Tissue-specific splicing and dietary interaction of a mutant As160 allele determine muscle metabolic fitness in rodents

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. 8; pp. 1826 - 1842
• Main Authors: Yang, Xinyu, Chen, Qiaoli, Ouyang, Qian, Rong, Ping, Feng, Weikuan, Quan, Chao, Li, Min, Jiang, Qing, Liang, Hui, Zhao, Tong-Jin, Wang, Hong Yu, Chen, Shuai
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.08.2021
• Subjects: Adaptation; Diabetes; Diabetes mellitus (non-insulin dependent); Diet; Glucose metabolism; Hyperglycemia; Hyperinsulinemia; Metabolic disorders; Metabolism; Minority & ethnic groups; Mutation; Myocytes; Oxidation; Rodents; Skeletal muscle
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/DB21-0039

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 utilisation 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 utilisation in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160 mutation.