Exposure of human islets to cytokines can result in disproportionately elevated proinsulin release

Hostens, Katleen; Pavlović, Dejan; Zambre, Yasmeeni; Ling, Zhidong; Schravendijk, Christiaan Van; Eizirik, Décio L.; Pipeleers, Daniël

doi:10.1172/jci6438

Cited by 99 publications

(91 citation statements)

References 34 publications

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“…This bears similarity to the pattern of insulin release observed in prediabetic subjects. The present data, together with our previous observations (13), raise the possibility that ␤-cell exposure to immune mediators during the course of insulitis is responsible for the key metabolic modifications observed in this period, namely disproportionately elevated proinsulin release and loss of first phase insulin release.…”

Section: Cytokines Effect On the Process Of Insulin Exocytosis 41273supporting

confidence: 76%

“…This initial ␤-cell functional suppression might be due to exposure to cytokines. Indeed, our previous observations (13) indicate that islet exposure to cytokines under in vitro conditions reproduce the disproportionately elevated proinsulin/insulin levels observed in prediabetic patients. Moreover, microarray analysis of purified ␤-cells or insulin-producing INS-1 cells cultured in the presence of IL-1 ␤ or IL-1␤ ϩ IFN-␥ showed inhibition of the expression of several genes involved in the exocytosis of insulin granules, including SNAP-25, VAMP-2, and Rab3 (14,15).…”

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confidence: 75%

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The Cytokine Interleukin-1β Reduces the Docking and Fusion of Insulin Granules in Pancreatic β-Cells, Preferentially Decreasing the First Phase of Exocytosis

Ohara‐Imaizumi

Cardozo²,

Kikuta

et al. 2004

Journal of Biological Chemistry

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The prediabetic period in type I diabetes mellitus is characterized by the loss of first phase insulin release. This might be due to islet infiltration mediated by mononuclear cells and local release of cytokines, but the mechanisms involved are unknown. To determine the role of cytokines in insulin exocytosis, we have presently utilized total internal reflection fluorescence microscopy (TIRFM) to image and analyze the dynamic motion of single insulin secretory granules near the plasma membrane in live ␤-cells exposed for 24 h to interleukin (IL)-1␤ or interferon (IFN)-␥. Immunohistochemistry observed via TIRFM showed that the number of docked insulin granules was decreased by 60% in ␤-cells treated with IL-1␤, while it was not affected by exposure to IFN-␥. This effect of IL-1␤ was paralleled by a 50% reduction in the mRNA and the number of clusters of SNAP-25 in the plasma membrane. TIRF images of single insulin granule motion during a 15-min stimulation by 22 mM glucose in IL-1␤-treated ␤-cells showed a marked reduction in the fusion events from previously docked granules during the first phase insulin release. Fusion from newcomers, however, was well preserved during the second phase of insulin release of IL-1␤-treated ␤-cells. The present observations indicate that IL-1␤, but not IFN-␥, has a preferential inhibitory effect on the first phase of glucose-induced insulin release, mostly via an action on previously docked granules. This suggests that ␤-cell exposure to immune mediators during the course of insulitis might be responsible for the loss of first phase insulin release.Accumulating evidence over the past 30 years suggests that ␤-cells are destroyed by an autoimmune process in type 1 diabetes mellitus (T1D) 1 (1). The prediabetic period in humans is characterized by the presence of islet cell autoantibodies (2), which seem to have a close correlation with histological evidence of autoimmunity (3). There are already subtle changes in ␤-cell function during this period, including both disproportionately elevated proinsulin/insulin levels (4, 5) and a preferential loss of the first phase insulin secretion in response to an intravenous glucose challenge (6 -9). Of note, ␤-cell suppression precedes ␤-cell death in T1D, as suggested by results obtained in islets isolated from prediabetic non-obese diabetic mice (10, 11) or from a patient who died immediately after diagnosis of T1D (12). This initial ␤-cell functional suppression might be due to exposure to cytokines. Indeed, our previous observations (13) indicate that islet exposure to cytokines under in vitro conditions reproduce the disproportionately elevated proinsulin/insulin levels observed in prediabetic patients. Moreover, microarray analysis of purified ␤-cells or insulin-producing INS-1 cells cultured in the presence of IL-1 ␤ or IL-1␤ ϩ IFN-␥ showed inhibition of the expression of several genes involved in the exocytosis of insulin granules, including SNAP-25, and Rab3 (14,15). This raised the intriguing possibility that cytokines could also co...

