scholarly journals Increased expression of viral sensor MDA5 in pancreatic islets and in hormone-negative endocrine cells in recent onset type 1 diabetic donors

2021 ◽  
Author(s):  
Laura Nigi ◽  
Noemi Brusco ◽  
Giuseppina Emanuela Grieco ◽  
Daniela Fignani ◽  
Giada Licata ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Endocrine Cells ◽  
Viral Infections ◽  
Islet Cells ◽  
Diabetic Control ◽  
Imaging Analysis ◽  
Β Cells ◽  
Recent Onset ◽  
Genetic And Environmental Factors

The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as Melanoma Differentiation Associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of non-diabetic and T1D donors is still missing. In the present study we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 non-diabetic autoantibody-negative, 2 autoantibody-positive, 8 recent-onset and 2 long-standing T1D). In non-diabetic control donors, MDA5 was expressed both in α- and in β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate MDA5-glucagon respect to MDA5-insulin in comparison to non-diabetic controls; such increase was more pronounced in recent onset respect to long standing T1D donors. Of note, an increased colocalization rate MDA5-glucagon was found in insulin-deficient-islets (IDI) respect to insulin containing islets (ICI). Strikingly, in T1D donors we detected the presence of MDA5-positive/hormones-negative endocrine islet-like clusters, putatively deriving from dedifferentiation or neogenesis phoenomena. These clusters were exclusively identified in recent onset donors and not detected in autoantibody-positive non-diabetic or T1D long-standing ones. In conclusion, we showed that MDA5 is preferentially expressed in α-cells and its expression is increased in recent onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells.

scholarly journals Tumour suppressor menin is essential for development of the pancreatic endocrine cells

2008 ◽  
Vol 199 (2) ◽  
pp. 287-298 ◽  
Author(s):  
Sandra Fontanière ◽  
Bertrand Duvillié ◽  
Raphaël Scharfmann ◽  
Christine Carreira ◽  
Zhao-Qi Wang ◽  
...  
Keyword(s):  
Endocrine Cells ◽  
Endocrine Pancreas ◽  
Islet Cells ◽  
Specific Effect ◽  
Pancreas Development ◽  
Β Cells ◽  
Neurogenin 3 ◽  
Pancreatic Endocrine Cells ◽  
Endocrine Tissues

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene predispose patients to MEN1 that affects mainly endocrine tissues, suggesting important physiological functions of the gene in adult endocrine cells. Homozygous disruption of Men1 in mice causes embryonic lethality, whereas the eventual involvement of the gene in embryonic development of the endocrine cells remains unknown. Here, we show that homozygous Men1 knockout mice demonstrate a reduced number of glucagon-positive cells in the E12.5 pancreatic bud associated with apoptosis, whereas the exocrine pancreas development in these mice is not affected. Our data suggest that menin is involved in the survival of the early pancreatic endocrine cells during the first developmental transition. Furthermore, chimerism assay revealed that menin has an autonomous and specific effect on the development of islet cells. In addition, using pancreatic bud culture mimicking the differentiation of α- and β-cells during the second transition, we show that loss of menin leads to the failure of endocrine cell development, altered pancreatic structure and a markedly decreased number of cells expressing neurogenin 3, indicating that menin is also required at this stage of the endocrine pancreas development. Taken together, our results suggest that menin plays an indispensable role in the development of the pancreatic endocrine cells.

scholarly journals Adenoviral-Mediated Transduction of Human Pancreatic Islets: Importance of Adenoviral Genome for Cell Viability and Association with a Deficient Antiviral Response

Endocrinology ◽  
2005 ◽  
Vol 146 (5) ◽  
pp. 2406-2414 ◽  
Author(s):  
Andreea R. Barbu ◽  
Göran Akusjärvi ◽  
Nils Welsh
Keyword(s):  
Pancreatic Islets ◽  
Genetic Manipulation ◽  
Islet Cells ◽  
Antiviral Response ◽  
Β Cells ◽  
Need To Evaluate ◽  
Exogenous Addition ◽  
E3 Region

Abstract As adenoviral vectors are extensively used for genetic manipulation of insulin-producing cells in vitro, there is an increasing need to evaluate their effects on the function, morphology, and viability of transduced pancreatic islets. In the present study we observed that specific adenoviral genotypes, carrying E4 and E1/E3 deletions, correlate with differential induction of necrosis in pancreatic islet cells. In particular, the adenovirus death protein encoded from the E3 region of the adenoviral genome was able to modulate the changes induced in the morphology and viability of the transduced cells. We also propose a putative role for the transcriptional regulator pIX. Although human islet cells showed an increased resistance in terms of viral concentrations required for the induction of cell toxicity, our results showed that they were unable to build up an efficient antiviral response after transduction and that their survival was dependent on the exogenous addition of α-interferon. An intact and fully functional β-cell is crucial for the successful application of gene therapy approaches in type 1 diabetes, and therefore, the implications of our findings need to be considered when designing vectors for gene transfer into pancreatic β-cells.

