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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.

Original publication




Journal article


Cell Metab

Publication Date





109 - 121


Animals, Biomarkers, Calcineurin, Cell Death, Cell Proliferation, Congenital Hyperinsulinism, DNA Breaks, Double-Stranded, Diabetes Mellitus, Type 2, Disease Models, Animal, Enzyme Activation, Enzyme Induction, Fasting, Glucagon-Like Peptide 1, Glucokinase, Glucose, Humans, Insulin-Secreting Cells, Membrane Potentials, Mice, Transgenes, Tumor Suppressor Protein p53