Tissue factor/factor VIIa signalling promotes cytokine-induced beta cell death and impairs glucose-stimulated insulin secretion from human pancreatic islets
2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 11, 2563-2572 p.Article in journal (Refereed) Published
Aims/hypothesis Patients diagnosed with type 1 or type 2 diabetes have elevated levels of coagulation factor VIIa (FVIIa) and its receptor tissue factor (TF) in their bloodstream. This may affect the fate of the beta cells. We aimed to study the effects of TF/FVIIa signalling on cytokine-induced beta cell death and islet function in vitro. Methods Human pancreatic islets and MIN-6 beta cells were used to study TF mRNA and protein expression using real-time PCR, immunoblotting and flow cytometry. The effects of TF/FVIIa on cytokine-induced beta cell death were studied in MIN-6 cells and human pancreatic islets using cell-death ELISA and propidium iodide and cleaved caspase-3 staining. Effects of TF/FVIIa on the phosphorylation of p38, extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK) were investigated by immunoblotting. Glucose-stimulated insulin secretion (GSIS) from human islets was measured with an insulin ELISA. Results A combination of the cytokines IL-1 beta, TNF-alpha and IFN-gamma induced TF expression in human pancreatic islets and in beta cells. TF/FVIIa did not affect basal beta cell death but, independently of downstream coagulation activity, augmented beta cell death in response to cytokines. The effect of TF/FVIIa on cytokine-induced beta cell death was found to be dependent on the stress kinase JNK, since FVIIa addition potentiated cytokine-induced JNK activation and JNK inhibition abolished the effect of TF/FVIIa on cytokine-induced beta cell death. Moreover, TF/FVIIa signalling resulted in inhibition of GSIS from human pancreatic islets. Conclusions/interpretation These results indicate that TF/FVIIa signalling has a negative effect on beta cell function and promotes beta cell death in response to cytokines.
Place, publisher, year, edition, pages
2015. Vol. 58, no 11, 2563-2572 p.
Beta cells, Cytokines, Diabetes, FVIIa, Glucose-stimulated insulin secretion, JNK, Pancreatic islets, Tissue factor
Endocrinology and Diabetes
IdentifiersURN: urn:nbn:se:uu:diva-265663DOI: 10.1007/s00125-015-3729-yISI: 000361993000013PubMedID: 26271343OAI: oai:DiVA.org:uu-265663DiVA: diva2:867478
FunderGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyStiftelsen Olle Engkvist ByggmästareMagnus Bergvall FoundationSwedish Society of MedicineSwedish Child Diabetes FoundationSwedish Research Council