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Section: Cytokines Effect On the Process Of Insulin Exocytosis 41273supporting

confidence: 76%

mentioning

confidence: 75%

The Cytokine Interleukin-1β Reduces the Docking and Fusion of Insulin Granules in Pancreatic β-Cells, Preferentially Decreasing the First Phase of Exocytosis

Ohara‐Imaizumi

Cardozo²,

Kikuta

et al. 2004

Journal of Biological Chemistry

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“…It was subsequently shown that IL-1β+ of NO production in the time period studied [12]. In human islets TNF-α+IFN-γ induces a more marked activation of the ER stress response [14], in spite of the fact that IL-1β+IFN-γ induces a nearly tenfold higher increase in NO production [22,47]. These conflicting observations caused confusion in the field, as it was not clear whether they were due to species differences or other reasons.…”

Section: Discussionmentioning

confidence: 99%

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

et al. 2015

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Aims/hypothesis Proinflammatory cytokines contribute to beta cell damage in type 1 diabetes in part through activation of endoplasmic reticulum (ER) stress. In rat beta cells, cytokineinduced ER stress involves NO production and consequent inhibition of the ER Ca 2+ transporting ATPase sarco/ endoplasmic reticulum Ca 2+ pump 2 (SERCA2B). However, the mechanisms by which cytokines induce ER stress and apoptosis in mouse and human pancreatic beta cells remain unclear. The purpose of this study is to elucidate the role of ER stress on cytokine-induced beta cell apoptosis in these three species and thus solve ongoing controversies in the field. Methods Rat and mouse insulin-producing cells, human pancreatic islets and human EndoC-βH1 cells were exposed to the cytokines IL-1β, TNF-α and IFN-γ, with or without NO inhibition. A global comparison of cytokine-modulated gene expression in human, mouse and rat beta cells was also performed. The chemical chaperone tauroursodeoxycholic acid (TUDCA) and suppression of C/EBP homologous protein (CHOP) were used to assess the role of ER stress in cytokineinduced apoptosis of human beta cells. Results NO plays a key role in cytokine-induced ER stress in rat islets, but not in mouse or human islets. Bioinformatics analysis indicated greater similarity between human and mouse than between human and rat global gene expression after cytokine exposure. The chemical chaperone TUDCA and suppression of CHOP or c-Jun N-terminal kinase (JNK) protected human beta cells against cytokine-induced apoptosis. Conclusions/interpretation These observations clarify previous results that were discrepant owing to the use of islets from different species, and confirm that cytokine-induced ER stress contributes to human beta cell death, at least in part via JNK activation.

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“…In IL-1β exposed islets both neuroendocrine convertase 1 and 2 are down-regulated more than fivefold explaining decreased insulin release after IL-1β exposure of islets in vitro [86]. In human islets exposed to cytokines expression of neuroendocrine convertase 1 and 2 is reduced [87].…”

Section: Cellular Defence (Two Proteins)mentioning

confidence: 96%

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

Sparre

Bjerre-Christensen

Larsen³

et al. 2002

Diabetologia

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Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is characterized by selective destruction of the insulin producing beta cells. Interleukin-1β (IL-1β) modulates the beta-cell function, protein synthesis, energy production and causes apoptosis. We have previously shown changes in the expression of 82 out of 1 815 protein spots detected by two dimensional gel electrophoresis in IL-1β exposed diabetes prone Bio Breeding (BB-DP) rat islets of Langerhans in vitro. The aim of this study was to identify the proteins in these 82 spots by mass spectrometry and compare these changes with those seen in IL-1β exposed Wistar Furth (WF) rat islets. Methods. The 82 protein spots, that changed expression after IL-1β exposure, were all re-identified on preparative gels of 200 000 neonatal WF rat islets, cut out and subjected to mass spectrometry for identification.Results. Forty-five different proteins were identified from 51 spots and grouped according to function: (i) energy transduction and redox potentials; (ii) glycolytic and Krebs cycle enzymes; (iii) protein, DNA and RNA synthesis, chaperoning and protein folding; (iv) signal transduction, regulation, differentiation and apoptosis; (v) cellular defence; and (vi) other functions. Comparison of IL-1β exposed BB-DP and WF islets showed common changes in 14 proteins and several proteins influencing similar pathways, suggesting that similar routes in the two strains lead to beta-cell destruction. Conclusion/interpretation. We demonstrate that proteome analysis is a powerful tool to identify proteins and pathways in BB-DP rat islets exposed to IL-1β. [Diabetologia (2002) 45:1550-1561

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Exposure of human islets to cytokines can result in disproportionately elevated proinsulin release

Cited by 99 publications

References 34 publications

The Cytokine Interleukin-1β Reduces the Docking and Fusion of Insulin Granules in Pancreatic β-Cells, Preferentially Decreasing the First Phase of Exocytosis

The Cytokine Interleukin-1β Reduces the Docking and Fusion of Insulin Granules in Pancreatic β-Cells, Preferentially Decreasing the First Phase of Exocytosis

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

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

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