title: Sitagliptin exerts an antinflammatory action.
abstract: BACKGROUND
  Sitagliptin is an inhibitor of the enzyme dipeptidyl peptidase-IV (DPP-IV), which degrades the incretins, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, and thus, sitagliptin increases their bioavailability. The stimulation of insulin and the suppression of glucagon secretion that follow exert a glucose lowering effect and hence its use as an antidiabetic drug. Because DPP-IV is expressed as CD26 on cell membranes and because CD26 mediates proinflammatory signals, we hypothesized that sitagliptin may exert an antiinflammatory effect.
  
  
  METHODS
  Twenty-two patients with type 2 diabetes were randomized to receive either 100 mg daily of sitagliptin or placebo for 12 wk. Fasting blood samples were obtained at baseline and at 2, 4, and 6 hours after a single dose of sitagliptin and at 2, 4, 8, and 12 wk of treatment.
  
  
  RESULTS
  Glycosylated hemoglobin fell significantly from 7.6 ± 0.4 to 6.9 ± 3% in patients treated with sitagliptin. Fasting glucagon-like peptide-1 concentrations increased significantly, whereas the mRNA expression in mononuclear cell of CD26, the proinflammatory cytokine, TNFα, the receptor for endotoxin, Toll-like receptor (TLR)-4, TLR-2, and proinflammatory kinases, c-Jun N-terminal kinase-1 and inhibitory-κB kinase (IKKβ), and that of the chemokine receptor CCR-2 fell significantly after 12 wk of sitagliptin. TLR-2, IKKβ, CCR-2, and CD26 expression and nuclear factor-κB binding also fell after a single dose of sitagliptin. There was a fall in protein expression of c-Jun N-terminal kinase-1, IKKβ, and TLR-4 and in plasma concentrations of C-reactive protein, IL-6, and free fatty acids after 12 wk of sitagliptin.
  
  
  CONCLUSIONS
  These effects are consistent with a potent and rapid antiinflammatory effect of sitagliptin and may potentially contribute to the inhibition of atherosclerosis. The suppression of CD26 expression suggests that sitagliptin may inhibit the synthesis of DPP-IV in addition to inhibiting its action.
authors: Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo, and Kaleida Health, Buffalo, New York 14209, USA.
authors: Antoine
authors: A
authors: Makdissi
authors: Husam
authors: H
authors: Ghanim
authors: Mehul
authors: M
authors: Vora
authors: Kelly
authors: K
authors: Green
authors: Sanaa
authors: S
authors: Abuaysheh
authors: Ajay
authors: A
authors: Chaudhuri
authors: Sandeep
authors: S
authors: Dhindsa
authors: Paresh
authors: P
authors: Dandona
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000032:analysis / Q000378:metabolism; D002469:Cell Separation; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000032:analysis / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000032:analysis / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D051550:I-kappa B Kinase / Q000032:analysis / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000032:analysis / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011446:Prospective Studies; D011719:Pyrazines / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000032:analysis / Q000378:metabolism; D000068900:Sitagliptin Phosphate; D051195:Toll-Like Receptor 2 / Q000032:analysis / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000032:analysis / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001786:Blood Glucose; D002097:C-Reactive Protein; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D051550:I-kappa B Kinase; D015850:Interleukin-6; D048670:MAP Kinase Kinase 4; D011719:Pyrazines; D054390:Receptors, CCR2; D000068900:Sitagliptin Phosphate; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha