Type 2 diabetes variants cause aberrant function of SLC16A11

DNA variants in the SLC16A11 coding region were identified to be strongly associated with type 2 diabetes (T2DM) in Mexicans. Previous studies suggested that these variants either contained a cis-eQTL for lower SLC16A11 expression in liver, or generated a mutant protein with disrupted membrane localization and consequently reduced function. It was therefore proposed that to enhance SLC16A11 levels or activity may be of therapeutic beneficial. However, with knockout mouse models, here we show that Slc16a11 depletion caused no significant metabolic defects. Further studies found that reconstitution of the mutant, but not the wild-type Slc16a11, in the liver of knockout mice caused more triglyceride accumulation and induction of insulin resistance via upregulation of Lipin 1, suggesting gaining of aberrant functions of the mutant protein that affect triglyceride metabolism. Altogether, our study offered 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 warrant further investigation.