Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells
| Autor: | Daniela Dadon, Ayat Hija, Benjamin Glaser, Kevan C. Herold, Rachel Schyr-Ben Haroush, Miri Stolovich-Rain, Tricia R. Bhatti, Oren Ziv, Tehila Kadosh, Sharona Tornovsky-Babeay, Frances M. Ashcroft, Louis H. Philipson, Peter In 'T Veld, Charles A. Stanley, Zvi Granot, Shay Porat, Elhanan Tzipilevich, Mark A. Magnuson, Yuval Dor, J Furth-Lavi, Ann Saada |
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| Přispěvatelé: | Pathological Anatomy, Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Programmed cell death mice Physiology DNA damage Cell Biology Membrane Potentials Glucagon-Like Peptide 1 Internal medicine Insulin-Secreting Cells medicine Animals Humans DNA Breaks Double-Stranded Transgenes glucose Molecular Biology glucokinase Glucokinase Cell growth Calcineurin biomarkers Cell Biology Fasting Cell cycle 3. Good health Enzyme Activation Disease Models Animal medicine.anatomical_structure Endocrinology cell death cell proliferation Diabetes Mellitus Type 2 Apoptosis Enzyme Induction Cancer research Congenital Hyperinsulinism Tumor Suppressor Protein p53 |
| Zdroj: | Cell Metabolism; Vol 19 |
| Popis: | Summaryβ 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. |
| Databáze: | OpenAIRE |
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