Payal Shah
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
Dr Amin Ardestani A.Ardestani@hull.ac.uk
Senior Lecturer
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 |
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