Type 2 Diabetes and Congenital Hyperinsulinism Cause DNA Double-Strand Breaks and p53 Activity in β Cells

beta cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with beta cell replication and apoptosis. Here, we show that genetic activation of beta cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (K-ATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase over-activity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues beta cells from glucokinase-induced death, but only GLP-1 analog rescues beta cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of beta cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via K-ATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of beta cell glucotoxicity and suggest pharmacological approaches to enhance beta cell survival in diabetes.