Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway

Dysfunction or death of pancreatic beta cells underlies both types of diabetes. This functional decline begins with beta cell stress and de-differentiation. Current drugs for T2D lower blood glucose levels, but do not directly alleviate beta cell stress nor prevent, let alone reverse, beta cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature beta cells, is down-regulated in the early stages of T2D in mice and when beta cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature beta cell state, we screen for factors that reverse beta cell de-differentiation. We find that a small molecule inhibitor of TGF beta receptor I (Alk5) protects cells from the loss of key beta cell transcription factors and restores a mature beta cell identity even after exposure to prolonged and severe diabetes.