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

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• 作者：Sharona Tornovsky-Babeay ; Daniela Dadon ; Oren Ziv ; Elhanan Tzipilevich ; Tehila Kadosh ; Rachel Schyr-Ben聽Haroush ; Ayat Hija ; Miri Stolovich-Rain ; Judith Furth-Lavi ; Zvi Granot ; Shay Porat ; Louis聽H. Philipson ; Kevan聽C. Herold ; Tricia聽R. Bhatti ; Charles Stanley ; Frances聽M. Ashcroft ; Peter In鈥檛聽Veld ; Ann Saada ; Mark聽A. Magnuson ; Benjamin Glaser ; Yuval Dor ; et al.
• 刊名：Cell Metabolism
• 出版年：7 January, 2014
• 年：2014
• 卷：19
• 期：1
• 页码：109-121
• 全文大小：3632 K

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Summary

尾 cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not聽fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with 尾 cell replication and apoptosis. Here, we show that genetic activation of 尾 cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (K_ATP channels) and calcineurin mediate this toxic effect.聽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 尾 cells from glucokinase-induced death, but only GLP-1 analog rescues 尾聽cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of 尾 cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via K_ATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of 尾 cell glucotoxicity and suggest pharmacological approaches to enhance 尾 cell survival in diabetes.