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

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

Author information

1
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
2
Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
3
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
4
Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Mount Scopus, Jerusalem 91240, Israel.
5
Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
6
Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
7
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
8
Department of Physiology, Anatomy & Genetics, Oxford University, Oxford OX1 3QX, UK.
9
Diabetes Research Center, Brussels Free University, Laarbeeklaan 103, B1090 Brussels, Belgium.
10
Monique and Jacques Roboh Department of Genetic Research and the Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
11
Center for Stem Cell Biology and Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
12
Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Electronic address: beng@cc.huji.ac.il.
13
Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. Electronic address: yuvald@ekmd.huji.ac.il.

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.

PMID:
24332968
DOI:
10.1016/j.cmet.2013.11.007
[Indexed for MEDLINE]
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