CRFR1 activation protects against cytokine-induced β-cell death

Blaabjerg, Lykke; Christensen, Gitte Lund; Matsumoto, Masahito; Meulen, Talitha van der; Huising, Mark O.; Billestrup, Nils; Vale, Wylie

doi:10.1530/jme-14-0056

Cited by 16 publications

(11 citation statements)

References 47 publications

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“…Akt can directly make Foxo1 phosphorylate, Phosphorylated FOX1 can be transferred from the nucleus to the cytoplasm and then lose activity (Barthel et al, 2005 ). Epidemiological statistics show that the polymorphism of Akt gene is closely related to diabetes mellitus, it can be activated by phosphorylation then play a role of anti-β cell apoptosis and promote the survival of β cells (Blaabjerg et al, 2014 ; Yin et al, 2017 ). Our observations suggest that high fat intake in KKAy mice can promote Foxo1 protein expression.…”

Section: Discussionmentioning

confidence: 99%

Jiang Tang Xiao Ke Granule Play an Anti-diabetic Role in Diabetic Mice Pancreatic Tissue by Regulating the mRNAs and MicroRNAs Associated with PI3K-Akt Signaling Pathway

Zhang

et al. 2017

Front. Pharmacol.

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Purpose: To investigate the effect of JTXK granule on the expression pattern of miRNA in pancreatic tissue of KKAy diabetic mice, and to explore the molecular mechanism and pathways of JTXK granule in anti-diabetic effect.Methods: We used high fat diet (HFD) to induce the KKAy diabetic mice and screened the differentially expressed miRNAs (DEMs) between JTXK-treated group (n = 6) and the diabetic group (n = 6) using MicroRNA (miRNA) Microarray. C57BL/6J mice were given a normal diet as the control group (n = 6). Subsequently, miRNA target gene prediction, GO and Pathway analysis were used to explore the function of DEMs. Finally, the mechanism of anti-diabetic effects of JTXK granule was tested by in vitro INS-1 pancreatic β-cell experiment.Results: The blood glucose and body weight of JTXK-treated group was significantly lower compared with the model group. Moreover, a total of 45 miRNAs with significant differences were detected in the model group and the JTXK-treated group (P ≤ 0.05, Fold Change > 2). Further, miRNA-mRNA analysis showed that the differential expression of mmu-miR-192-5p, mmu-miR-291a-3p, mmu-miR-320-3p, mmu-miR-139-5p and mmu-miR-378a-3p are closely related to pancreatic histological changes. In addition, pathway analysis showed that the DEMs were closely related to PI3K-Akt Signaling Pathway. Furthermore, the levels of serine/threonine-protein kinase (Akt), phosphorylated Akt (p-Akt) and phosphorylated forkhead transcription factor O1 (p-Foxo1) in INS-1-FOXO1 overexpressing model cells were lower than those in normal group, while JTXK granules could increase the expression of Akt, p-Akt and p-Foxo1.Conclusions: The results showed that JTXK granule could play an anti-diabetic role by regulating the mRNA and miRNAs associated with PI3K-Akt pathway in diabetic mice pancreatic tissue.

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Section: Discussionmentioning

confidence: 99%

Jiang Tang Xiao Ke Granule Play an Anti-diabetic Role in Diabetic Mice Pancreatic Tissue by Regulating the mRNAs and MicroRNAs Associated with PI3K-Akt Signaling Pathway

Zhang

et al. 2017

Front. Pharmacol.

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“…The impoverishment or functional decline in pancreatic beta cells is the main cause of all forms of diabetes [ 1 ]. Currently, therapy for diabetes comprises drug therapy or pancreatic islet transplantation.…”

Section: Introductionmentioning

confidence: 99%

A New Way for Beta Cell Neogenesis: Transdifferentiation from Alpha Cells Induced by Glucagon-Like Peptide 1

