IL-1β induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis

Sparre, Thomas; Bjerre-Christensen, Ulla; Larsen, Peter Mose; Fey, Stephen J.; Wrzesinski, Krzysztof; Roepstorff, Peter; Mandrup-Poulsen, Thomas; Pociot, Flemming; Karlsen, Allan E.; Nerup, Jørn

doi:10.1007/s00125-002-0953-z

Cited by 50 publications

(2 citation statements)

References 92 publications

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“…Secretagogin has previously been suggested to be involved in beta cell homeostasis by protecting against IL-1β-mediated beta cell destruction in diabetes-prone biobreeding rat islets [ 43 ]. These results are in contrast with our study, which indicated that cytokines did not change the apoptotic susceptibility of secretagogin silenced human beta cells.…”

Section: Discussionmentioning

confidence: 99%

Secretagogin is increased in plasma from type 2 diabetes patients and potentially reflects stress and islet dysfunction

et al. 2018

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Beta cell dysfunction accompanies and drives the progression of type 2 diabetes mellitus (T2D), but there are few clinical biomarkers available to assess islet cell stress in humans. Secretagogin, a protein enriched in pancreatic islets, demonstrates protective effects on beta cell function in animals. However, its potential as a circulating biomarker released from human beta cells and islets has not been studied. In this study primary human islets, beta cells and plasma samples were used to explore secretion and expression of secretagogin in relation to the T2D pathology. Secretagogin was abundantly and specifically expressed and secreted from human islets. Furthermore, T2D patients had an elevated plasma level of secretagogin compared with matched healthy controls, which was confirmed in plasma of diabetic mice transplanted with human islets. Additionally, the plasma secretagogin level of the human cohort had an inverse correlation to clinical assessments of beta cell function. To explore the mechanism of secretagogin release in vitro, human beta cells (EndoC-βH1) were exposed to elevated glucose or cellular stress-inducing agents. Secretagogin was not released in parallel with glucose stimulated insulin release, but was markedly elevated in response to endoplasmic reticulum stressors and cytokines. These findings indicate that secretagogin is a potential novel biomarker, reflecting stress and islet cell dysfunction in T2D patients.

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Section: Discussionmentioning

confidence: 99%

Secretagogin is increased in plasma from type 2 diabetes patients and potentially reflects stress and islet dysfunction

et al. 2018

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“…Proteomic technique has been widely used to investigate the protein changes elicited by exposure of islets or insulinoma cells to glucose [21], [22], cytokines [23], [24] and others substances [25], [26]. Here we report the proteomic characterization of β-TC3R.…”

Section: Resultsmentioning

confidence: 96%

In Vitro Phenotypic, Genomic and Proteomic Characterization of a Cytokine-Resistant Murine β-TC3 Cell Line

et al. 2012

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Type 1 diabetes mellitus (T1DM) is caused by the selective destruction of insulin-producing β-cells. This process is mediated by cells of the immune system through release of nitric oxide, free radicals and pro-inflammatory cytokines, which induce a complex network of intracellular signalling cascades, eventually affecting the expression of genes involved in β-cell survival.The aim of our study was to investigate possible mechanisms of resistance to cytokine-induced β-cell death. To this purpose, we created a cytokine-resistant β-cell line (β-TC3R) by chronically treating the β-TC3 murine insulinoma cell line with IL-1β + IFN-γ. β-TC3R cells exhibited higher proliferation rate and resistance to cytokine-mediated cell death in comparison to the parental line. Interestingly, they maintained expression of β-cell specific markers, such as PDX1, NKX6.1, GLUT2 and insulin. The analysis of the secretory function showed that β-TC3R cells have impaired glucose-induced c-peptide release, which however was only moderately reduced after incubation with KCl and tolbutamide. Gene expression analysis showed that β-TC3R cells were characterized by downregulation of IL-1β and IFN-γ receptors and upregulation of SOCS3, the classical negative regulator of cytokines signaling. Comparative proteomic analysis showed specific upregulation of 35 proteins, mainly involved in cell death, stress response and folding. Among them, SUMO4, a negative feedback regulator in NF-kB and JAK/STAT signaling pathways, resulted hyper-expressed. Silencing of SUMO4 was able to restore sensitivity to cytokine-induced cell death in β-TC3R cells, suggesting it may play a key role in acquired cytokine resistance by blocking JAK/STAT and NF-kB lethal signaling.In conclusion, our study represents the first extensive proteomic characterization of a murine cytokine-resistant β-cell line, which might represent a useful tool for studying the mechanisms involved in resistance to cytokine-mediated β-cell death. This knowledge may be of potential benefit for patients with T1DM. In particular, SUMO4 could be used as a therapeutical target.

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Bone marrow mesenchymal stem cells ameliorate inflammatory factor‐induced dysfunction of INS‐1 cells on chip

Sun

Yao

Lin

et al. 2014

Cell Biology International

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Using a microfluidic chip, we have investigated whether bone marrow mesenchymal stem cells (BM-MSCs) could ameliorate IL-1β/IFN-γ-induced dysfunction of INS-1 cells. BM-MSCs were obtained from diabetes mellitus patients and their cell surface antigen expression profiles were analyzed by flow cytometric. INS-1 cells were cocultured with BM-MSCs on a microfluidic chip with persistent perfusion of medium containing 1 ng/mL IL-1β and 2.5 U/mL IFN-γ for 72 h. BM-MSCs could partially rescue INS-1 cells from cytokine-induced dysfunction and ameliorate the expression of insulin and PDX-1 gene in INS-1 cells. Thus BM-MSCs can be viewed as a promising stem cell source to depress inflammatory factor-induced dysfunction of pancreatic β cells in diabetic patients.

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IL-1β induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis

Cited by 50 publications

References 92 publications

Secretagogin is increased in plasma from type 2 diabetes patients and potentially reflects stress and islet dysfunction

Secretagogin is increased in plasma from type 2 diabetes patients and potentially reflects stress and islet dysfunction

In Vitro Phenotypic, Genomic and Proteomic Characterization of a Cytokine-Resistant Murine β-TC3 Cell Line

Bone marrow mesenchymal stem cells ameliorate inflammatory factor‐induced dysfunction of INS‐1 cells on chip

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