scholarly journals The Effect of Suppressor of Cytokine Signaling 3 on GH Signaling in β-Cells

2002 ◽  
Vol 16 (9) ◽  
pp. 2124-2134 ◽  
Author(s):  
Sif G. Rønn ◽  
Johnny A. Hansen ◽  
Karen Lindberg ◽  
Allan E. Karlsen ◽  
Nils Billestrup
Keyword(s):  
Cell Lines ◽  
Inducible Promoter ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Insulin Production ◽  
Β Cells ◽  
Β Cell ◽  
Cellular Effects ◽  
Socs Proteins ◽  
Induced Signal

Abstract GH is an important regulator of cell growth and metabolism. In the pancreas, GH stimulates mitogenesis as well as insulin production in β-cells. The cellular effects of GH are exerted mainly through activation of the Janus kinase-signal transducer and activator of transcription (STAT) pathway. Recently it has been found that suppressors of cytokine signaling (SOCS) proteins are able to inhibit GH-induced signal transduction. In the present study, the role of SOCS-3 in GH signaling was investigated in the pancreatic β-cell lines RIN-5AH and INS-1 by means of inducible expression systems. Via stable transfection of the β-cell lines with plasmids expressing SOCS-3 under the control of an inducible promoter, a time- and dose-dependent expression of SOCS-3 in the cells was obtained. EMSA showed that SOCS-3 is able to inhibit GH-induced DNA binding of both STAT3 and STAT5 in RIN-5AH cells. Furthermore, using Northern blot analysis it was shown that SOCS-3 can completely inhibit GH-induced insulin production in these cells. Finally, 5-bromodeoxyuridine incorporation followed by fluorescence-activated cell sorting analysis showed that SOCS-3 inhibits GH-induced proliferation of INS-1 cells. These findings support the hypothesis that SOCS-3 is a major regulator of GH signaling in insulin-producing cells.

Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

2016 ◽  
Vol 26 (1) ◽  
Author(s):  
Amira Alkharusi ◽  
Mercedes Mirecki-Garrido ◽  
Zuheng Ma ◽  
Fahad Zadjali ◽  
Amilcar Flores-Morales ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Type I ◽  
Suppressor Of Cytokine Signaling ◽  
Β Cell ◽  
Diabetes In Mice ◽  
Socs Proteins ◽  
Stat Pathway

AbstractDiabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity.The elevated sensitivity of SOCS2We show that 6-month-old SOCS2Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy, and which is protective against MLDSTZ-induced type I diabetes in mice. SOCS2-dependent control of β-cell survival may be of relevance to islet regeneration and survival in transplantation.

scholarly journals The efficiency of insulin production and its content in insulin-expressing model β-cells correlate with their Zn 2+ levels

Open Biology ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 200137
Author(s):  
Petra Dzianová ◽  
Seiya Asai ◽  
Martina Chrudinová ◽  
Lucie Kosinová ◽  
Pavlo Potalitsyn ◽  
...  
Keyword(s):  
Cell Lines ◽  
Secretory Granules ◽  
Zinc Content ◽  
Zinc Homeostasis ◽  
Insulin Production ◽  
Β Cells ◽  
Β Cell ◽  
Impaired Insulin ◽  
The Impact ◽  
And Storage

Insulin is produced and stored inside the pancreatic β-cell secretory granules, where it is assumed to form Zn 2+ -stabilized oligomers. However, the actual storage forms of this hormone and the impact of zinc ions on insulin production in vivo are not known. Our initial X-ray fluorescence experiment on granules from native Langerhans islets and insulinoma-derived INS-1E cells revealed a considerable difference in the zinc content. This led our further investigation to evaluate the impact of the intra-granular Zn 2+ levels on the production and storage of insulin in different model β-cells. Here, we systematically compared zinc and insulin contents in the permanent INS-1E and BRIN-BD11 β-cells and in the native rat pancreatic islets by flow cytometry, confocal microscopy, immunoblotting, specific messenger RNA (mRNA) and total insulin analysis. These studies revealed an impaired insulin production in the permanent β-cell lines with the diminished intracellular zinc content. The drop in insulin and Zn 2+ levels was paralleled by a lower expression of ZnT8 zinc transporter mRNA and hampered proinsulin processing/folding in both permanent cell lines. To summarize, we showed that the disruption of zinc homeostasis in the model β-cells correlated with their impaired insulin and ZnT8 production. This indicates a need for in-depth fundamental research about the role of zinc in insulin production and storage.

