scholarly journals Ex vivo transcriptional profiling of human pancreatic islets following chronic exposure to monounsaturated fatty acids

2007 ◽  
Vol 196 (3) ◽  
pp. 455-464 ◽  
Author(s):  
George Bikopoulos ◽  
Aurelio da Silva Pimenta ◽  
Simon C Lee ◽  
Jonathan R Lakey ◽  
Sandy D Der ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Pancreatic Islets ◽  
Chronic Exposure ◽  
Ex Vivo ◽  
Transcriptional Profiling ◽  
Gene Clusters ◽  
Human Islets ◽  
Insulin Content ◽  
Ros Generation ◽  
Human Pancreatic Islets

The aim of this study was to assess the effects of chronic free fatty acid (FFA) exposure on gene expression and the functional state of human pancreatic islets. Chronic exposure of islets to oleate (OA) resulted in a significant reduction in glucose-stimulated insulin secretion (GSIS) compared with control (466±82 vs 234±57 ng/μg DNA, P<0.05). OA treatment also led to reduction in total insulin content of the islets (17 609±3816 vs 10 599±3876 ng insulin/μg DNA) and to an increase in the rate of reactive oxygen species (ROS) generation. Interestingly, the suppressive effects of OA on biosynthesis and secretion of insulin were accompanied by alteration in the expression of 40 genes, as determined by microarray analysis and subsequent qPCR validation. The majority of genes regulated by OA encoded metabolic enzymes. The expression of enzymes involved in oxidative defense was elevated, indicating a link between ROS generation and antioxidant defense activation. Additionally, pretreatment of human islets with OA led to a significant increase (30%) in the rate of oxidation of this fatty acid and to a significant decrease (75%) in glucose oxidation. Importantly, individual analysis of gene clusters from the islets of all donors revealed the induction of genes involved in inflammation and immunity, which provides further evidence that FFA are risk factors for the development of type 2 diabetes. In summary, our data indicate that chronic exposure of human islets to FFA activates inflammatory and metabolic pathways that lead to oxidative stress, reduced β-cell insulin content, and inhibition of GSIS.

scholarly journals Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Sophie Bauer ◽  
Charlotte Wennberg Huldt ◽  
Kajsa P. Kanebratt ◽  
Isabell Durieux ◽  
Daniela Gunne ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Ex Vivo ◽  
Functional Coupling ◽  
Human Pancreatic Islets ◽  
Diabetes Model

scholarly journals Beneficial effect of 1,25 dihydroxyvitamin D3 on cytokine-treated human pancreatic islets

2001 ◽  
Vol 169 (1) ◽  
pp. 161-168 ◽  
Author(s):  
R Riachy ◽  
B Vandewalle ◽  
S Belaich ◽  
J Kerr-Conte ◽  
V Gmyr ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vitamin D ◽  
Cell Viability ◽  
Pancreatic Islets ◽  
Mhc Class I ◽  
Class I ◽  
Insulin Content ◽  
Hsp70 Expression ◽  
Human Pancreatic Islets ◽  
Mnsod Activity

We examined whether 1,25 dihydroxyvitamin D(3) (1,25 D(3)), the active form of vitamin D involved in the regulation of the immune system, may also protect human pancreatic islet cells from destruction induced by cytokines. In this study, we specifically investigated the effect of 1,25 D(3) on oxidative stress and major histocompatibility complex (MHC) induction, both implicated in cytokine-induced islet cell dysfunction and destruction. We also investigated the effects of 1,25 D(3) on interleukin (IL)-6, a pleiotropic cytokine implicated in the pathogenesis of immunoinflammatory disorders. Human pancreatic islets, isolated from heart-beating donors, were treated with a combination of three cytokines, IL-1beta+tumor necrosis factor alpha+interferon gamma, in the presence or absence of vitamin D, and compared with with untreated control cells. Metabolic activity was assessed by cell viability and insulin content. Oxidative stress was estimated by heat shock protein 70 (hsp70) expression, cell manganese superoxide dismutase (MnSOD) activity and nitrite release, a reflexion of nitric oxide (NO) synthesis. Variation of immunogenicity of islet preparations was determined by analysis of the MHC class I and class II transcripts. Inflammatory status was evaluated by IL-6 production. After 48 h of contact with cytokines, insulin content was significantly decreased by 40% but cell viability was not altered. MHC expression significantly increased six- to sevenfold as well as NO and IL-6 release (two- to threefold enhancement). MnSOD activity was not significantly induced and hsp70 expression was not affected by the combination of cytokines. The addition of 1,25 D(3) significantly reduced nitrite release, IL-6 production and MHC class I expression which then became not significantly different from controls. These results suggest that the effect of 1,25 D(3) in human pancreatic islets cells may be a reduction of the vulnerability of cells to cytotoxic T lymphocytes and a reduction of cytotoxic challenge. Hence, 1,25 D(3) might play a role in the prevention of type 1 diabetes and islet allograft rejection.

