Inhibition of dipeptidyl peptidase IV (DPP-IV) activity by NVP-DPP728, a DPP-IV inhibitor, improves the therapeutic efficacy of glucagon-like peptide-1 (GLP-1). CD26 is a membrane-associated glycoprotein with DPP-IV activity and is expressed on lymphocytes. We investigated the effect of NVP-DPP728 on reversing new-onset diabetes in nonobese diabetic (NOD) mice and modulating the inflammatory response and stimulating beta-cell regeneration. New-onset diabetic NOD mice were treated with NVP-DPP728 for 2, 4, and 6 wk. Blood glucose level was monitored. Regulatory T cells in thymus and secondary lymph nodes, TGF-beta1 and GLP-1 in plasma, and the insulin content in the pancreas were measured. Immunostaining for insulin and bromodeoxyuridine (BrdU) were performed. The correlation of beta-cell replication with inflammation was determined. In NVP-DPP728-treated NOD mice, diabetes could be reversed in 57, 74, and 73% of mice after 2, 4, and 6 wk treatment, respectively. Insulitis was reduced and the percentage of CD4(+)CD25(+)FoxP3(+) regulatory T cells was increased in treated NOD mice with remission. Plasma TGF-beta1 and GLP-1, the insulin content, and both insulin(+) and BrdU(+) beta-cells in pancreas were also significantly increased. No significant correlations were found between numbers of both insulin(+) and BrdU(+) beta-cells in islets and beta-cell area or islets with different insulitis score in NOD mice with remission of diabetes. In conclusion, NVP-DPP728 treatment can reverse new-onset diabetes in NOD mice by reducing insulitis, increasing CD4(+)CD25(+)FoxP3(+) regulatory T cells, and stimulating beta-cell replication. beta-Cell replication is not associated with the degree of inflammation in NVP-DPP728-treated NOD mice.
Summary
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.
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