Summary 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.
Bibliographical noteFunding Information:
This work was funded by grants from the Beta Cell Biology Consortium, JDRF, ERC, EU/FP7 (BetaCellTherapy, grant 241883), the Helmsley trust, the Dutch friends of Hebrew University, and the I-CORE Program of The Israel Science Foundation #41.11 (to Y.D.). This work was supported in part by a grant from USAID’s American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University Medical School Flow Cytometry laboratory. This study was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a JDRF-sponsored collaborative T1D research project. Organ Procurement Organizations (OPO) partnering with nPOD are listed at www.jdrfnpod.org/our-partners.php . O.Z. is a New York Stem Cell Foundation-Druckenmiller Fellow. M.S.-R. was supported by a postdoctoral fellowship from Novo Nordisk and A.H. by a fellowship from Mr. Alan Harper. We thank Norma Kidess-Bassir for excellent technical assistance, Donald K. Scott for the gift of rat glucokinase cDNA, Orr Spiegel for advice with statistical analysis, and Christian Broberger, Muli Ben-Sasson, and Ittai Ben-Porath for insightful discussions.