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

摘要: 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) replication and apoptosis. Here, we show that genetic activation of glucokinase, initially triggering replication, causes apoptosis DNA double-strand breaks tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) calcineurin mediate this toxic effect. Toxicity long-term overactivity was confirmed finding late-onset older members a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues cells from glucokinase-induced death, only GLP-1 analog function. damage activity T2D suggest shared hyperglycemia CHI. Our results reveal membrane depolarization via KATP channels, signaling, breaks, as determinants glucotoxicity pharmacological approaches to enhance survival diabetes.