scholarly journals Screening enteroviruses for β-cell tropism using foetal porcine β-cells

2001 ◽  
Vol 82 (8) ◽  
pp. 1909-1916 ◽  
Author(s):  
Merja Roivainen ◽  
Petri Ylipaasto ◽  
Jarkko Ustinov ◽  
Tapani Hovi ◽  
Timo Otonkoski
Keyword(s):  
Cell Function ◽  
Biological Properties ◽  
Human Islets ◽  
Cell Tropism ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Systematic Screening ◽  
Adult Human ◽  
Β Cell Function

Primary adult human insulin-producing β-cells are susceptible to infection by prototype strains of coxsackieviruses (CV) and infection may result in impaired β-cell function and/or cell death, as shown for coxsackie B virus (CVB) types 4 and 5, or have no apparent immediate adverse effects, as shown for CVA-9. Because of the limited availability of human pancreatic β-cells, the aim of this study was to find out if foetal porcine pancreatic islets could be used as a substitute in enterovirus (EV) screening. These cells resemble human β-cells in several biological properties. CVB infection resulted in a rapid progressive decline of insulin content and reponsiveness to insulin release. The amount of virus inoculum sufficient for this destruction was small, corresponding to only 55 infectious units per pancreas. In contrast to CVBs, CVA-9 replicated poorly, and sometimes not at all, in foetal porcine β-cells. The first signs of functional impairment and cell destruction, if present at all, were seen only after 1–3 weeks of incubation. Furthermore, CVA-16, several strains of echoviruses and human parechovirus type 1 were unable to replicate in foetal porcine pancreatic β-cells. Based on these results, foetal porcine islets are somewhat more sensitive to CVB infection than adult human islets, whereas many other human EV strains do not infect porcine β-cells. Therefore, foetal porcine β-cells cannot be used for systematic screening of human EV strains and isolates for β-cell tropism, but they might provide a useful model for detailed studies on the interaction of CVBs with β-cells.

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 Optical control of GPR40 signalling in pancreatic β-cells

2017 ◽  
Vol 8 (11) ◽  
pp. 7604-7610 ◽  
Author(s):  
James Allen Frank ◽  
Dmytro A. Yushchenko ◽  
Nicholas H. F. Fine ◽  
Margherita Duca ◽  
Mevlut Citir ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cell Function ◽  
Optical Control ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function

Fatty acids activate GPR40 and K+ channels to modulate β-cell function.

scholarly journals Oxytocin signal contributes to the adaptative growth of islets during gestation

2021 ◽  
Author(s):  
Ping Gu ◽  
Yuege Lin ◽  
Qi Wan ◽  
Dongming Su ◽  
Qun Shu
Keyword(s):  
Insulin Secretion ◽  
Pregnant Women ◽  
Cell Function ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Cell Adaptation ◽  
Β Cell Function ◽  
Insulinoma Cells

Background: Increased insulin production and secretion by pancreatic β-cells are important for ensuring the high insulin demand during gestation. However, the underlying mechanism of β-cell adaptation during gestation or in gestational diabetes mellitus (GDM) remains unclear. Oxytocin is an important physiological hormone in gestation and delivery, and it also contributes to the maintenance of β-cell function. The aim of this study was to investigate the role of oxytocin in β-cell adaptation during pregnancy. Methods: The relationship between the blood oxytocin level and pancreatic β-cell function in patients with GDM and healthy pregnant women was investigated. Gestating and non-gestating mice were used to evaluate the in vivo effect of oxytocin signal on β-cells during pregnancy. In vitro experiments were performed on INS-1 insulinoma cells. Results: The blood oxytocin levels were lower in patients with GDM than in healthy pregnant women and were associated with impaired pancreatic β-cell function. Acute administration of oxytocin increased insulin secretion in both gestating and non-gestating mice. A three-week oxytocin treatment promoted the proliferation of pancreatic β-cells and increased the β-cell mass in gestating but not non-gestating mice. Antagonism of oxytocin receptors by atosiban impaired insulin secretion and induced GDM in gestating but not non-gestating mice. Oxytocin enhanced glucose-stimulated insulin secretion, activated the mitogen-activated protein kinase pathway, and promoted cell proliferation in INS-1 cells. Conclusions: These findings provide strong evidence that oxytocin is needed for β-cell adaptation during pregnancy to maintain β-cell function, and lack of oxytocin could be associated with the risk of GDM.

Calcium and pancreatic β-cell function. 12. Modification of 45Ca fluxes by excess of K+

1981 ◽  
Vol 96 (1) ◽  
pp. 87-92 ◽  
Author(s):  
T. Andersson ◽  
C. Betsholtz ◽  
B. Hellman
Keyword(s):  
Cell Function ◽  
Secretory Granules ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Deficient Medium ◽  
Β Cell Function ◽  
Cell Handling ◽  
Stimulation Of ◽  
Glucose Effects

Abstract. Glucose stimulation of insulin release is supposed to result from depolarization of the pancreatic β-cells with subsequent influx of Ca2+. Isolated islets from non-inbred ob/ob-mice were employed for elucidating whether the glucose effects on the β-cell handling of Ca2+ could be simulated by the depolarization evoked by excess of K+. Addition of 25 mm K+ was as effective as 20 mm glucose in stimulating the intracellular uptake of 45Ca. In both instances the additional amounts of incorporated 45Ca appeared in the mitochondria and the secretory granules. When analysing the washout pattern for 45Ca it was evident that the effects of raising K+ differed from those evoked by glucose. Whereas glucose inhibited 45Ca efflux during perifusion with Ca2+-deficient medium the addition of K+ resulted in a slight stimulation. Furthermore, the 45Ca incorporated in response to K+ was more readily mobilised.

Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function

2018 ◽  
Vol 460 ◽  
pp. 47-56 ◽  
Author(s):  
Marie Balslev Backe ◽  
Jan Legaard Andersson ◽  
Karl Bacos ◽  
Dan Ploug Christensen ◽  
Jakob Bondo Hansen ◽  
...  
Keyword(s):  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function ◽  
Lysine Demethylase

scholarly journals A Putative Prohibitin-Calcium Nexus in β-Cell Mitochondria and Diabetes

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Gaurav Verma ◽  
Aparna Dixit ◽  
Craig S. Nunemaker
Keyword(s):  
Cell Function ◽  
Mitochondrial Protein ◽  
Active Role ◽  
Targeted Drugs ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Β Cell Function ◽  
Significant Attention

The role of mitochondria in apoptosis is well known; however, the mechanisms linking mitochondria to the proapoptotic effects of proinflammatory cytokines, hyperglycemia, and glucolipotoxicity are not completely understood. Complex Ca2+ signaling has emerged as a critical contributor to these proapoptotic effects and has gained significant attention in regulating the signaling processes of mitochondria. In pancreatic β-cells, Ca2+ plays an active role in β-cell function and survival. Prohibitin (PHB), a mitochondrial chaperone, is actively involved in maintaining the architecture of mitochondria. However, its possible interaction with Ca2+-activated signaling pathways has not been explored. The present review aims to examine potential crosstalk between Ca2+ signaling and PHB function in pancreatic β-cells. Moreover, this review will focus on the effects of cytokines and glucolipotoxicity on Ca2+ signaling and its possible interaction with PHB. Improved understanding of this important mitochondrial protein may aid in the design of more targeted drugs to identify specific pathways involved with stress-induced dysfunction in the β-cell.

scholarly journals Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD): a phase 2, multicentre, double-blind, randomized, placebo-controlled trial

2020 ◽  
Vol 5 ◽  
pp. 49
Author(s):  
M. Loredana Marcovecchio ◽  
Linda S. Wicker ◽  
David B. Dunger ◽  
Susan J. Dutton ◽  
Sylwia Kopijasz ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Low Dose ◽  
Cell Function ◽  
Controlled Trial ◽  
Interleukin 2 ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Double Blind ◽  
Β Cell Function

Type 1 diabetes is a common autoimmune disease due to destruction of pancreatic β cells, resulting in lifelong need for insulin. Evidence suggest that maintaining residual β-cell function can improve glucose control and reduce risk of hypoglycaemia and vascular complications. Non-clinical, preclinical and some preliminary clinical data suggest that low-dose interleukin-2 (IL-2) therapy could block pancreatic β cells destruction by increasing the number of functional regulatory T cells (Tregs) that inhibit islet-specific autoreactive effector T cells (Teffs). However, there is lack of data on the effect of low-dose IL-2 in newly diagnosed children and adolescents with T1D as well as lack of specific data on its potential effect on β-cell function. The ‘Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD)’ is a phase 2, multicentre, double-blind, randomised, placebo-controlled trial in children and adolescents (6-18 years; having detectable C-peptide) initiated within 6 weeks of T1D diagnosis. A total of 45 participants will be randomised in a 2:1 ratio to receive either ultra-low dose IL-2 (aldesleukin), at a dose of 0.2 x 106 IU/m2 twice-weekly, given subcutaneously, or placebo, for 6 months. The primary objective is to assess the effects of ultra-low dose aldesleukin administration on endogenous β-cell function as measured by frequent home dried blood spot (DBS) fasting and post-prandial C-peptide in children and adolescents with newly diagnosed T1D. The secondary objectives are: 1) to assess the efficacy of regular dosing of aldesleukin in increasing Treg levels; 2) to confirm the clinical safety and tolerability of ultra-low dose aldesleukin; 3) to assess changes in the immune system indicating benefit or potential risk for future gains/loss in β-cell function and immune function; 4) to assess treatment effect on glycaemic control. Trial registration: EudraCT 2017-002126-20 (06/02/2019)

scholarly journals The RNA-binding profile of the splicing factor SRSF6 in immortalized human pancreatic β-cells

