MOE Key Laboratory of Model Animal for Disease Study, Department of Endocrinology, Nanjing Drum Tower Hospital, and Model Animal Research Center, School of Medicine, Nanjing University, Nanjing.
Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, China.
Diabetes. 2021 Aug;70(8):1826-1842. doi: 10.2337/db21-0039. Epub 2021 May 12.
Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160 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 AS160 mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160 rats. The AS160 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 AS160 mutation.
族群在生理和基因上适应了他们的饮食。因纽特人携带有一种常见的 AS160 突变，这种突变会导致 2 型糖尿病。由于人类研究的局限性，这种突变是否在因纽特人中进化赋予了适应性，以及它如何在饮食改变时导致代谢紊乱，目前还不得而知。在这里，我们开发了一种携带同源 AS160 突变的基因修饰大鼠模型，该模型模拟了表现出餐后高血糖和高胰岛素血症的人类患者。重要的是，富含糖的饮食会加重 AS160 大鼠的代谢异常。AS160 突变削弱了骨骼肌中占主导地位的长变体 AS160，而不影响次要的短变体 AS160，这抑制了肌肉葡萄糖利用，但诱导了脂肪酸氧化。这种燃料转换表明，传统上食用富含脂肪的低血糖饮食的因纽特人可能已经适应了这种情况。最后，诱导短变体 AS160 可恢复大鼠心肌细胞和小鼠模型中的葡萄糖利用。我们的发现为携带 AS160 突变的患者的精准治疗的发展提供了依据。
