Gain-of-Function Mutations of SLC16A11 Contribute to the Pathogenesis of Type 2 Diabetes

DNA variants in the SLC16A11 coding region were identified to be strongly associated with type 2 diabetes (T2DM) in a Mexican population. Previous studies suggested that these variants disrupt SLC16A11 function and therefore proposed to revive SLC16A11 levels or activity to achieve therapeutic benefit. However, with knockout mouse models, here we show that Slc16a11 depletion has no significant metabolic defects. Further studies demonstrate that reconstitution of the mutant, but not the wild-type Slc16a11, in the liver of knockout mice causes more triglyceride accumulation and induction of insulin resistance via upregulation of lipin 1, suggesting gaining of aberrant functions of the mutant protein that affects lipid metabolism. Our findings offer a different explanation to the function of these diabetic variants, challenging the concept of enhancing SLC16A11 function to treat T2DM. The contradictory results by our and previous studies suggest that how the SLC16A11 locus contributes to human metabolism warrants further investigation. [Display omitted] •Slc16a11 knockout mice have minimal metabolic consequences•Mice carrying SLC16A11 mutations have disrupted lipid metabolism and fatty liver•Mutant SLC16A11 upregulates lipin 1 and increases liver triglyceride accumulation Zhao et al. show that genetic variants associated with type 2 diabetes in the SLC16A11 coding region produce a gain-of-function mutant protein that affects lipid metabolism in the liver.