Pancreatic beta cells in very old mice retain capacity for compensatory proliferation

Miri Stolovich-Rain, Ayat Hija, Joseph Grimsby, Benjamin Glaser, Yuval Dor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Recent studies suggested that in old mice, beta cells lose their regenerative potential and cannot respond to mitogenic triggers. These studies examined beta cell replication in aged mice under basal conditions and in response to specific stimuli including treatment with the glucagon-like peptide-1 analog exenatide, streptozotocin injection, partial pancreatectomy, and high fat diet. However, it remains possible that the ability to mount a compensatory response of beta cells is retained in old age, but depends on the specific stimulus. Here, we asked whether partial ablation of beta cells in transgenic mice, using doxycycline-inducible expression of diphtheria toxin, triggers a significant compensatory proliferative response in 1-2-year-old animals. Consistent with previous reports, the basal rate of beta cell replication declines dramatically with age, averaging 0.1% in 2-year-old mice. Transient expression of diphtheria toxin in beta cells of old mice resulted in impaired glucose homeostasis and disruption of islet architecture (ratio of beta to alpha cells). Strikingly, the replication rate of surviving beta cells increased 3-fold over basal rate, similarly to the -fold increase in replication rate of beta cells in young transgenic mice. Islet architecture and glucose tolerance slowly normalized, indicating functional significance of compensatory beta cell replication in this setting. Finally, administration of a small molecule glucokinase activator to old mice doubled the frequency of beta cell replication, further showing that old beta cells can respond to the mitogenic trigger of enhanced glycolysis. We conclude that the potential for functionally significant compensatory proliferation of beta cells is retained in old mice, despite a decline in basal replication rate.

Original languageAmerican English
Pages (from-to)27407-27414
Number of pages8
JournalJournal of Biological Chemistry
Volume287
Issue number33
DOIs
StatePublished - 10 Aug 2012

Fingerprint

Dive into the research topics of 'Pancreatic beta cells in very old mice retain capacity for compensatory proliferation'. Together they form a unique fingerprint.

Cite this