160 without affecting a minor short-variant AS160 in skeletal muscle, which suppresses muscle glucose utilization but induces fatty acid oxidation. This fuel switch suggests a possible adaptation in Inuit who traditionally had lipid-rich hypoglycemic diets. Finally, induction of the short-variant AS160 restores glucose utilization in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160R684X mutation.

Tissue-Specific Splicing and Dietary Interaction of a Mutant As160 Allele Determine Muscle Metabolic Fitness in Rodents

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