title: Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells.
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.
authors: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Sharona
authors: S
authors: Tornovsky-Babeay
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Daniela
authors: D
authors: Dadon
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Oren
authors: O
authors: Ziv
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Elhanan
authors: E
authors: Tzipilevich
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Tehila
authors: T
authors: Kadosh
authors: 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.
authors: Rachel
authors: R
authors: Schyr-Ben Haroush
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Ayat
authors: A
authors: Hija
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Miri
authors: M
authors: Stolovich-Rain
authors: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Judith
authors: J
authors: Furth-Lavi
authors: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors: Zvi
authors: Z
authors: Granot
authors: 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.
authors: Shay
authors: S
authors: Porat
authors: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors: Louis H
authors: LH
authors: Philipson
authors: Departments of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA.
authors: Kevan C
authors: KC
authors: Herold
authors: Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Tricia R
authors: TR
authors: Bhatti
authors: Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Charles
authors: C
authors: Stanley
authors: Department of Physiology, Anatomy & Genetics, Oxford University, Oxford OX1 3QX, UK.
authors: Frances M
authors: FM
authors: Ashcroft
authors: Diabetes Research Center, Brussels Free University, Laarbeeklaan 103, B1090 Brussels, Belgium.
authors: Peter
authors: P
authors: In't Veld
authors: Monique and Jacques Roboh Department of Genetic Research and the Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors: Ann
authors: A
authors: Saada
authors: Center for Stem Cell Biology and Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors: Mark A
authors: MA
authors: Magnuson
authors: Endocrinology and Metabolism Service, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Electronic address: beng@cc.huji.ac.il.
authors: Benjamin
authors: B
authors: Glaser
authors: 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.
authors: Yuval
authors: Y
authors: Dor
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D044903:Congenital Hyperinsulinism / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005215:Fasting / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D005941:Glucokinase / Q000096:biosynthesis; D005947:Glucose / Q000633:toxicity; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016159:Tumor Suppressor Protein p53; D052216:Glucagon-Like Peptide 1; D005941:Glucokinase; D019703:Calcineurin; D005947:Glucose