scholarly journals Integrin α3, But Not β1, Regulates Islet Cell Survival and Function via PI3K/Akt Signaling Pathways

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 424-435 ◽  
Author(s):  
Mansa Krishnamurthy ◽  
Jinming Li ◽  
George F. Fellows ◽  
Lawrence Rosenberg ◽  
Cynthia G. Goodyer ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Function ◽  
Islet Cells ◽  
Glycogen Synthase ◽  
Specific Effect ◽  
Signaling Cascades ◽  
Β1 Integrin ◽  
Β Cell ◽  
Downstream Signaling ◽  
And Function

Abstract β1-Integrin is a well-established regulator of β-cell activities; however, the role of its associated α-subunits is relatively unknown. Previously, we have shown that human fetal islet and INS-1 cells highly express α3β1-integrin and that collagens I and IV significantly enhance their survival and function; in addition, blocking β1 function in the fetal islet cells decreased adhesion on collagen I and increased apoptosis. The present study investigates the effect of blocking α3. Using α3 blocking antibody or small interfering RNA, the effects of α3-integrin blockade were examined in isolated human fetal or adult islet cells or INS-1 cells, cultured on collagens I or IV. In parallel, β1 blockade was analyzed in INS-1 cells. Perturbing α3 function in human islet or INS-1 cells resulted in significant decreases in cell function (adhesion, spreading, proliferation and Pdx1 and insulin expression/secretion), primarily on collagen IV. A significant decrease in focal adhesion kinase and ERK1/2 phosphorylation and increased caspase3 cleavage were observed on both collagens. These effects were similar to changes after β1 blockade. Interestingly, only α3 blockade reduced expression of phospho-Akt and members of its downstream signaling cascades (glycogen synthase kinase β and X-linked inhibitor of apoptosis), demonstrating a specific effect of α3 on the phosphatidylinositol 3-kinase/Akt pathway. These results suggest that α3- as well as β1-integrin-extracellular matrix interactions are critical for modulating β-cell survival and function through specialized signaling cascades and enhance our understanding of how to improve islet microenvironments for cell-based treatments of diabetes.

scholarly journals Non-Coding RNA in Pancreas and β-Cell Development

2018 ◽  
Vol 4 (4) ◽  
pp. 41 ◽  
Author(s):  
Wilson K. M. Wong ◽  
Anja E. Sørensen ◽  
Mugdha V. Joglekar ◽  
Anand A. Hardikar ◽  
Louise T. Dalgaard
Keyword(s):  
Cell Function ◽  
Islet Cells ◽  
Current Knowledge ◽  
Cell Development ◽  
Pancreas Development ◽  
Β Cell ◽  
Neighboring Gene ◽  
Non Coding Rnas ◽  
And Function

In this review, we provide an overview of the current knowledge on the role of different classes of non-coding RNAs for islet and β-cell development, maturation and function. MicroRNAs (miRNAs), a prominent class of small RNAs, have been investigated for more than two decades and patterns of the roles of different miRNAs in pancreatic fetal development, islet and β-cell maturation and function are now emerging. Specific miRNAs are dynamically regulated throughout the period of pancreas development, during islet and β-cell differentiation as well as in the perinatal period, where a burst of β-cell replication takes place. The role of long non-coding RNAs (lncRNA) in islet and β-cells is less investigated than for miRNAs, but knowledge is increasing rapidly. The advent of ultra-deep RNA sequencing has enabled the identification of highly islet- or β-cell-selective lncRNA transcripts expressed at low levels. Their roles in islet cells are currently only characterized for a few of these lncRNAs, and these are often associated with β-cell super-enhancers and regulate neighboring gene activity. Moreover, ncRNAs present in imprinted regions are involved in pancreas development and β-cell function. Altogether, these observations support significant and important actions of ncRNAs in β-cell development and function.