Immunotherapy: Building a bridge to a cure for type 1 diabetes

Science ◽  
2021 ◽  
Vol 373 (6554) ◽  
pp. 510-516
Author(s):  
Jeffrey A. Bluestone ◽  
Jane H. Buckner ◽  
Kevan C. Herold
Keyword(s):  
Type 1 Diabetes ◽  
Immune Cell ◽  
Cell Types ◽  
Underlying Disease ◽  
Β Cells ◽  
Current State ◽  
Islet Inflammation ◽  
Genetic And Environmental Factors ◽  
Key Events

Type 1 diabetes (T1D) is an autoimmune disease in which T cells attack and destroy the insulin-producing β cells in the pancreatic islets. Genetic and environmental factors increase T1D risk by compromising immune homeostasis. Although the discovery and use of insulin have transformed T1D treatment, insulin therapy does not change the underlying disease or fully prevent complications. Over the past two decades, research has identified multiple immune cell types and soluble factors that destroy insulin-producing β cells. These insights into disease pathogenesis have enabled the development of therapies to prevent and modify T1D. In this review, we highlight the key events that initiate and sustain pancreatic islet inflammation in T1D, the current state of the immunological therapies, and their advantages for the treatment of T1D.

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 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 Exploration of NPTX2 in Islets of Langerhans

2020 ◽  
Vol 21 (2) ◽  
Author(s):  
Lindsay Elisha Wald
Keyword(s):  
Type 1 Diabetes ◽  
Insulin Secretion ◽  
Islet Cells ◽  
The Body ◽  
Immunofluorescent Staining ◽  
Β Cells ◽  
Healthy Human ◽  
Neuronal Pentraxin ◽  
The Brain

NPTX2 (neuronal pentraxin-2) is a synaptic protein found abundantly in only two locations in a healthy human body: the brain and the pancreas, specifically islet of Langerhans cells. NPTX2’s role in the brain has been a focus of study in the pathology of Parkinson’s disease, as it is upregulated in PD patients. Its primary functions in the brain are to establish excitatory synapses and to recruit alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors to said synapses. These AMPA receptors signal for the neurotransmitter, glutamate, that regulates insulin secretion. This is of pathological significance to the onset of type 1 diabetes. Type 1 diabetes is characterized by the depletion of islet β-cells in the pancreas, which are responsible for insulin secretion. Without a supply of insulin, fatal consequences will ensue. NPTX2’s function in the pancreas is unstudied and extremely relevant to unraveling the complex processes that the body undergoes with the onset of this autoimmune disease. In recent mRNA studies, NPTX2 mRNA was significantly downregulated in type 1 diabetes. To understand the underlying cause of this downregulation and its potential role in the destruction of islet β-cells, it is first necessary to localize NPTX2 in the islet cells of type 1 diabetic, auto-antibody positive, and control donors. Immunofluorescent staining indicates that NPTX2’s co-expression in 

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 SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but are Not Enriched in Islet Endocrine Cells

2020 ◽  
Author(s):  
Katie C. Coate ◽  
Jeeyeon Cha ◽  
Shristi Shrestha ◽  
Wenliang Wang ◽  
Luciana Mateus Gonçalves ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Endocrine Cells ◽  
Islet Cells ◽  
Cell Entry ◽  
Pancreatic Ducts ◽  
Human Pancreas ◽  
Β Cells ◽  
Ductal Cells ◽  
Putative Receptor ◽  
New Onset

Summary/AbstractReports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into host β cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. ACE2 and TMPRSS2 transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in α or β cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet β cells through these cell entry proteins.

scholarly journals Expression Pattern of 12-Lipoxygenase in Human Islets With Type 1 Diabetes and Type 2 Diabetes

2015 ◽  
Vol 100 (3) ◽  
pp. E387-E395 ◽  
Author(s):  
Wojciech J. Grzesik ◽  
Joseph L. Nadler ◽  
Yui Machida ◽  
Jerry L. Nadler ◽  
Yumi Imai ◽  
...  
Keyword(s):  
Outcome Measure ◽  
Islet Cells ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Diabetes Development ◽  
12 Lipoxygenase ◽  
Type 2 Diabetic

Context: Inflammation in the pancreas can cause β-cell stress, leading to diabetes development. Access to human pancreas tissues via the Network for Pancreatic Organ Donors with Diabetes (nPOD) has allowed characterization of pathways leading to this inflammation. Objective: 12-Lipoxygenase (12-LO) induces inflammation and has been implicated in diabetes development. Our goal was to determine expression of 12-LO in human islets from control, autoantibody-positive, type 1 diabetic, and type 2 diabetic nPOD pancreas donors. Design: Pancreas tissues from nPOD donors were examined by immunohistochemistry and immunofluorescence for islet expression of 12-LO in different subsets of islet cells. Participants: Donor pancreas samples were obtained from nPOD based on disease status (control, n = 7; autoantibody-positive, n = 8; type 1 diabetic, n = 17; or type 2 diabetic donors, n = 15). Main Outcome Measure: Determination of 12-LO expression within human islets served as the main outcome measure, including distinguishing which types of islet cells expressed 12-LO. Results: Islets from control participants (nondiabetic) lacked islet expression of 12-LO. Of donors in the other groups, 25% to 37% expressed islet 12-LO with a clear inverse relation between the numbers of β-cells and 12-LO+ cells within islets of 12-LO+ cases. 12-LO expression was not seen within macrophages, endothelial cells, α-cells, or β-cells, but only within cells expressing low levels of pancreatic polypeptide (PP) and increased levels of vimentin. Conclusions: 12-LO expression colocalizes within a specific type of islet PP+ cell under prediabetic and diabetic conditions. The costaining of PP and vimentin suggests that 12-LO participates in the process leading to β-cell dedifferentiation in the islet.

β Cell Protecting and Immunomodulatory Activities of Paecilomyces Hepiali Chen Mycelium in STZ Induced T1DM Mice

2009 ◽  
Vol 37 (02) ◽  
pp. 361-372 ◽  
Author(s):  
Ming Xiang ◽  
Jing Tang ◽  
Xiao-Lei Zou ◽  
Zeng-Yu Zhao ◽  
Yun-Yang Wang ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Insulin Level ◽  
Inflammatory Cells ◽  
Diabetic Control ◽  
Control Group ◽  
Β Cells ◽  
Β Cell ◽  
Diabetic Control Group ◽  
Paecilomyces Hepiali

The anti-hyperglycemic and immunomodulatory activities of the ethanol extract from Paecilomyces Hepiali Chen (PHC), a Chinese medicine, were investigated in streptozotocin-induced type 1 diabetic (T1DM) mice. Male Balb/c mice, which were i.p. injected with streptozotocin (STZ, 50 mg/kg, for 5 consecutive days) on Day 7, were orally administered saline (the normal control and diabetic control group), Metformin (60 mg/kg, b.w., positive group), or the extract (100 mg/kg, b.w., PHC prevention group) from Day 1 to Day 28, Mice i.p. injected with streptozotocin (STZ, 50 mg/kg, b.w.) for 5 consecutive days prior to PHC treatment (100 mg/kg, b.w.) were used as the PHC treatment group. The effects of PHC on postprandial blood glucose concentrations, plasmatic insulin levels, morphology of pancreatic β cells and CD4+ T cells proliferation after 28-day treatment were monitored. Results showed that PHC administered 6 days before STZ induction of diabetes in mice significantly decreased blood glucose level (p < 0.01). An increase of insulin level was also observed as compared to those in the diabetic control group (p < 0.01). In addition, fewer inflammatory cells infiltrated the pancreatic islet and fewer β cells death by apoptosis within the inflamed islets were observed. More importantly, the CD4+ T cell proliferation was remarkably attenuated ex vivo in mice preventively treated with PHC (p < 0.01). In comparison to the PHC prevention group, no significant hypoglycemia, changes of insulin level and β cell protection were observed in mice treated with PHC after STZ administration. Our findings demonstrated that preventive administration of PHC protected β cells from apoptosis in type 1 diabetes induced by STZ, and the underlying mechanism may be involved in suppressing CD4+ T cells reaction, reducing inflammatory cells infiltration and protecting beta cell apoptosis in pancreatic islet.

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