Document Detail

Sitagliptin exerts an antinflammatory action.
MedLine Citation:
PMID:  22745245     Owner:  NLM     Status:  MEDLINE    
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.
Antoine Makdissi; Husam Ghanim; Mehul Vora; Kelly Green; Sanaa Abuaysheh; Ajay Chaudhuri; Sandeep Dhindsa; Paresh Dandona
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Publication Detail:
Type:  Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-28
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  97     ISSN:  1945-7197     ISO Abbreviation:  J. Clin. Endocrinol. Metab.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-10     Completed Date:  2012-11-26     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3333-41     Citation Subset:  AIM; IM    
Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo, and Kaleida Health, Buffalo, New York 14209, USA.
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MeSH Terms
Anti-Inflammatory Agents, Non-Steroidal*
Blood Glucose / analysis,  metabolism
Blotting, Western
C-Reactive Protein / analysis,  metabolism
Cell Separation
Diabetes Mellitus, Type 2 / drug therapy,  physiopathology
Dipeptidyl Peptidase 4 / analysis,  metabolism
Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
Double-Blind Method
Glucagon-Like Peptide 1 / analysis,  metabolism
Hemoglobin A, Glycosylated / analysis
I-kappa B Kinase / analysis,  metabolism
Interleukin-6 / analysis,  metabolism
MAP Kinase Kinase 4 / analysis,  metabolism
Middle Aged
Monocytes / drug effects,  metabolism
Prospective Studies
Pyrazines / pharmacology*
Receptors, CCR2 / analysis,  metabolism
Toll-Like Receptor 2 / analysis,  metabolism
Toll-Like Receptor 4 / analysis,  metabolism
Triazoles / pharmacology*
Tumor Necrosis Factor-alpha / analysis,  metabolism
Grant Support
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Blood Glucose; 0/Dipeptidyl-Peptidase IV Inhibitors; 0/Hemoglobin A, Glycosylated; 0/Interleukin-6; 0/Pyrazines; 0/Receptors, CCR2; 0/Toll-Like Receptor 2; 0/Toll-Like Receptor 4; 0/Triazoles; 0/Tumor Necrosis Factor-alpha; 89750-14-1/Glucagon-Like Peptide 1; 9007-41-4/C-Reactive Protein; EC B Kinase; EC Kinase Kinase 4; EC Peptidase 4; QFP0P1DV7Z/sitagliptin

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