Age-Dependent Decline in β-Cell Proliferation Restricts the Capacity of β-Cell Regeneration in Mice

  1. Shuen-Ing Tschen1,
  2. Sangeeta Dhawan1,
  3. Tatyana Gurlo1 and
  4. Anil Bhushan1,2
  1. 1Larry L. Hillblom Islet Research Center, Department of Medicine, University of California, Los Angeles, Los Angeles, California;
  2. 2Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California.
  1. Corresponding author: Anil Bhushan, abhushan{at}mednet.ucla.edu.

Abstract

OBJECTIVE The aim of this study was to elucidate whether age plays a role in the expansion or regeneration of β-cell mass.

RESEARCH DESIGN AND METHODS We analyzed the capacity of β-cell expansion in 1.5- and 8-month-old mice in response to a high-fat diet, after short-term treatment with the glucagon-like peptide 1 (GLP-1) analog exendin-4, or after streptozotocin (STZ) administration.

RESULTS Young mice responded to high-fat diet by increasing β-cell mass and β-cell proliferation and maintaining normoglycemia. Old mice, by contrast, did not display any increases in β-cell mass or β-cell proliferation in response to high-fat diet and became diabetic. To further assess the plasticity of β-cell mass with respect to age, young and old mice were injected with a single dose of STZ, and β-cell proliferation was analyzed to assess the regeneration of β-cells. We observed a fourfold increase in β-cell proliferation in young mice after STZ administration, whereas no changes in β-cell proliferation were observed in older mice. The capacity to expand β-cell mass in response to short-term treatment with the GLP-1 analog exendin-4 also declined with age. The ability of β-cell mass to expand was correlated with higher levels of Bmi1, a polycomb group protein that is known to regulate the Ink4a locus, and decreased levels of p16Ink4aexpression in the β-cells. Young Bmi1−/− mice that prematurely upregulate p16Ink4afailed to expand β-cell mass in response to exendin-4, indicating that p16Ink4alevels are a critical determinant of β-cell mass expansion.

CONCLUSIONS β-Cell proliferation and the capacity of β-cells to regenerate declines with age and is regulated by the Bmi1/p16Ink4apathway.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • See accompanying original article, p. 1365.

    • Received September 2, 2008.
    • Accepted February 8, 2009.
  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Diabetes vol. 58 no. 6 1312-1320
  1. All Versions of this Article:
    1. db08-1651v1
    2. 58/6/1312 most recent