TY - JOUR
T1 - Reversal of new-onset diabetes through modulating inflammation and stimulating β-cell replication in nonobese diabetic mice by a dipeptidyl peptidase IV inhibitor
AU - Tian, Lei
AU - Gao, Jie
AU - Hao, Jianqiang
AU - Zhang, Yu
AU - Yi, Huimin
AU - O'Brien, Timothy D.
AU - Sorenson, Robert
AU - Luo, Jian
AU - Guo, Zhiguang
PY - 2010/7
Y1 - 2010/7
N2 - 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 β-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-β1 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 β-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 6wk 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-β1 and GLP-1, the insulin content, and both insulin+ and BrdU+ β-cells in pancreas were also significantly increased.Nosignificant correlations were found between numbers of both insulin+ and BrdU+ β-cells in islets and β-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 β-cell replication. β-Cell replication is not associated with the degree of inflammation in NVP-DPP728-treated NOD mice.
AB - 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 β-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-β1 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 β-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 6wk 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-β1 and GLP-1, the insulin content, and both insulin+ and BrdU+ β-cells in pancreas were also significantly increased.Nosignificant correlations were found between numbers of both insulin+ and BrdU+ β-cells in islets and β-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 β-cell replication. β-Cell replication is not associated with the degree of inflammation in NVP-DPP728-treated NOD mice.
UR - http://www.scopus.com/inward/record.url?scp=77954611378&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77954611378&partnerID=8YFLogxK
U2 - 10.1210/en.2010-0068
DO - 10.1210/en.2010-0068
M3 - Article
C2 - 20444936
AN - SCOPUS:77954611378
SN - 0013-7227
VL - 151
SP - 3049
EP - 3060
JO - Endocrinology
JF - Endocrinology
IS - 7
ER -