Comparison of exendin-4 on beta-cell replication in mouse and human islet grafts

Abstract

Exendin-4 can stimulate β-cell replication in mice. Whether it can stimulate β-cell replication in human islet grafts remains unknown. Therefore, we compared the effects of exendin-4 on β-cell replication in mouse and human islet grafts. Islets, isolated from mouse and human donors at different ages, were transplanted into diabetic mice and/or diabetic nude mice that were given bromodeoxyuridine (BrdU) with or without exendin-4. At 4 weeks post-transplantation, islet grafts were removed for insulin and BrdU staining and quantification of insulin(+)/BrdU(+) cells. Although diabetes was reversed in all mice transplanting syngeneic mouse islets from young or old donors, normoglycemia was achieved significantly faster in exendin-4 treated mice. Mouse islet grafts in exendin-4 treated mice had significantly more insulin(+)/BrdU(+) β cells than in untreated mice (P < 0.01). Human islet grafts from ≤22-year-old donors had more insulin(+)/BrdU(+) β cells in exendin-4 treated mice than that in untreated mice (P < 0.01). However, human islet grafts from ≥35-year-old donors contained few insulin(+)/BrdU(+) β cells in exendin-4 treated or untreated mice. Our data demonstrated that the capacity for β-cell replication in mouse and human islet grafts is different with and without exendin-4 treatment and indicated that GLP-1 agonists can stimulate β-cell replication in human islets from young donors.