Type 2 Diabetes and Congenital Hyperinsulinism Cause DNA Double-Strand Breaks and p53 Activity in β Cells

• Published in: Cell metabolism Vol. 19; no. 1; pp. 109 - 121
• Main Authors: Tornovsky-Babeay, Sharona, Dadon, Daniela, Ziv, Oren, Tzipilevich, Elhanan, Kadosh, Tehila, Schyr-Ben Haroush, Rachel, Hija, Ayat, Stolovich-Rain, Miri, Furth-Lavi, Judith, Granot, Zvi, Porat, Shay, Philipson, Louis H., Herold, Kevan C., Bhatti, Tricia R., Stanley, Charles, Ashcroft, Frances M., In’t Veld, Peter, Saada, Ann, Magnuson, Mark A., Glaser, Benjamin, Dor, Yuval
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.01.2014
• Subjects: Animals; Biomarkers - metabolism; Calcineurin - metabolism; Cell Death - drug effects; Cell Proliferation - drug effects; Congenital Hyperinsulinism - complications; Congenital Hyperinsulinism - enzymology; Congenital Hyperinsulinism - pathology; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - pathology; Disease Models, Animal; DNA Breaks, Double-Stranded - drug effects; 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
• ISSN: 1550-4131; 1932-7420
• 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. [Display omitted] •β cell DNA damage and p53 activity in type 2 diabetes and congenital hyperinsulinism•Hyperglycolysis causes DNA breaks and β cell death via KATP channel inactivation•A GLP-1 analog or p53 deletion prevents glucotoxic β cell death