scholarly journals Differential cell autonomous responses determine the outcome of coxsackievirus infections in murine pancreatic α and β cells

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Laura Marroqui ◽  
Miguel Lopes ◽  
Reinaldo S dos Santos ◽  
Fabio A Grieco ◽  
Merja Roivainen ◽  
...  
Keyword(s):  
Gene Networks ◽  
Viral Infections ◽  
Islet Cells ◽  
Global Gene Expression ◽  
Cell Types ◽  
Autoimmune Response ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Antiviral Responses ◽  
Different Cell Types

Type 1 diabetes (T1D) is an autoimmune disease caused by loss of pancreatic β cells via apoptosis while neighboring α cells are preserved. Viral infections by coxsackieviruses (CVB) may contribute to trigger autoimmunity in T1D. Cellular permissiveness to viral infection is modulated by innate antiviral responses, which vary among different cell types. We presently describe that global gene expression is similar in cytokine-treated and virus-infected human islet cells, with up-regulation of gene networks involved in cell autonomous immune responses. Comparison between the responses of rat pancreatic α and β cells to infection by CVB5 and 4 indicate that α cells trigger a more efficient antiviral response than β cells, including higher basal and induced expression of STAT1-regulated genes, and are thus better able to clear viral infections than β cells. These differences may explain why pancreatic β cells, but not α cells, are targeted by an autoimmune response during T1D.

scholarly journals Pancreatic α and β cells are globally phase-locked

2020 ◽  
Author(s):  
Huixia Ren ◽  
Yanjun Li ◽  
Chengsheng Han ◽  
Yi Yu ◽  
Bowen Shi ◽  
...  
Keyword(s):  
Islet Cells ◽  
Cell Types ◽  
Phase Oscillators ◽  
Β Cells ◽  
Oscillation Modes ◽  
Different Types ◽  
Glucagon And Insulin ◽  
Different Cell Types

ABSTRACTThe Ca2+ modulated pulsatile secretions of glucagon and insulin by pancreatic α and β cells play a key role in glucose metabolism and homeostasis. However, how different types of islet cells couple and coordinate via paracrine interactions to produce various Ca2+ oscillation patterns are still elusive. By designing a microfluidic device to facilitate long-term recording of islet Ca2+ activity at single cell level and simultaneously identifying different cell types in live islet imaging, we show heterogeneous but intrinsic Ca2+ oscillation patterns of islets upon glucose stimulation. The α and β cells oscillate in antiphase and are globally phase locked to various phase delays, causing fast, slow or mixed oscillations. A mathematical model of coupled phase oscillators quantitatively agrees with experiments and reveals the essential role of paracrine regulations in tuning the oscillation modes. Our study highlights the importance of cell-cell interactions to generate stable but tunable islet oscillation patterns.

scholarly journals Increased vimentin in human α- and β-cells in type 2 diabetes

2017 ◽  
Vol 233 (3) ◽  
pp. 217-227 ◽  
Author(s):  
Maaike M Roefs ◽  
Françoise Carlotti ◽  
Katherine Jones ◽  
Hannah Wills ◽  
Alexander Hamilton ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Epithelial To Mesenchymal Transition ◽  
Islet Cells ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Mesenchymal Transition ◽  
Cell Expression

Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; P < 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.

Harnessing immune cells to enhance β-cell mass in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Ercument Dirice ◽  
Rohit N Kulkarni
Keyword(s):  
Type 1 Diabetes ◽  
Mononuclear Cells ◽  
Islet Cells ◽  
Cell Mass ◽  
Cell Loss ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Autoimmune Attack

Type 1 diabetes is characterized by early β-cell loss leading to insulin dependence in virtually all patients with the disease in order to maintain glucose homeostasis. Most studies over the past few decades have focused on limiting the autoimmune attack on the β cells. However, emerging data from patients with long-standing diabetes who continue to harbor functional insulin-producing cells in their diseased pancreas have prompted scientists to examine whether proliferation of existing β cells can be enhanced to promote better glycemic control. In support of this concept, several studies indicate that mononuclear cells that infiltrate the islets have the capacity to trigger proliferation of islet cells including β cells. These observations indicate the exciting possibility of identifying those mononuclear cell types and their soluble factors and harnessing their ability to promote β-cell growth concomitant with autoimmune therapy to prevent the onset and/or halt the progression of the disease.

scholarly journals Global Analysis of Cell Type-Specific Gene Expression

2003 ◽  
Vol 4 (2) ◽  
pp. 208-215 ◽  
Author(s):  
David W. Galbraith
Keyword(s):  
Gene Expression ◽  
Fluorescent Protein ◽  
Global Analysis ◽  
Expression Patterns ◽  
Three Dimensional ◽  
Global Gene Expression ◽  
Cell Types ◽  
Reasonable Assumption ◽  
Specific Gene ◽  
Different Cell Types