2020 ◽  
Vol 4 (3) ◽  
pp. e202000825
Author(s):  
Maria Inês Alvelos ◽  
Mirko Brüggemann ◽  
FX Reymond Sutandy ◽  
Jonàs Juan-Mateu ◽  
Maikel Luis Colli ◽  
...  
Keyword(s):  
Rna Binding ◽  
Cell Function ◽  
Susceptibility Gene ◽  
Splicing Factor ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Diabetes Susceptibility ◽  
Β Cell Function ◽  
Nucleotide Resolution

In pancreatic β-cells, the expression of the splicing factor SRSF6 is regulated by GLIS3, a transcription factor encoded by a diabetes susceptibility gene. SRSF6 down-regulation promotes β-cell demise through splicing dysregulation of central genes for β-cells function and survival, but how RNAs are targeted by SRSF6 remains poorly understood. Here, we define the SRSF6 binding landscape in the human pancreatic β-cell line EndoC-βH1 by integrating individual-nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP) under basal conditions with RNA sequencing after SRSF6 knockdown. We detect thousands of SRSF6 bindings sites in coding sequences. Motif analyses suggest that SRSF6 specifically recognizes a purine-rich consensus motif consisting of GAA triplets and that the number of contiguous GAA triplets correlates with increasing binding site strength. The SRSF6 positioning determines the splicing fate. In line with its role in β-cell function, we identify SRSF6 binding sites on regulated exons in several diabetes susceptibility genes. In a proof-of-principle, the splicing of the susceptibility gene LMO7 is modulated by antisense oligonucleotides. Our present study unveils the splicing regulatory landscape of SRSF6 in immortalized human pancreatic β-cells.

miR-124-3p Down-Regulation Influences Pancreatic-β-Cell Function by Targeting Secreted Frizzled-Related Protein 5 (SFRP5) in Diabetes Mellitus

2021 ◽  
Vol 11 (4) ◽  
pp. 711-717
Author(s):  
Zhenhuan Jiang ◽  
Min Yang ◽  
Jianming Jin ◽  
Zhenqiang Song ◽  
Chenguang Li ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cell Function ◽  
Luciferase Reporter ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Down Regulation ◽  
Β Cell Function ◽  
Direct Target

Diabetes mellitus (DM) is a complex metabolic disease characterized by hyperglycemia, insulin resistance and pancreatic β-cell dysfunction. There are evidences showed that microRNAs (miRNAs) play important roles in DM. The purpose of our study was to determine the role of miR-124-3p in DM. Quantitative reverse transcription PCR (qRT-PCR) was applied to measure the level of miR- 124-3p in peripheral blood from healthy control patients and DM patients. Then we explored the effects of miR-124-3p inhibitor on the secretion of insulin of pancreatic β-cells. Moreover, we determined the effects of miR-124-3p inhibitor on the apoptosis and viability of pancreatic β-cells through flow cytometry and MTT assay. And we also used western blotting to detect the protein expression of cleaved-caspase3/pro-caspase3, and the activity of caspase3 was detected. In addition, we confirmed the direct target of miR-124-3p using Dual luciferase reporter assay. Our data showed that in the blood of DM patients, SFRP5 was significantly reduced, while miR-124-3p was increased significantly. Furthermore, we found that down-regulation of miR-124-3p increased total insulin content in INS-1 cells, enhanced insulin secretion in INS-1 cells. Furthermore, we revealed that miR-124-3p inhibitor enhanced INS-1 cell viability, decreased apoptosis of INS-1 cells, increased pro-caspase3 expression, decreased cleaved-caspase3 expression and caspase3 activity. In addition, we proved SFRP5 was a direct target of miR-124-3p in pancreatic β-cells. Moreover, SFRP5-siRNA reversed all the effects of miR-124-3p knockdown on pancreatic β-cells.

CALCIUM AND PANCREATIC β-CELL FUNCTION

1979 ◽  
Vol 90 (4) ◽  
pp. 624-636 ◽  
Author(s):  
Bo Hellman
Keyword(s):  
Cell Function ◽  
Secretory Granules ◽  
Metabolic Inhibitors ◽  
Antimycin A ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
A 23187 ◽  
Β Cell Function

ABSTRACT Glucose is believed to stimulate incorporation of calcium into the secretory granules of the pancreatic β-cells. The mechanism of the glucose-stimulated accumulation of calcium in the granule pool was evaluated by measuring fluxes of 45Ca in β-cell-rich pancreatic islets microdissected from ob/ob-mice. The incorporation of lanthanum-nondisplaceable 45Ca in response to glucose differed from both the basal uptake and that seen in response to phosphate in being suppressed by 10 μm antimycin A, 0.3 mm 2,4-dinitrophenol or 1 mm N-ethylmaleimide. Exposure to each of these metabolic inhibitors also resulted in a protracted efflux of the glucose-sensitive 45Ca under conditions when neither the 45Ca incorporated in the presence of 3 mm glucose nor in response to phosphate was significantly affected. The glucose-stimulated intracellular 45Ca existed in a state allowing it to be washed out with the ionophore A-23187. The results suggest that the glucose-stimulated incorporation of calcium into the secretory granules is mediated by transport against a concentration gradient into the granule sac.

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