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The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization

Shah, Payal; Ardestani, Amin; Dharmadhikari, Gitanjali; Laue, Svenja; Schumann, Desiree M.; Kerr-Conte, Julie; Pattou, Francois; Klein, Thomas; Maedler, Kathrin

Authors

Payal Shah

Gitanjali Dharmadhikari

Svenja Laue

Desiree M. Schumann

Julie Kerr-Conte

Francois Pattou

Thomas Klein

Kathrin Maedler



Abstract

Context: Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potent strategy to increase glucose-dependent insulinotropic polypeptide and glucagon like peptide 1 (GLP-1) induced insulin secretion in diabetes. It is important to know whether new drugs approved for the treatment of type 2 diabetes have direct effects on the β-cell. Objective: Herein we investigated the effect of linagliptin, a novel DPP-4 inhibitor, on β-cell function and survival. Design: Human islets were exposed to a diabetic milieu (11.1-33.3 mM glucose, 0.5 mM palmitate, the mixture of 2 ng/mL IL-1β+ 1000 U/mL interferon-γ, or 50 μM H2O2) with or without 500 ng/mL IL-1 receptor antagonist (IL-1Ra) or 30-50 nM linagliptin. Results: Linagliptin restored β-cell function and turnover, which was impaired when islets were exposed to elevated glucose, palmitate, cytokines, or H 2O2. Pretreatment with IL-1Ra was similarly effective, except against H2O2 treatment. Nitrotyrosine concentrations in islet lysates, an indicator of oxidative stress, were highly elevated under diabetic conditions but not in islets treated with linagliptin or IL-1Ra. Linagliptin also reduced cytokine secretion and stabilized GLP-1 in islet supernatants. Conclusions: We show that the novel DPP-4 inhibitor linagliptin protected from gluco-, lipo-, and cytokine-toxicity and stabilized active GLP-1 secreted from human islets. This provides a direct GLP-1 mediated protective effect of linagliptin on β-cell function and survival. Copyright © 2013 by The Endocrine Society.

Citation

Shah, P., Ardestani, A., Dharmadhikari, G., Laue, S., Schumann, D. M., Kerr-Conte, J., Pattou, F., Klein, T., & Maedler, K. (2013). The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization. Journal of Clinical Endocrinology and Metabolism, 98(7), E1163–E1172. https://doi.org/10.1210/jc.2013-1029

Journal Article Type Article
Acceptance Date Apr 22, 2013
Online Publication Date Jul 1, 2013
Publication Date Jul 1, 2013
Deposit Date Jan 4, 2024
Journal Journal of Clinical Endocrinology and Metabolism
Print ISSN 0021-972X
Electronic ISSN 1945-7197
Publisher Endocrine Society
Peer Reviewed Peer Reviewed
Volume 98
Issue 7
Pages E1163–E1172
DOI https://doi.org/10.1210/jc.2013-1029
Public URL https://hull-repository.worktribe.com/output/4461737