Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells.
Tornovsky-Babeay S., Dadon D., Ziv O., Tzipilevich E., Kadosh T., Schyr-Ben Haroush R., Hija A., Stolovich-Rain M., Furth-Lavi J., Granot Z., Porat S., Philipson LH., Herold KC., Bhatti TR., Stanley C., Ashcroft FM., In't Veld P., Saada A., Magnuson MA., Glaser B., Dor Y.
β 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 β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity 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 β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.