摘要：SummaryThe rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene (TM6SF2) is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of theTM6SF2rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts. The E167K variant was significantly associated with T2D, especially in males. Using an E167K knockin (KI) mouse model, we found that male but not the female KI mice exhibited impaired glucose tolerance. As an ER membrane protein, TM6SF2 was found to interact with inositol-requiring enzyme 1 α (IRE1α), a primary ER stress sensor. The maleTm6sf2KI mice exhibited impaired IRE1α signaling in the liver. In conclusion, the E167K variant of TM6SF2 is associated with glucose intolerance primarily in males, both in humans and mice.Graphical abstractDisplay OmittedHighlights•TheTM6SF2E167K variant is significantly associated with T2D, primarily in males•Male, but not female,Tm6sf2KI mice exhibited impaired glucose tolerance•IRE1α signaling is attenuated in the liver of maleTm6sf2KI mice•IDE and LIPIN1 were dysregulated in the liver of male KI mice but not the femalesPhysiology; Molecular physiology; Diabetology; Genomics
