Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Targeting the cell cycle inhibitor p57Kip2 promotes adult human β cell replication
Dana Avrahami, … , Benjamin Glaser, Klaus H. Kaestner
Dana Avrahami, … , Benjamin Glaser, Klaus H. Kaestner
Published January 16, 2014
Citation Information: J Clin Invest. 2014;124(2):670-674. https://doi.org/10.1172/JCI69519.
View: Text | PDF
Brief Report Metabolism

Targeting the cell cycle inhibitor p57Kip2 promotes adult human β cell replication

  • Text
  • PDF
Abstract

Children with focal hyperinsulinism of infancy display a dramatic, non-neoplastic clonal expansion of β cells that have undergone mitotic recombination, resulting in paternal disomy of part of chromosome 11. This disomic region contains imprinted genes, including the gene encoding the cell cycle inhibitor p57Kip2 (CDKN1C), which is silenced as a consequence of the recombination event. We hypothesized that targeting p57Kip2 could stimulate adult human β cell replication. Indeed, when we suppressed CDKN1C expression in human islets obtained from deceased adult organ donors and transplanted them into hyperglycemic, immunodeficient mice, β cell replication increased more than 3-fold. The newly replicated cells retained properties of mature β cells, including the expression of β cell markers such as insulin, PDX1, and NKX6.1. Importantly, these newly replicated cells demonstrated normal glucose-induced calcium influx, further indicating β cell functionality. These findings provide a molecular explanation for the massive β cell replication that occurs in children with focal hyperinsulinism. These data also provided evidence that β cells from older humans, in which baseline replication is negligible, can be coaxed to re-enter and complete the cell cycle while maintaining mature β cell properties. Thus, controlled manipulation of this pathway holds promise for the expansion of β cells in patients with type 2 diabetes.

Authors

Dana Avrahami, Changhong Li, Ming Yu, Yang Jiao, Jia Zhang, Ali Naji, Seyed Ziaie, Benjamin Glaser, Klaus H. Kaestner

×

Figure 3

Newly replicated β cells retain their functionality as assessed by glucose-stimulated calcium influx assay.

Options: View larger image (or click on image) Download as PowerPoint
Newly replicated β cells retain their functionality as assessed by gluco...
(A) Dispersed human islet cells retrieved from grafts and loaded with the [Ca2+]i sensor Fura-2 were analyzed for [Ca2+]i, followed by costaining for insulin (white), turbo-GFP (green), BrdU (red), and DNA (blue). Blue box surrounds a BrdU-negative β cell and red box surrounds a BrdU-positive β cell. (B) Calcium traces corresponding to the two β cells identified in A, showing the change in [Ca2+]i as a response to an increase in extracellular glucose levels. Each graph represents the [Ca2+]i profile of one cell during the course of the experiment. Original magnification, ×400.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts