ADAPTIVE BETA CELL PROLIFERATION IS SEVERELY RESTRICTED WITH ADVANCED AGE

Abstract

Objective Regeneration of the insulin secreting ß-cells is a fundamental research goal that could benefit patients with either Type 1 or Type 2 diabetes mellitus. ß-cell proliferation can be acutely stimulated by a variety of stimuli in young rodents. However, it is unknown if this “adaptive” ß-cell regeneration capacity is retained into old age.

Research Design and Methods We assessed adaptive ß-cell proliferation capacity in adult mice across a wide range of ages with a variety of stimuli: Partial pancreatectomy, low dose administration of the ß-cell toxin streptozotocin, and Exendin-4, a glucagon like peptide (GLP-1) agonist. ß-cell proliferation was measured by administration of BrdU in the drinking water.

Results Basal ß-cell proliferation was severely decreased with advanced age. Partial pancreatectomy greatly stimulated ß-cell proliferation in young mice but failed to increase ß-cell replication in old mice. Streptozotocin stimulated ß-cell replication in young mice but had little effect in old mice. Moreover, administration of the glucagon like peptide (GLP-1) agonist Exendin-4 stimulated ß-cell proliferation in young mice but not in old mice. Surprisingly, adaptive ß-cell proliferation capacity was minimal after 12 months of age, early middle age for the adult mouse lifespan.

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