Adaptive β-Cell Proliferation Is Severely Restricted With Advanced Age

  1. Matthew M. Rankin and
  2. Jake A. Kushner
  1. From the Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
  1. Corresponding author: Jake A. Kushner, kushnerj{at}mail.med.upenn.edu.

Abstract

OBJECTIVE Regeneration of the insulin-secreting β-cells is a fundamental research goal that could benefit patients with either type 1 or type 2 diabetes. β-Cell proliferation can be acutely stimulated by a variety of stimuli in young rodents. However, it is unknown whether this adaptive β-cell regeneration capacity is retained into old age.

RESEARCH DESIGN AND METHODS We assessed adaptive β-cell proliferation capacity in adult mice across a wide range of ages with a variety of stimuli: partial pancreatectomy, low-dose administration of the β-cell toxin streptozotocin, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist. β-Cell proliferation was measured by administration of 5-bromo-2′-deoxyuridine (BrdU) in the drinking water.

RESULTS Basal β-cell proliferation was severely decreased with advanced age. Partial pancreatectomy greatly stimulated β-cell proliferation in young mice but failed to increase β-cell replication in old mice. Streptozotocin stimulated β-cell replication in young mice but had little effect in old mice. Moreover, administration of GLP-1 agonist exendin-4 stimulated β-cell proliferation in young but not in old mice. Surprisingly, adaptive β-cell proliferation capacity was minimal after 12 months of age, which is early middle age for the adult mouse life span.

CONCLUSIONS Adaptive β-cell proliferation is severely restricted with advanced age in mice, whether stimulated by partial pancreatectomy, low-dose streptozotocin, or exendin-4. Thus, β-cells in middle-aged mice appear to be largely postmitotic. Young rodents may not faithfully model the regenerative capacity of β-cells in mature adult mice.

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. 1312.

    • Received August 29, 2008.
    • Accepted February 27, 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.

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  1. Diabetes vol. 58 no. 6 1365-1372
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