scholarly journals Regulation of pancreatic β-cell mass and proliferation by SOCS-3

2005 ◽  
Vol 35 (2) ◽  
pp. 231-243 ◽  
Author(s):  
K Lindberg ◽  
S G Rønn ◽  
D Tornehave ◽  
H Richter ◽  
J A Hansen ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cell Proliferation ◽  
Cell Volume ◽  
Cytokine Signaling ◽  
Wild Type ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Female Mice ◽  
Socs Proteins

Growth hormone and prolactin are important growth factors for pancreatic β-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in β-cells are largely mediated through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Suppressors of cytokine signaling (SOCS) proteins are specific inhibitors of the JAK/STAT pathway acting through a negative-feedback loop. To investigate in vivo effects of SOCS-3 in growth hormone (GH)/prolactin signaling in β-cells we generated transgenic mice with β-cell-specific overexpression of SOCS-3. The relative β-cell proliferation and volume in the mice were measured by morphometry. β-Cell volume of transgenic female mice was reduced by over 30% compared with β-cell volume in wild-type female mice. Stimulation of transgenic islets in vitro with GH showed a reduced tyrosine phosphorylation of STAT-5 when compared with wild-type islets. Transduction of primary islet cultures with adenoviruses expressing various SOCS proteins followed by stimulation with GH or glucagon-like peptide-1 (GLP-1) revealed that SOCS-3 inhibited GH- but not GLP-1-mediated islet cell proliferation, indicating that the decreased β-cell volume observed in female transgenic mice could be caused by an inhibition of GH-induced β-cell proliferation by SOCS-3. In spite of the reduced β-cell volume the transgenic female mice exhibited enhanced glucose tolerance compared with wild-type littermates following an oral glucose-tolerance test. Together these data suggest that SOCS-3 modulates cytokine signaling in pancreatic β-cells and therefore potentially could be a candidate target for development of new treatment strategies for diabetes.

scholarly journals Anti-inflammatory, antioxidant and renoprotective effects of SOCS1 mimetic peptide in the BTBR ob/ob mouse model of type 2 diabetes

2020 ◽  
Vol 8 (1) ◽  
pp. e001242 ◽  
Author(s):  
Lucas Opazo-Ríos ◽  
Yenniffer Sanchez Matus ◽  
Raúl R Rodrigues-Díez ◽  
Daniel Carpio ◽  
Alejandra Droguett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Kidney Disease ◽  
Mouse Model ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Mimetic Peptide ◽  
Active Peptide ◽  
Socs Proteins

IntroductionDiabetic nephropathy (DN) is the leading cause of chronic kidney disease worldwide. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway participates in the development and progression of DN. Among the different mechanisms involved in JAK/STAT negative regulation, the family of suppressor of cytokine signaling (SOCS) proteins has been proposed as a new target for DN. Our aim was to evaluate the effect of SOCS1 mimetic peptide in a mouse model of obesity and type 2 diabetes (T2D) with progressive DN.Research design and methodsSix-week-old BTBR (black and tan brachyuric) mice with the ob/ob (obese/obese) leptin-deficiency mutation were treated for 7 weeks with two different doses of active SOCS1 peptide (MiS1 2 and 4 µg/g body weight), using inactive mutant peptide (Mut 4 µg) and vehicle as control groups. At the end of the study, the animals were sacrificed to obtain blood, urine and kidney tissue for further analysis.ResultsTreatment of diabetic mice with active peptide significantly decreased urine albumin to creatinine ratio by up to 50%, reduced renal weight, glomerular and tubulointerstitial damage, and restored podocyte numbers. Kidneys from treated mice exhibited lower inflammatory infiltrate, proinflammatory gene expression and STAT activation. Concomitantly, active peptide administration modulated redox balance markers and reduced lipid peroxidation and cholesterol transporter gene expression in diabetic kidneys.ConclusionTargeting SOCS proteins by mimetic peptides to control JAK/STAT signaling pathway ameliorates albuminuria, morphological renal lesions, inflammation, oxidative stress and lipotoxicity, and could be a therapeutic approach to T2D kidney disease.

