Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release

Autor: Claudia Weber, Daniel Kammerer, Alexander H. Licht, Bettina Streit
Jazyk: angličtina
Předmět:
Insulin pump
Chemokine
CCL2
chemokine ligand 2
Humalog (PubChem CID: 16132438)
Health
Toxicology and Mutagenesis
medicine.medical_treatment
CD
cluster of differentiation
IgG
immunoglobulin G
TNFα
tumor necrosis factor alpha
Inflammation
Phenol (PubChem CID: 996)
Pharmacology
CCL2
DMSO
dimethyl sulfoxide
Toxicology
Phenolic excipients
Article
NovoRapid (PubChem CID: 16132418)
APC
allophycocyanin
ERK
extracellular signal-regulated kinase
lcsh:RA1190-1270
Apidra (PubChem CID: 72941761)
medicine
Mip-1α
macrophage inflammatory protein-1alpha
Insulin
Viability assay
m-Cresol (PubChem CID: 342)
lcsh:Toxicology. Poisons
CSII
continuous subcutaneous insulin infusion
biology
Chemistry
Adverse effects
Monocyte
PE
phycoerythrin
MCP-1
monocyte chemotactic protein-1
Insulin (PubChem CID: 70678557)
IL
interleukin
MAP kinase
mitogen-activated protein kinase
medicine.anatomical_structure
JNK
Jun N-terminal kinase
biology.protein
Tumor necrosis factor alpha
medicine.symptom
XTT
2
3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide
MCP-1
Zdroj: Toxicology Reports
Toxicology Reports, Vol 2, Iss C, Pp 194-202 (2015)
ISSN: 2214-7500
DOI: 10.1016/j.toxrep.2014.11.019
Popis: Highlights • Insulin formulations are cytotoxic in vitro. • Toxicity is caused by the excipients phenol and m-cresol. • Phenolic excipients activate stress kinases and attenuate AKT phosphorylation. • Phenolic excipients induce pro-inflammatory responses and MCP-1 release. • The toxic effects of excipients might explain inflammation of infusion sites in vivo.
Skin reactions at the infusion site are a common side effect of continuous subcutaneous insulin infusion therapy. We hypothesized that local skin complications are caused by components of commercial insulin formulations that contain phenol or m-cresol as excipients. The toxic potential of insulin solutions and the mechanisms leading to skin reactions were explored in cultured cells. The toxicity of insulin formulations (Apidra, Humalog, NovoRapid, Insuman), excipient-free insulin, phenol and m-cresol was investigated in L929 cells, human adipocytes and monocytic THP-1 cells. The cells were incubated with the test compounds dose- and time-dependently. Cell viability, kinase signaling pathways, monocyte activation and the release of pro-inflammatory cytokines were analyzed. Insulin formulations were cytotoxic in all cell-types and the pure excipients phenol and m-cresol were toxic to the same extent. P38 and JNK signaling pathways were activated by phenolic compounds, whereas AKT phosphorylation was attenuated. THP-1 cells incubated with sub-toxic levels of the test compounds showed increased expression of the activation markers CD54, CD11b and CD14 and secreted the chemokine MCP-1 indicating a pro-inflammatory response. Insulin solutions displayed cytotoxic and pro-inflammatory potential caused by phenol or m-cresol. We speculate that during insulin pump therapy phenol and m-cresol might induce cell death and inflammatory reactions at the infusion site in vivo. Inflammation is perpetuated by release of MCP-1 by activated monocytic cells leading to enhanced recruitment of inflammatory cells. To minimize acute skin complications caused by phenol/m-cresol accumulation, a frequent change of infusion sets and rotation of the infusion site is recommended.
Databáze: OpenAIRE
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