Downregulation of Fas activity rescues early onset of diabetes in c-KitWv/+ mice

2013 ◽  
Vol 304 (6) ◽  
pp. E557-E565 ◽  
Author(s):  
Zhi-Chao Feng ◽  
Matthew Riopel ◽  
Jinming Li ◽  
Lisa Donnelly ◽  
Rennian Wang
Keyword(s):  
Cell Survival ◽  
Cell Apoptosis ◽  
Fas Ligand ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Apoptotic Pathway ◽  
Β Cell Function ◽  
And Function

c-Kit and its ligand stem cell factor (SCF) are important for β-cell survival and maturation; meanwhile, interactions between the Fas receptor (Fas) and Fas ligand are capable of triggering β-cell apoptosis. Disruption of c-Kit signaling leads to severe loss of β-cell mass and function with upregulation of Fas expression in c-Kit Wv/+ mouse islets, suggesting that there is a critical balance between c-Kit and Fas activation in β-cells. In the present study, we investigated the interrelationship between c-Kit and Fas activation that mediates β-cell survival and function. We generated double mutant, c-Kit Wv/+ ;Fas lpr/lpr ( Wv −/−), mice to study the physiological and functional role of Fas with respect to β-cell function in c-Kit Wv/+ mice. Isolated islets from these mice and the INS-1 cell line were used. We observed that islets in c-Kit Wv/+ mice showed a significant increase in β-cell apoptosis along with upregulated p53 and Fas expression. These results were verified in vitro in INS-1 cells treated with SCF or c-Kit siRNA combined with a p53 inhibitor and Fas siRNA. In vivo, Wv −/− mice displayed improved β-cell function, with significantly enhanced insulin secretion and increased β-cell mass and proliferation compared with Wv +/+ mice. This improvement was associated with downregulation of the Fas-mediated caspase-dependent apoptotic pathway and upregulation of the cFlip/NF-κB pathway. These findings demonstrate that a balance between the c-Kit and Fas signaling pathways is critical in the regulation of β-cell survival and function.

scholarly journals Activation of Melatonin Signaling Promotes β-Cell Survival and Function

2015 ◽  
Vol 29 (5) ◽  
pp. 682-692 ◽  
Author(s):  
Safia Costes ◽  
Marti Boss ◽  
Anthony P. Thomas ◽  
Aleksey V. Matveyenko
Keyword(s):  
Insulin Secretion ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Human Islets ◽  
Β Cell ◽  
Amino Terminal ◽  
Chronic Hyperglycemia ◽  
Β Cell Function ◽  
And Function

Abstract Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of β-cell secretory function and mass. Studies have identified a link between a variance in the gene encoding melatonin (MT) receptor 2, T2DM, and impaired insulin secretion. This genetic linkage raises the question whether MT signaling plays a role in regulation of β-cell function and survival in T2DM. To address this postulate, we used INS 832/13 cells to test whether activation of MT signaling attenuates proteotoxicity-induced β-cell apoptosis and through which molecular mechanism. We also used nondiabetic and T2DM human islets to test the potential of MT signaling to attenuate deleterious effects of glucotoxicity and T2DM on β-cell function. MT signaling in β-cells (with duration designed to mimic typical nightly exposure) significantly enhanced activation of the cAMP-dependent signal transduction pathway and attenuated proteotoxicity-induced β-cell apoptosis evidenced by reduced caspase-3 cleavage (∼40%), decreased activation of stress-activated protein kinase/Jun-amino-terminal kinase (∼50%) and diminished oxidative stress response. Activation of MT signaling in human islets was shown to restore glucose-stimulated insulin secretion in islets exposed to chronic hyperglycemia as well as in T2DM islets. Our data suggest that β-cell MT signaling is important for the regulation of β-cell survival and function and implies a preventative and therapeutic potential for preservation of β-cell mass and function in T2DM.

scholarly journals Isx9 Regulates Calbindin D28K Expression in Pancreatic β Cells and Promotes β Cell Survival and Function

2018 ◽  
Vol 19 (9) ◽  
pp. 2542 ◽  
Author(s):  
Julien Pujol ◽  
Eija Heikkila ◽  
Claudia Savoia ◽  
Asghar Hajibeigi ◽  
Umberto De Marchi ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Function ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Activated T Cells ◽  
Expression Of Genes ◽  
Β Cell Function ◽  
Calbindin D28k ◽  
And Function

Pancreatic β-cell dysfunction and death contribute to the onset of diabetes, and novel strategies of β-cell function and survival under diabetogenic conditions need to be explored. We previously demonstrated that Isx9, a small molecule based on the isoxazole scaffold, drives neuroendocrine phenotypes by increasing the expression of genes required for β-cell function and improves glycemia in a model of β cell regeneration. We further investigated the role of Isx9 in β-cell survival. We find that Isx9 drives the expression of Calbindin-D28K (D28K), a key regulator of calcium homeostasis, and plays a cytoprotective role through its calcium buffering capacity in β cells. Isx9 increased the activity of the calcineurin (CN)/cytoplasmic nuclear factor of the activated T-cells (NFAT) transcription factor, a key regulator of D28K, and improved the recruitment of NFATc1, cAMP response element-binding protein (CREB), and p300 to the D28K promoter. We found that nutrient stimulation increased D28K plasma membrane enrichment and modulated calcium channel activity in order to regulate glucose-induced insulin secretion. Isx9-mediated expression of D28K protected β cells against chronic stress induced by serum withdrawal or chronic inflammation by reducing caspase 3 activity. Consequently, Isx9 improved human islet function after transplantation in NOD-SCID mice in a streptozotocin-induced diabetes model. In summary, Isx9 significantly regulates expression of genes relevant to β cell survival and function, and may be an attractive therapy to treat diabetes and improve islet function post-transplantation.

scholarly journals Assessment of β-Cell Mass and α- and β-Cell Survival and Function by Arginine Stimulation in Human Autologous Islet Recipients

Diabetes ◽  
2014 ◽  
Vol 64 (2) ◽  
pp. 565-572 ◽  
Author(s):  
R. Paul Robertson ◽  
Lindsey D. Bogachus ◽  
Elizabeth Oseid ◽  
Susan Parazzoli ◽  
Mary Elizabeth Patti ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Mass ◽  
Β Cell ◽  
And Function

Conditional β1-integrin-deficient mice display impaired pancreatic β cell function

2011 ◽  
Vol 224 (1) ◽  
pp. 45-55 ◽  
Author(s):  
M. Riopel ◽  
M. Krishnamurthy ◽  
J. Li ◽  
S. Liu ◽  
A. Leask ◽  
...  
Keyword(s):  
Cell Function ◽  
Β1 Integrin ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Β Cell Function ◽  
Deficient Mice

scholarly journals Salidroside, A Natural Antioxidant, Improves β-Cell Survival and Function via Activating AMPK Pathway

2017 ◽  
Vol 8 ◽  
Author(s):  
Linjie Ju ◽  
Xiaohua Wen ◽  
Chunjun Wang ◽  
Yingjie Wei ◽  
Yunru Peng ◽  
...  
Keyword(s):  
Cell Survival ◽  
Natural Antioxidant ◽  
Β Cell ◽  
Ampk Pathway ◽  
And Function

scholarly journals Transcription Factor 7-Like 2 Regulates β-Cell Survival and Function in Human Pancreatic Islets. Diabetes 2008;57:645–653

Diabetes ◽  
2014 ◽  
Vol 63 (11) ◽  
pp. 3974-3974 ◽  
Author(s):  
Luan Shu ◽  
Nadine S. Sauter ◽  
Fabienne T. Schulthess ◽  
Aleksey V. Matveyenko ◽  
José Oberholzer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Survival ◽  
Pancreatic Islets ◽  
Β Cell ◽  
Human Pancreatic Islets ◽  
And Function

scholarly journals Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1892
Author(s):  
Emily S. Krueger ◽  
Joseph L. Beales ◽  
Kacie B. Russon ◽  
Weston S. Elison ◽  
Jordan R. Davis ◽  
...  
Keyword(s):  
Cell Function ◽  
Cell Mass ◽  
Caloric Intake ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Granule Formation ◽  
Β Cell Function ◽  
Molecular Effects ◽  
And Function

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.

scholarly journals Imeglimin Ameliorates β-cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

2021 ◽  
Author(s):  
Jinghe Li ◽  
Ryota Inoue ◽  
Yu Togashi ◽  
Tomoko Okuyama ◽  
Aoi Satoh ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Akita Mice ◽  
The Impact

The effects of imeglimin, a novel anti-diabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules including <i>Chop (Ddit3),</i> <i>Gadd34</i> (<i>Ppp1r15a</i>), <i>Atf3</i>, and <i>Sdf2l1</i>, and decreased eIF2α phosphorylation, after treatment with thapsigargin, and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell (<a>hPSC)-derived β-like cells</a>. <a>Taken together, imeglimin modulates ER homeostasis pathway, which results in the prevention of β-cell apoptosis both <i>in vitro</i> and <i>in vivo</i>.</a>

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