| Summary: | Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160 R684X 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 R693X mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160 R693X rats. The AS160 R693X 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 R684X mutation.
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