PGJ2-stimulated β-cell apoptosis is associated with prolonged UPR activation

2007 ◽  
Vol 292 (4) ◽  
pp. E1052-E1061 ◽  
Author(s):  
Kari T. Chambers ◽  
Sarah M. Weber ◽  
John A. Corbett
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Cellular Response ◽  
Caspase 3 ◽  
Initiation Factor ◽  
Cytokine Signaling ◽  
Peroxisome Proliferator ◽  
Β Cells ◽  
Β Cell ◽  
Cell Death Pathway

Peroxisome proliferator-activated receptor-γ (PPARγ) ligands have been shown to possess anti-inflammatory properties that include the inhibition of transcription factor activation and the expression of inflammatory genes. Using pancreatic β-cells, we have shown that PPARγ ligands such as 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) attenuate interferon-γ-induced signal transducer and activator of transcription 1 activation and interleukin (IL)-1β-induced nuclear factor-κB activation by a pathway that correlates with endoplasmic reticulum stress and the induction of the unfolded protein response (UPR). The UPR is a conserved cellular response activated by a number of cell stressors and is believed to alleviate the stress and promote cell survival. However, prolonged activation of the UPR results in cellular death by apoptosis. In this report, we have examined the effects of PGJ2 on UPR activation and the consequences of this activation on cell survival. Consistent with induction of a cell death pathway, treatment of rat islets and RINm5F cells for 24 h with PGJ2 results in caspase-3 activation and caspase-dependent β-cell death. The actions of these ligands do not appear to be selective for β-cells, because PGJ2 stimulates macrophage apoptosis in a similar fashion. Associated with cell death is the enhanced phosphorylation of eukaryotic initiation factor 2α (eIF2α), and in cells expressing a mutant of eIF2α that cannot be phosphorylated, the stimulatory actions of PGJ2 on caspase-3 activation are augmented. These findings suggest that, whereas PGJ2-induced UPR activation is associated with an inhibition of cytokine signaling, prolonged UPR activation results in cell death, and that eIF2α phosphorylation may function in a protective manner to attenuate cell death.

scholarly journals Silymarin Protects Pancreatic β-Cells against Cytokine-Mediated Toxicity: Implication of c-Jun NH2-Terminal Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Pathways

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 175-185 ◽  
Author(s):  
Takeru Matsuda ◽  
Kevin Ferreri ◽  
Ivan Todorov ◽  
Yoshikazu Kuroda ◽  
Craig V. Smith ◽  
...  
Keyword(s):  
Cell Death ◽  
Human Islets ◽  
Janus Kinase ◽  
Time Dependent ◽  
No Production ◽  
Rinm5f Cells ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Ifn Γ

Silymarin is a polyphenolic flavonoid that has a strong antioxidant activity and exhibits anticarcinogenic, antiinflammatory, and cytoprotective effects. Although its hepatoprotective effect has been well documented, the effect of silymarin on pancreatic β-cells is largely unknown. In this study, the effect of silymarin on IL-1β and/or interferon (IFN)-γ-induced β-cell damage was investigated using RINm5F cells and human islets. IL-1β and/or IFN-γ induced cell death in a time-dependent manner in RINm5F cells. The time-dependent increase in cytokine-induced cell death appeared to correlate with the time-dependent nitric oxide (NO) production. Silymarin dose-dependently inhibited both cytokine-induced NO production and cell death in RINm5F cells. Treatment of human islets with a combination of IL-1β and IFN-γ (IL-1β+IFN-γ), for 48 h and 5 d, resulted in an increase of NO production and the impairment of glucose-stimulated insulin secretion, respectively. Silymarin prevented IL-1β+IFN-γ-induced NO production and β-cell dysfunction in human islets. These cytoprotective effects of silymarin appeared to be mediated through the suppression of c-Jun NH2-terminal kinase and Janus kinase/signal transducer and activator of transcription pathways. Our data show a direct cytoprotective effect of silymarin in pancreatic β-cells and suggest that silymarin may be therapeutically beneficial for type 1 diabetes.

