title: The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors: Centre for Biomolecular Interactions Bremen, University of Bremen, 28359 Bremen, Germany.
authors: Payal
authors: P
authors: Shah
authors: Amin
authors: A
authors: Ardestani
authors: Gitanjali
authors: G
authors: Dharmadhikari
authors: Svenja
authors: S
authors: Laue
authors: Desiree M
authors: DM
authors: Schumann
authors: Julie
authors: J
authors: Kerr-Conte
authors: Francois
authors: F
authors: Pattou
authors: Thomas
authors: T
authors: Klein
authors: Kathrin
authors: K
authors: Maedler
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054314:Drug Inverse Agonism; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000069476:Linagliptin; D019308:Palmitic Acid / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D011687:Purines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D011799:Quinazolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000068900:Sitagliptin Phosphate; D046509:Tissue Culture Techniques; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; C508585:IL1B protein, human; C507763:IL1RN protein, human; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D010446:Peptide Fragments; D011687:Purines; D011719:Pyrazines; D011799:Quinazolines; D011994:Recombinant Proteins; D014230:Triazoles; D019308:Palmitic Acid; D000069476:Linagliptin; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate