Age-dependent Human β Cell Proliferation Induced by Glucagon-Like Peptide 1 and Calcineurin Signaling

J Clin Invest. 2017 Oct 2;127(10):3835-3844. doi: 10.1172/JCI91761. Epub 2017 Sep 18.

Abstract

Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human β cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes for proliferation-promoting factors, including NFATC1, FOXM1, and CCNA1. By contrast, expression of these factors in adult islet β cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human β cell proliferation, and identify elements that could be adapted for therapeutic expansion of human β cells.

MeSH terms

  • Adult
  • Aging / metabolism*
  • Animals
  • Calcineurin / metabolism*
  • Cyclin A1 / metabolism
  • Exenatide
  • Female
  • Forkhead Box Protein M1 / metabolism
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice, Inbred NOD
  • Middle Aged
  • NFATC Transcription Factors / metabolism
  • Peptides / pharmacology
  • Signal Transduction*
  • Venoms / pharmacology

Substances

  • CCNA1 protein, human
  • Cyclin A1
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • NFATC Transcription Factors
  • NFATC1 protein, human
  • Peptides
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide
  • Calcineurin