scholarly journals Resveratrol and curcumin enhance pancreatic β-cell function by inhibiting phosphodiesterase activity

2014 ◽  
Vol 223 (2) ◽  
pp. 107-117 ◽  
Author(s):  
Michael Rouse ◽  
Antoine Younès ◽  
Josephine M Egan
Keyword(s):  
Insulin Secretion ◽  
Cell Lines ◽  
Cell Function ◽  
Human Islets ◽  
Dependent Manner ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pde Inhibitors ◽  
Β Cell Function

Resveratrol (RES) and curcumin (CUR) are polyphenols that are found in fruits and turmeric, and possess medicinal properties that are beneficial in various diseases, such as heart disease, cancer, and type 2 diabetes mellitus (T2DM). Results from recent studies have indicated that their therapeutic properties can be attributed to their anti-inflammatory effects. Owing to reports stating that they protect against β-cell dysfunction, we studied their mechanism(s) of action in β-cells. In T2DM, cAMP plays a critical role in glucose- and incretin-stimulated insulin secretion as well as overall pancreatic β-cell health. A potential therapeutic target in the management of T2DM lies in regulating the activity of phosphodiesterases (PDEs), which degrade cAMP. Both RES and CUR have been reported to act as PDE inhibitors in various cell types, but it remains unknown if they do so in pancreatic β-cells. In our current study, we found that both RES (0.1–10 μmol/l) and CUR (1–100 pmol/l)-regulated insulin secretion under glucose-stimulated conditions. Additionally, treating β-cell lines and human islets with these polyphenols led to increased intracellular cAMP levels in a manner similar to 3-isobutyl-1-methylxanthine, a classic PDE inhibitor. When we investigated the effects of RES and CUR on PDEs, we found that treatment significantly downregulated the mRNA expression of most of the 11 PDE isozymes, including PDE3B, PDE8A, and PDE10A, which have been linked previously to regulation of insulin secretion in islets. Furthermore, RES and CUR inhibited PDE activity in a dose-dependent manner in β-cell lines and human islets. Collectively, we demonstrate a novel role for natural-occurring polyphenols as PDE inhibitors that enhance pancreatic β-cell function.

scholarly journals American Ginseng Stimulates Insulin Production and Prevents Apoptosis through Regulation of Uncoupling Protein-2 in Cultured β Cells

2006 ◽  
Vol 3 (3) ◽  
pp. 365-372 ◽  
Author(s):  
John Zeqi Luo ◽  
Luguang Luo
Keyword(s):  
Cell Death ◽  
Uncoupling Protein ◽  
American Ginseng ◽  
Uncoupling Protein 2 ◽  
Insulin Production ◽  
Caspase 9 ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Insulin Synthesis

American ginseng root displays the ability to achieve glucose homeostasis both experimentally and clinically but the unknown mechanism used by ginseng to achieve its therapeutic effects on diabetes limits its application. Disruption in the insulin secretion of pancreatic β cells is considered the major cause of diabetes. A mitochondrial protein, uncoupling protein-2 (UCP-2) has been found to play a critical role in insulin synthesis and β cell survival. Our preliminary studies found that the extracts of American ginseng inhibit UCP-2 expression which may contribute to the ability of ginseng protecting β cell death and improving insulin synthesis. Therefore, we hypothesized that ginseng extracts suppress UCP-2 in the mitochondria of pancreatic β cells, promoting insulin synthesis and anti-apoptosis (a programmed cell-death mechanism). To test the hypothesis, the serum-deprived quiescent β cells were cultured with or without interleukin-1β (IL-1β), (200 pg ml−1, a cytokine to induce β cell apoptosis) and water extracts of American ginseng (25 μg per 5 μl administered to wells of 0.5 ml culture) for 24 h. We evaluated effects of ginseng on UCP-2 expression, insulin production, anti-/pro-apoptotic factors Bcl-2/caspase-9 expression and cellular ATP levels. We found that ginseng suppresses UCP-2, down-regulates caspase-9 while increasing ATP and insulin production/secretion and up-regulates Bcl-2, reducing apoptosis. These findings suggest that stimulation of insulin production and prevention of β cell loss by American ginseng extracts can occur via the inhibition of mitochondrial UCP-2, resulting in increase in the ATP level and the anti-apoptotic factor Bcl-2, while down-regulation of pro-apoptotic factor caspase-9 occurs, lowering the occurrence of apoptosis, which support the hypothesis.

scholarly journals Calcium channel blockers do not protect against saturated fatty acid-induced ER stress and apoptosis in human pancreatic β-cells

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Jan Šrámek ◽  
Vlasta Němcová ◽  
Jan Kovář
Keyword(s):  
Er Stress ◽  
Calcium Channel ◽  
Cell Lines ◽  
Calcium Channel Blockers ◽  
Calcium Influx ◽  
Saturated Fatty Acids ◽  
Channel Blockers ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

AbstractIt was evidenced that saturated fatty acids (FAs) have a detrimental effect on pancreatic β-cells function and survival, leading to endoplasmic reticulum (ER) calcium release, ER stress, and apoptosis. In the present study, we have tested the effect of three calcium influx inhibitors, i.e., diazoxide, nifedipine, and verapamil, on the apoptosis-inducing effect of saturated stearic acid (SA) in the human pancreatic β-cell lines NES2Y and 1.1B4. We have demonstrated that the application of all three calcium influx inhibitors tested has no inhibitory effect on SA-induced ER stress and apoptosis in both tested cell lines. Moreover, these inhibitors have pro-apoptotic potential per se at higher concentrations. Interestingly, these findings are in contradiction with those obtained with rodent cell lines and islets. Thus our data obtained with human β-cell lines suggest that the prospective usage of calcium channel blockers for prevention and therapy of type 2 diabetes mellitus, developed with the contribution of the saturated FA-induced apoptosis of β-cells, seems rather unlikely.

scholarly journals Piezo1 channel activation mimics high glucose as a stimulator of insulin release

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Vijayalakshmi Deivasikamani ◽  
Savitha Dhayalan ◽  
Yilizila Abudushalamu ◽  
Romana Mughal ◽  
Asjad Visnagri ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Insulin Release ◽  
Cell Lines ◽  
High Glucose ◽  
Mammalian Cells ◽  
Cell Swelling ◽  
Β Cells ◽  
Β Cell ◽  
Intracellular Ca ◽  
Mouse Pancreatic Islets

AbstractGlucose and hypotonicity induced cell swelling stimulate insulin release from pancreatic β-cells but the mechanisms are poorly understood. Recently, Piezo1 was identified as a mechanically-activated nonselective Ca2+ permeable cationic channel in a range of mammalian cells. As cell swelling induced insulin release could be through stimulation of Ca2+ permeable stretch activated channels, we hypothesised a role for Piezo1 in cell swelling induced insulin release. Two rat β-cell lines (INS-1 and BRIN-BD11) and freshly-isolated mouse pancreatic islets were studied. Intracellular Ca2+ measurements were performed using the fura-2 Ca2+ indicator dye and ionic current was recorded by whole cell patch-clamp. Piezo1 agonist Yoda1, a competitive antagonist of Yoda1 (Dooku1) and an inactive analogue of Yoda1 (2e) were used as chemical probes. Piezo1 mRNA and insulin secretion were measured by RT-PCR and ELISA respectively. Piezo1 mRNA was detected in both β-cell lines and mouse islets. Yoda1 evoked Ca2+ entry was inhibited by Yoda1 antagonist Dooku1 as well as other Piezo1 inhibitors gadolinium and ruthenium red, and not mimicked by 2e. Yoda1, but not 2e, stimulated Dooku1-sensitive insulin release from β-cells and pancreatic islets. Hypotonicity and high glucose increased intracellular Ca2+ and enhanced Yoda1 Ca2+ influx responses. Yoda1 and hypotonicity induced insulin release were significantly inhibited by Piezo1 specific siRNA. Pancreatic islets from mice with haploinsufficiency of Piezo1 released less insulin upon exposure to Yoda1. The data show that Piezo1 channel agonist induces insulin release from β-cell lines and mouse pancreatic islets suggesting a role for Piezo1 in cell swelling induced insulin release. Hence Piezo1 agonists have the potential to be used as enhancers of insulin release.

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