Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells

Cell Metab. 2014 Jan 7;19(1):109-21. doi: 10.1016/j.cmet.2013.11.007. Epub 2013 Dec 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Calcineurin / metabolism
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Congenital Hyperinsulinism / complications*
  • Congenital Hyperinsulinism / enzymology
  • Congenital Hyperinsulinism / pathology
  • DNA Breaks, Double-Stranded* / drug effects
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetes Mellitus, Type 2 / enzymology
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Fasting / metabolism
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucokinase / biosynthesis
  • Glucose / toxicity
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / enzymology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology*
  • Membrane Potentials / drug effects
  • Mice
  • Transgenes
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Biomarkers
  • Tumor Suppressor Protein p53
  • Glucagon-Like Peptide 1
  • Glucokinase
  • Calcineurin
  • Glucose