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Cited by 114Diabetes Treatment and ManagementSepsis Diagnosis and TreatmentNitric Oxide and Endothelin Effects

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Gliptin and GLP‐1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide‐induced endotoxemia

Steven, Sebastian, Hausding, Michael, Kröller-Schön, Swenja, Mader, Michael, Mikhed, Yuliya, Stamm, Paul, Zinßius, Elena, Pfeffer, Amanda, Welschof, Philipp, Agdauletova, Saule, Sudowe, Stephan, Li, Huige, Oelze, Matthias, Schulz, Eberhard, Klein, Thomas, Münzel, Thomas, Daiber, Andreas·2015·Basic Research in Cardiology
DOI 10.1007/s00395-015-0465-x
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Abstract

Dipeptidyl peptidase (DPP)-4 inhibitors are used to treat hyperglycemia by increasing the incretin glucagon-like peptide-1 (GLP-1). Previous studies showed anti-inflammatory and antiatherosclerotic effects of DPP-4 inhibitors. Here, we compared the effects of linagliptin versus sitagliptin and liraglutide on survival and vascular function in animal models of endotoxic shock by prophylactic therapy and treatment after lipopolysaccharide (LPS) injection. Gliptins were administered either orally or subcutaneously: linagliptin (5 mg/kg/day), sitagliptin (50 mg/kg/day) or liraglutide (200 µg/kg/day). Endotoxic shock was induced by LPS injection (mice 17.5-20 mg/kg i.p., rats 10 mg/kg/day). Linagliptin and liraglutide treatment or DPP-4 knockout improved the survival of endotoxemic mice, while sitagliptin was ineffective. Linagliptin, liraglutide and sitagliptin ameliorated LPS-induced hypotension and vascular dysfunction in endotoxemic rats, suppressed inflammatory parameters such as whole blood nitrosyl-iron hemoglobin (leukocyte-inducible nitric oxide synthase activity) or aortic mRNA expression of markers of inflammation as well as whole blood and aortic reactive oxygen species formation. Hemostasis (tail bleeding time, activated partial thromboplastin time) was impaired in endotoxemic rats and recovered under cotreatment with linagliptin and liraglutide. Finally, the beneficial effects of linagliptin on vascular function and inflammatory parameters in endotoxemic mice were impaired in AMP-activated kinase (alpha1) knockout mice. The improved survival of endotoxemic animals and other data shown here may warrant further clinical evaluation of these drugs in patients with septic shock beyond the potential improvement of inflammatory complications in diabetic individuals with special emphasis on the role of AMP-activated kinase (alpha1) in the DPP-4/GLP-1 cascade.

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  • Treatment with linagliptin (5 mg/kg/day) and sitagliptin (50 mg/kg/day), and liraglutide (200 μg/kg/day), significantly reduced inflammatory markers such as inducible NO synthase, cyclooxygenase, and VCAM-1 via the AMPK pathway in LPS-induced endotoxemic shock in rats as a model of human sepsis.

    “Treatment with the DPP-4 inhibitors, linagliptin (5 mg/kg/day) and sitagliptin (50 mg/kg/day), and the GLP-1 analogue, liraglutide (200 μg/kg/day), significantly reduced inflammatory markers such as inducible NO synthase, cyclooxygenase, and VCAM-1 via the AMPK pathway in LPS-induced endotoxemic shock in rats as a model of human sepsis [115].”

    From Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control (2016) · cites this paper as [115]

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Authors
Steven, S., Hausding, M., Kröller-Schön, S., Mader, M., Mikhed, Y., Stamm, P., Zinßius, E., Pfeffer, A., Welschof, P., Agdauletova, S., Sudowe, S., Li, H., Oelze, M., Schulz, E., Klein, T., Münzel, T., & Daiber, A.
Affiliations
  • Johannes Gutenberg University Mainz (DE)
  • Boehringer Ingelheim (Germany) (DE)
Corresponding author
Daiber, Andreas
ORCID
Venue
Basic Research in Cardiology
Publisher
Springer Science and Business Media LLC
Published
2015-01-20
Volume
110
Issue
2
Pages
6-6
ISSN
  • 0003-9217 (ISSN-L)
  • 0300-8428
  • 1435-1803
DOI
10.1007/s00395-015-0465-x
OpenAlex
W1972876739
Cited by
114
References
2
Citations by year
2026: 6 · 2025: 15 · 2024: 14 · 2023: 9 · 2022: 6 · 2021: 10 · 2020: 5 · 2019: 10 · 2018: 11 · 2017: 15 · 2016: 8 · 2015: 4
FWCI
10.98
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Basic Research in Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Keywords
DPP-4 inhibitors, GLP-1 analogues, linagliptin, sitagliptin, liraglutide, endotoxemia, lipopolysaccharide, septic shock, vascular inflammation, vascular dysfunction, AMPK, nitric oxide synthase, reactive oxygen species, hemostasis, survival
MeSH terms
Sitagliptin Phosphate, Liraglutide, Linagliptin, Animals, Disease Models, Animal, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Purines, Pyrazines, Quinazolines, Triazoles, Rats, Wistar, Mice, Knockout, Oxidative Stress, Endotoxemia, Mice, Rats, Glucagon-Like Peptide 1, Dipeptidyl-Peptidase IV Inhibitors, Real-Time Polymerase Chain Reaction

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