Sitagliptin exerts an antinflammatory action

J Clin Endocrinol Metab. 2012 Sep;97(9):3333-41. doi: 10.1210/jc.2012-1544. Epub 2012 Jun 28.

Abstract

Context: 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.

Patients and 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Inflammatory Agents, Non-Steroidal*
  • Blood Glucose / analysis
  • Blood Glucose / metabolism
  • Blotting, Western
  • C-Reactive Protein / analysis
  • C-Reactive Protein / metabolism
  • Cell Separation
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dipeptidyl Peptidase 4 / analysis
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
  • Double-Blind Method
  • Female
  • Glucagon-Like Peptide 1 / analysis
  • Glucagon-Like Peptide 1 / metabolism
  • Glycated Hemoglobin A / analysis
  • Humans
  • I-kappa B Kinase / analysis
  • I-kappa B Kinase / metabolism
  • Interleukin-6 / analysis
  • Interleukin-6 / metabolism
  • MAP Kinase Kinase 4 / analysis
  • MAP Kinase Kinase 4 / metabolism
  • Male
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Prospective Studies
  • Pyrazines / pharmacology*
  • Receptors, CCR2 / analysis
  • Receptors, CCR2 / metabolism
  • Sitagliptin Phosphate
  • Toll-Like Receptor 2 / analysis
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / analysis
  • Toll-Like Receptor 4 / metabolism
  • Triazoles / pharmacology*
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Blood Glucose
  • Dipeptidyl-Peptidase IV Inhibitors
  • Glycated Hemoglobin A
  • Interleukin-6
  • Pyrazines
  • Receptors, CCR2
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Triazoles
  • Tumor Necrosis Factor-alpha
  • Glucagon-Like Peptide 1
  • C-Reactive Protein
  • I-kappa B Kinase
  • MAP Kinase Kinase 4
  • Dipeptidyl Peptidase 4
  • Sitagliptin Phosphate