The tissues and organs of multicellular eukaryotes are frequently observed to comprise complex three-dimensional interspersions of different cell types. It is a reasonable assumption that different global patterns of gene expression are found within these different cell types. This review outlines general experimental strategies designed to characterize these global gene expression patterns, based on a combination of methods of transgenic fluorescent protein (FP) expression and targeting, of flow cytometry and sorting and of high-throughput gene expression analysis.

scholarly journals Reducing sugars trigger oxidative modification and apoptosis in pancreatic β-cells by provoking oxidative stress through the glycation reaction

1996 ◽  
Vol 320 (3) ◽  
pp. 855-863 ◽  
Author(s):  
Hideaki KANETO ◽  
Junichi FUJII ◽  
Theingi MYINT ◽  
Nobuko MIYAZAWA ◽  
Kazi N. ISLAM ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Cleavage ◽  
Reducing Sugars ◽  
Islet Cells ◽  
Chromatin Condensation ◽  
Oxidative Modification ◽  
Lipid Peroxidation Product ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Peroxidation Product

Several reducing sugars brought about apoptosis in isolated rat pancreatic islet cells and in the pancreatic β-cell-derived cell line HIT. This apoptosis was characterized biochemically by internucleosomal DNA cleavage and morphologically by nuclear shrinkage, chromatin condensation and apoptotic body formation. N-Acetyl-l-cysteine, an antioxidant, and aminoguanidine, an inhibitor of the glycation reaction, inhibited this apoptosis. We also showed directly that proteins in β-cells were actually glycated by using an antibody which can specifically recognize proteins glycated by fructose, but not by glucose. Furthermore, fluorescence-activated cell sorting analysis using dichlorofluorescein diacetate showed that reducing sugars increased intracellular peroxide levels prior to the induction of apoptosis. Levels of carbonyl, an index of oxidative modification, and of malondialdehyde, a lipid peroxidation product, were also increased. Taken together, these results suggest that reducing sugars trigger oxidative modification and apoptosis in pancreatic β-cells by provoking oxidative stress mainly through the glycation reaction, which may explain the deterioration of β-cells under conditions of diabetes.

Carbamoylcholine regulation of polyphosphoinositide synthesis and hydrolysis in cultured, dispersed, digitonin-permeabilized mouse pancreatic islet cells

1997 ◽  
Vol 136 (5) ◽  
pp. 539-545 ◽  
Author(s):  
Andrew M Kardasz ◽  
Peter Thams ◽  
Kirsten Capito ◽  
Carl J Hedeskov
Keyword(s):  
Pancreatic Islet ◽  
Kinase Activity ◽  
Inositol Phosphates ◽  
Islet Cells ◽  
Pancreatic Islet Cells ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Mouse Pancreatic Islet ◽  
Phosphatidylinositol 4 ◽  
Stimulation Of

Abstract Continuing formation of inositol phosphates during stimulation of pancreatic β-cells by hormones and neurotransmitters requires the continued synthesis of the polyphosphoinositides phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5 bisphosphate (PIP2) from phosphatidylinositol (PI). In the present study we have investigated how this pathway and the activity of phosphoinositide-specific phospholipase C (PI-PLC) are regulated by carbamoylcholine (CCh), Ca2+, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), GTPγS and NaF in 44-h [3H]inositol-labelled, dispersed and digitonin-permeabilized mouse pancreatic islet cells. CCh stimulated not only PI-PLC (G-protein-mediated) but also, by an as yet unknown mechanism, significantly enhanced PI 4-kinase activity, estimated as the PIP:PI ratio, by 100%, and further increased the flux from PI to PIP and PIP2. GTPγS and NaF mimicked the effects of CCh on PI-PLC but had no effect on the levels of PIP and PIP2. TPA raised the PIP:PI ratio by 75%. In addition TPA counteracted the CCh stimulation of PI-PLC. There was no effect of 10−6 mol/l Ca2+ on the levels of PIP and PIP2. Experiments with quinacrine and adenosine confirmed that PI-PLC and PI 4-kinase could be regulated independently of each other. In conclusion, these data point to differential regulation of polyphosphoinositide synthesis and breakdown. European Journal of Endocrinology 136 539–545

