Here, we report that glibenclamide 1) protected the mouse insulinoma MIN6 cells against the apoptosis and loss of Cx36, which are induced by pro-inflammatory cytokines; 2) protected diabetes-prone NOD mice, in a dose-dependent manner, against the progressive development of hyperglycemia, as well as the loss of insulin-producing beta cells and of Cx36 expression; 3) did not stop insulitis progression, but induced a shift in the phenotype of immune cells remaining in the pancreatic draining lymph nodes to a CD44hiCD62L- effector profile. Here, GJD2 is linked to pancreatic insulinoma.