Zhang

et al. 2019

Journal of Diabetes Research

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Recent studies showed that alpha cells, especially immature cells and proalpha cells, might be the precursors of beta cells. Exposure to glucagon-like peptide 1 (GLP1) can ameliorate hyperglycemia in diabetic mice and restore the beta cell mass. In the present study, we adopted single high-dose (60 mg/kg, i.p.) streptozotocin (STZ) to model diabetes mellitus (DM) and randomly assigned short-tail (SD) rats to a normal group, a diabetic group, GLP1 groups (50 μg/kg, 100 μg/kg, and 200 μg/kg), a GLP1 (200 μg/kg) with exendin (9-39) group, and a GLP1 with LY294002 group. We found that the pancreatic insulin-glucagon-positive cell populations increased according to the increase in GLP1 exposure. By contrast, no insulin-amylase-positive cell populations or insulin/pan-cytokeratin cells were observed in the pancreatic sections. The GLP1 receptor antagonist exendin (9-39) and the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) family inhibitor LY294002 not only suppressed protein kinase B (Akt), pancreatic and duodenal homeobox 1 (Pdx1), forkhead box O 1 (FoxO1), and mast cell function-associated antigen A (MafA) mRNA expression but also increased MAFB expression. We concluded that treatment with GLP1 might result in beta cell neogenesis by promoting the transdifferentiation of alpha cells but not by pancreatic acinar cells, ductal cells, or the self-replication of beta cells. The regulation on the GLP1 receptor and its downstream transcription factor PI3K/AKT/FOXO1 pathway, which causes increased pancreatic and duodenal homeobox 1 (Pdx1) and MafA mRNA expression but causes decreased MAFB expression, may be the mechanism involved in this process.

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“…Blocking efferent immune responses will likely be more demanding since islet killing can be mediated by effector cytokines such as IFN-γ, IL-1β, and TNF-α in addition to direct contact of immune cells with the grafts. 31–33 These cytokines have molecular weights of 17 to 51 kDa and have hydrodynamic radii of 2 to 3 nm, close to that of insulin (MW 5.8 kDa, radius 1.3 nm). Despite these concerns, we found that Encaptra™ robustly prevented rejection in fully sensitized and autoimmune recipients while supporting β cell function as shown by normalization of blood glucose in spontaneously diabetic NOD recipients.…”

Section: Discussionmentioning

confidence: 97%

Assessment of Immune Isolation of Allogeneic Mouse Pancreatic Progenitor Cells by a Macroencapsulation Device

et al. 2016

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Background Embryonic-stem-cell (ESC)-derived islets hold the promise of providing a renewable source of tissue for the treatment of insulin-dependent diabetes. Encapsulation may allow ESC-derived islets to be transplanted without immunosuppression, thus enabling wider application of this therapy. Methods In this study, we investigated the immunogenicity of mouse pancreatic progenitor cells and efficacy of a new macroencapsulation device in protecting these cells against alloimmune and autoimmune responses in mouse models. Results Mouse pancreatic progenitor cells activated the indirect but not the direct pathway of alloimmune response and were promptly rejected in immune competent hosts. The new macroencapsulation device abolished T cell activation induced by allogeneic splenocytes and protected allogeneic MIN6 β cells and pancreatic progenitors from rejection even in pre-sensitized recipients. In addition, the device was effective in protecting MIN6 cells in spontaneously diabetic non-obese diabetic recipients against both alloimmune and recurring autoimmune responses. Conclusion Our results demonstrate that macroencapsulation can effectively prevent immune sensing and rejection of allogeneic pancreatic progenitor cells in fully sensitized and autoimmune hosts.

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CRFR1 activation protects against cytokine-induced β-cell death

Cited by 16 publications

References 47 publications

Jiang Tang Xiao Ke Granule Play an Anti-diabetic Role in Diabetic Mice Pancreatic Tissue by Regulating the mRNAs and MicroRNAs Associated with PI3K-Akt Signaling Pathway

Jiang Tang Xiao Ke Granule Play an Anti-diabetic Role in Diabetic Mice Pancreatic Tissue by Regulating the mRNAs and MicroRNAs Associated with PI3K-Akt Signaling Pathway

A New Way for Beta Cell Neogenesis: Transdifferentiation from Alpha Cells Induced by Glucagon-Like Peptide 1

Assessment of Immune Isolation of Allogeneic Mouse Pancreatic Progenitor Cells by a Macroencapsulation Device

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