| First Author | Tornovsky-Babeay S | Year | 2014 |
| Journal | Cell Metab | Volume | 19 |
| Issue | 1 | Pages | 109-21 |
| PubMed ID | 24332968 | Mgi Jnum | J:210493 |
| Mgi Id | MGI:5571253 | Doi | 10.1016/j.cmet.2013.11.007 |
| Citation | Tornovsky-Babeay S, et al. (2014) Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in beta cells. Cell Metab 19(1):109-21 |
| abstractText | 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. |
