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 H₂O₂. 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.