scholarly journals Publisher Correction: Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Sophie Bauer ◽  
Charlotte Wennberg Huldt ◽  
Kajsa P. Kanebratt ◽  
Isabell Durieux ◽  
Daniela Gunne ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
Ex Vivo ◽  
Functional Coupling ◽  
Human Pancreatic Islets ◽  
Diabetes Model

Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose

Diabetes ◽  
1999 ◽  
Vol 48 (6) ◽  
pp. 1230-1236 ◽  
Author(s):  
S. Marshak ◽  
G. Leibowitz ◽  
F. Bertuzzi ◽  
C. Socci ◽  
N. Kaiser ◽  
...  
Keyword(s):  
Beta Cell ◽  
Pancreatic Islets ◽  
High Glucose ◽  
Chronic Exposure ◽  
Human Pancreatic Islets ◽  
Cell Functions

Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPARγ2 in the modulation of insulin secretion

2004 ◽  
Vol 286 (4) ◽  
pp. E560-E567 ◽  
Author(s):  
R. Lupi ◽  
S. Del Guerra ◽  
L. Marselli ◽  
M. Bugliani ◽  
U. Boggi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Mrna Expression ◽  
Pancreatic Islets ◽  
Human Islets ◽  
Acid Mixture ◽  
Human Pancreatic Islets ◽  
Pparγ Agonist ◽  
Pparγ Agonists ◽  
Insulin Mrna

Peroxisome proliferator-activated receptors (PPARs) are a subgroup of the superfamily of nuclear receptors, with three distinct main types: α, β and γ (subdivided into γ1 and γ2). Recently, the presence of PPARγ has been reported in human islets. Whether other PPAR types can be found in human islets, how islet PPARγ mRNA expression is regulated by the metabolic milieu, their role in insulin secretion, and the effects of a PPARγ agonist are not known. In this study, human pancreatic islets were prepared by collagenase digestion and density gradient purification from nonobese adult donors. The presence of PPAR mRNAs was assessed by RT-PCR, and the effect was evaluated of exposure for up to 24 h to either 22.2 mmol/l glucose and/or 0.25, 0.5, or 1.0 mmol/l long-chain fatty acid mixture (oleate to palmitate, 2:1). PPARβ and, to a greater extent, total PPARγ and PPARγ2 mRNAs were expressed in human islets, whereas PPARα mRNA was not detected. Compared with human adipose tissue, PPARγ mRNA was expressed at lower levels in the islets, and PPARβ at similar levels. The expression of PPARγ2 mRNA was not affected by exposure to 22.2 mmol/l glucose, whereas it decreased markedly and time dependently after exposure to progressively higher free fatty acids (FFA). This latter effect was not affected by the concomitant presence of high glucose. Exposure to FFA caused inhibition of insulin mRNA expression, glucose-stimulated insulin release, and reduction of islet insulin content. The PPARγ agonists rosiglitazone and 15-deoxy-Δ-12,14prostaglandin J2 prevented the cytostatic effect of FFA as well as the FFA-induced changes of PPAR and insulin mRNA expression. In conclusion, this study shows that PPARγ mRNA is expressed in human pancreatic islets, with predominance of PPARγ2; exposure to FFA downregulates PPARγ2 and insulin mRNA expression and inhibits glucose-stimulated insulin secretion; exposure to PPARγ agonists can prevent these effects.

scholarly journals Transcriptional profiling of type 1 diabetes genes on chromosome 21 in a rat beta-cell line and human pancreatic islets

2007 ◽  
Vol 8 (3) ◽  
pp. 232-238 ◽  
Author(s):  
R Bergholdt ◽  
A E Karlsen ◽  
P H Hagedorn ◽  
M Aalund ◽  
J H Nielsen ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Pancreatic Islets ◽  
Cell Line ◽  
Transcriptional Profiling ◽  
Chromosome 21 ◽  
Human Pancreatic Islets ◽  
Beta Cell Line

scholarly journals Persistent Infection of Human Pancreatic Islets by Coxsackievirus B Is Associated with Alpha Interferon Synthesis in β Cells

2000 ◽  
Vol 74 (21) ◽  
pp. 10153-10164 ◽  
Author(s):  
Wassim Chehadeh ◽  
Julie Kerr-Conte ◽  
François Pattou ◽  
Gunar Alm ◽  
Jean Lefebvre ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Islet Cells ◽  
Human Islets ◽  
Adult Brain ◽  
Viral Rna ◽  
Alpha Interferon ