Type 2 Diabetes Variants in the SLC16A11 Coding Region Are Not Loss-of-Function Mutations

This Matters Arising Response paper addresses the Hoch et al. (2019) Matters Arising paper published concurrently in this issue of Cell Reports. The genetic study in humans revealed a strong association of DNA variants in the SLC16A11 coding region with type 2 diabetes mellitus (T2DM). However, how these T2D variants affect the function of SLC16A11 remains controversial. In Zhao et al. (2019), with studies using genetic knockout mouse models and in vivo gene reconstitution experiments, we demonstrated gain of aberrant functions of mutant SLC16A11-carrying T2D variants, which cause liver steatosis and insulin resistance. Hoch et al. (2019) raise concerns regarding the animal models and experimental settings used in the study. Here, we address their concerns and emphasize that discoveries from the physiological studies of SLC16A11 by using mouse models disagree with the previous proposal by Rusu et al. (2017) that "therapeutics that enhance SLC16A11 levels or activity may be beneficial for T2D."