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PLoS One. 2014 Sep 30;9(9):e107935. doi: 10.1371/journal.pone.0107935. eCollection 2014.

Combining MK626, a novel DPP-4 inhibitor, and low-dose monoclonal CD3 antibody for stable remission of new-onset diabetes in mice.

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Laboratory of Clinical and Experimental Endocrinology, Campus Gasthuisberg O&N1, Faculty of Medicine, Katholieke Universiteit Leuven (KU LEUVEN), Leuven, Belgium.
Laboratory of Diabetes Pathology and Therapy, Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Laboratory of Beta Cell Neogenesis (BENE), Diabetes Research Center, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
MSD A/S, Ballerup, Denmark.


Combining immune intervention with therapies that directly influence the functional state of the β-cells is an interesting strategy in type 1 diabetes cure. Dipeptidyl peptidase-4 (DPP-4) inhibitors elevate circulating levels of active incretins, which have been reported to enhance insulin secretion and synthesis, can support β-cell survival and possibly stimulate β-cell proliferation and neogenesis. In the current study, we demonstrate that the DPP-4 inhibitor MK626, which has appropriate pharmacokinetics in mice, preceded by a short-course of low-dose anti-CD3 generated durable diabetes remission in new-onset diabetic non-obese diabetic (NOD) mice. Induction of remission involved recovery of β-cell secretory function with resolution of destructive insulitis and preservation of β-cell volume/mass, along with repair of the islet angioarchitecture via SDF-1- and VEGF-dependent actions. Combination therapy temporarily reduced the CD4-to-CD8 distribution in spleen although not in pancreatic draining lymph nodes (PLN) and increased the proportion of effector/memory T cells as did anti-CD3 alone. In contrast, only combination therapy amplified Foxp3+ regulatory T cells in PLN and locally in pancreas. These findings open new opportunities for the treatment of new-onset type 1 diabetes by introducing DPP-4 inhibitors in human CD3-directed clinical trials.

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