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
Cell Metab. 2014 19 (1): 109-21

PMID: 24332968 · DOI:10.1016/j.cmet.2013.11.007

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

MeSH Terms (21)

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

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