Reversal of new-onset diabetes through modulating inflammation and stimulating beta-cell replication in nonobese diabetic mice by a dipeptidyl peptidase IV inhibitor.
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.
Tian
Lei
L
Schulze Diabetes Institute and Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Gao
Jie
J
Hao
Jianqiang
J
Zhang
Yu
Y
Yi
Huimin
H
O'Brien
Timothy D
TD
Sorenson
Robert
R
Luo
Jian
J
Guo
Zhiguang
Z
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D015704:CD4 Antigens / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D009570:Nitriles / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000097:blood
C121834:1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine; D001786:Blood Glucose; D015704:CD4 Antigens; D054873:Dipeptidyl-Peptidase IV Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D009570:Nitriles; D011759:Pyrrolidines; D053773:Transforming Growth Factor beta1; D052216:Glucagon-Like Peptide 1