详细记录  
题名:Type 2 Diabetes and Congenital Hyperinsulinism Cause DNA Double-Strand Breaks and p53 Activity in beta Cells.
作者:TORNOVSKY-BABEAY S; DADON D; ZIV O; TZIPILEVICH E; KADOSH T; SCHYR-BEN HAROUSH R; HIJA A; STOLOVICH-RAIN M; FURTH-LAVI J; GRANOT Z; PORAT S; PHILIPSON LH; HEROLD KC; BHATTI TR; STANLEY C; ASHCROFT FM; IN'T VELD P; SAADA A; MAGNUSON MA; GLASER B; DOR Y;
来源:Cell Metab. 2013 Dec 10. pii: S1550-4131(13)00456-7. doi: [ IF= 0.00 ] ]
URL :10.1016/j.cmet.2013.11.007
日期:20140217
摘要:beta 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 beta cell replication and
apoptosis. Here, we show that genetic activation of beta 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 beta cells from
glucokinase-induced death, but only GLP-1 analog rescues beta cell function. DNA
damage and p53 activity in T2D suggest shared mechanisms of beta cell failure in
hyperglycemia and CHI. Our results reveal membrane depolarization via KATP
channels, calcineurin signaling, DNA breaks, and p53 as determinants of beta cell
glucotoxicity and suggest pharmacological approaches to enhance beta cell
survival in diabetes.

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