scholarly journals Potential Mimicry of Viral and Pancreatic β Cell Antigens Through Non-Spliced and cis-Spliced Zwitter Epitope Candidates in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Michele Mishto ◽  
Artem Mansurkhodzhaev ◽  
Teresa Rodriguez-Calvo ◽  
Juliane Liepe
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Viral Infections ◽  
Hla Class I ◽  
Class I ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Increasing evidence suggests that post-translational peptide splicing can play a role in the immune response under pathological conditions. This seems to be particularly relevant in Type 1 Diabetes (T1D) since post-translationally spliced epitopes derived from T1D-associated antigens have been identified among those peptides bound to Human Leucocyte Antigen (HLA) class I and II complexes. Their immunogenicity has been confirmed through CD4+ and CD8+ T cell-mediated responses in T1D patients. Spliced peptides theoretically have a large sequence variability. This might increase the frequency of viral-human zwitter peptides, i.e. peptides that share a complete sequence homology irrespective of whether they originate from human or viral antigens, thereby impinging upon the discrimination between self and non-self antigens by T cells. This might increase the risk of autoimmune responses triggered by viral infections. Since enteroviruses and other viral infections have historically been associated with T1D, we investigated whether cis-spliced peptides derived from selected viruses might be able to trigger CD8+ T cell-mediated autoimmunity. We computed in silico viral-human non-spliced and cis-spliced zwitter epitope candidates, and prioritized peptide candidates based on: (i) their binding affinity to HLA class I complexes, (ii) human pancreatic β cell and medullary thymic epithelial cell (mTEC) antigens’ mRNA expression, (iii) antigen association with T1D, and (iv) potential hotspot regions in those antigens. Neglecting potential T cell receptor (TCR) degeneracy, no viral-human zwitter non-spliced peptide was found to be an optimal candidate to trigger a virus-induced CD8+ T cell response against human pancreatic β cells. Conversely, we identified some zwitter peptide candidates, which may be produced by proteasome-catalyzed peptide splicing, and might increase the likelihood of pancreatic β cells recognition by virus-specific CD8+ T cell clones, therefore promoting β cell destruction in the context of viral infections.

scholarly journals A pipeline for multidimensional confocal analysis of mitochondrial morphology, function and dynamics in pancreatic β-cells

2019 ◽  
Author(s):  
Ahsen Chaudhry ◽  
Rocky Shi ◽  
Dan S. Luciani
Keyword(s):  
Metabolic Diseases ◽  
Super Resolution ◽  
Cell Types ◽  
Mitochondrial Morphology ◽  
State Function ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Health And Disease ◽  
Mitochondrial Networks ◽  
Functional Analyses

ABSTRACTLive-cell imaging of mitochondrial function and dynamics can provide vital insights into both physiology and pathophysiology, including of metabolic diseases like type 2 diabetes. However, without super-resolution microscopy and commercial analysis software it is challenging to accurately extract features from dense multi-layered mitochondrial networks, such as those in insulin-secreting pancreatic β-cells. Motivated by this, we developed a comprehensive pipeline, and associated ImageJ plugin, that enables 2D/3D quantification of mitochondrial network morphology and dynamics in mouse β-cells, and by extension other similarly challenging cell-types. The approach is based on standard confocal microscopy and shareware, making it widely accessible. The pipeline was validated using mitochondrial photo-labelling and unsupervised cluster analysis, and is capable of morphological and functional analyses on a per-organelle basis, including in 4D (xyzt). Overall, this tool offers a powerful framework for multiplexed analysis of mitochondrial state/function, and provides a valuable resource to accelerate mitochondrial research in health and disease.

scholarly journals A pipeline for multidimensional confocal analysis of mitochondrial morphology, function, and dynamics in pancreatic β-cells

2020 ◽  
Vol 318 (2) ◽  
pp. E87-E101 ◽  
Author(s):  
Ahsen Chaudhry ◽  
Rocky Shi ◽  
Dan S. Luciani
Keyword(s):  
Metabolic Diseases ◽  
Super Resolution ◽  
Cell Types ◽  
Mitochondrial Morphology ◽  
State Function ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Health And Disease ◽  
Mitochondrial Networks ◽  
Functional Analyses

Live-cell imaging of mitochondrial function and dynamics can provide vital insights into both physiology and pathophysiology, including of metabolic diseases like type 2 diabetes. However, without super-resolution microscopy and commercial analysis software, it is challenging to accurately extract features from dense multilayered mitochondrial networks, such as those in insulin-secreting pancreatic β-cells. Motivated by this, we developed a comprehensive pipeline and associated ImageJ plugin that enables 2D/3D quantification of mitochondrial network morphology and dynamics in mouse β-cells and by extension other similarly challenging cell types. The approach is based on standard confocal microscopy and shareware, making it widely accessible. The pipeline was validated using mitochondrial photolabeling and unsupervised cluster analysis and is capable of morphological and functional analyses on a per-organelle basis, including in 4D ( xyzt). Overall, this tool offers a powerful framework for multiplexed analysis of mitochondrial state/function and provides a valuable resource to accelerate mitochondrial research in health and disease.

scholarly journals Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

2007 ◽  
Vol 193 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Shin Tsunekawa ◽  
Naoki Yamamoto ◽  
Katsura Tsukamoto ◽  
Yuji Itoh ◽  
Yukiko Kaneko ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Islet Cells ◽  
Binding Protein ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic β-cells against their cell death. In in vivo experiments, we used β-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their β-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1α, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in β-cell-specific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic β-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

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