A novel dipeptidyl peptidase IV inhibitor DA-1229 ameliorates streptozotocin-induced diabetes by increasing β-cell replication and neogenesis

Treatment of autoimmune diabetes in NOD mice by Toll-like receptor 2 tolerance in conjunction with dipeptidyl peptidase 4 inhibition

“…1a). This probably occurred because DA-1229 alone cannot inhibit autoimmunity despite its potential beneficial effect on beta cell mass [10]. Moreover, feeding 0.3% DA-1229-containing chow alone did not inhibit the development of diabetes in NOD mice (electronic supplementary material [ESM] Fig.…”

“…To study the mechanism of the increased beta cell mass, we assessed beta cell proliferation that could be upregulated by DPP4 inhibitors [6,10] by quantifying the number of beta cells incorporating BrdU. The BrdU + beta cell number was significantly higher in NOD mice treated with Pam3CSK 4 +DA-1229 for 3 weeks compared with untreated diabetic NOD mice and those treated with either Pam3CSK 4 or DA-1229 alone for 3 weeks (Fig.…”

“…Hence, our results may not be sufficient to conclude that Pam3CSK 4 +DA-1229 increases beta cell neogenesis. While a suppressive effect of DPP4 inhibitors on serum glucagon level or glucagon secretion from alpha cells has been reported [10,38], the effect of DPP4 inhibition on alpha cell mass has not been widely studied. Our results showing diminished alpha cell mass in diabetic NOD mice are consistent with a recent paper reporting reduced alpha cell mass in animal models of type 1 diabetes [39].…”

“…DA-1229, a DPP4-selective inhibitor with an IC 50 value of 0.9 nmol/l [10], was provided by Dong-A Pharmaceutical (Yong-In, Korea). All other chemicals were from Sigma (St Louis, MO, USA), unless indicated otherwise.…”

“…Strategies with potential beneficial effects on beta cell mass include glucagon-like peptide 1 (GLP-1) agonists [5,6] or inhibitors of dipeptidyl peptidase 4 (DPP4) [7,8], which degrades GLP-1 [9]. We have reported that a DPP4 inhibitor ameliorated diabetes induced by streptozotocin (STZ), and that this was attributable an increased beta cell mass [10]. However, DPP4 inhibition alone may not be able to reverse clinically overt type 1 diabetes as established autoimmunity against beta cells would destroy newly formed beta cells.…”