sitagliptin-phosphate and exendin-(9-39)

Exaggerated secretion of glucagon-like peptide 1 (GLP-1) is important for postprandial glucose tolerance after Roux-en-Y gastric bypass (RYGB), whereas the role of glucose-dependent insulinotropic polypeptide (GIP) remains to be resolved. We aimed to explore the relative importance of endogenously secreted GLP-1 and GIP on glucose tolerance and β-cell function after RYGB. We used DPP-4 inhibition to enhance concentrations of intact GIP and GLP-1 and the GLP-1 receptor antagonist exendin-(9-39) (Ex-9) for specific blockage of GLP-1 actions. Twelve glucose-tolerant patients were studied after RYGB in a randomized, placebo-controlled, 4-day crossover study with standard mixed-meal tests and concurrent administration of placebo, oral sitagliptin, Ex-9 infusion, or combined Ex-9-sitagliptin. GLP-1 receptor antagonism increased glucose excursions, clearly attenuated β-cell function, and aggravated postprandial hyperglucagonemia compared with placebo, whereas sitagliptin had no effect despite two- to threefold increased concentrations of intact GLP-1 and GIP. Similarly, sitagliptin did not affect glucose tolerance or β-cell function during GLP-1R blockage. This study confirms the importance of GLP-1 for glucose tolerance after RYGB via increased insulin and attenuated glucagon secretion in the postprandial state, whereas amplification of the GIP signal (or other DPP-4-sensitive glucose-lowering mechanisms) did not appear to contribute to the improved glucose tolerance seen after RYGB.

Topics: Adult; Blood Glucose; C-Peptide; Cross-Over Studies; Enzyme-Linked Immunosorbent Assay; Female; Gastric Bypass; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Linear Models; Male; Obesity; Peptide Fragments; Postprandial Period; Single-Blind Method; Sitagliptin Phosphate

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.. Herein we investigated the effect of linagliptin, a novel DPP-4 inhibitor, on β-cell function and survival.. 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.. 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.. 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.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cell Survival; Cytokines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Inverse Agonism; Glucagon-Like Peptide 1; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Linagliptin; Palmitic Acid; Peptide Fragments; Protein Stability; Purines; Pyrazines; Quinazolines; Recombinant Proteins; Sitagliptin Phosphate; Tissue Culture Techniques; Triazoles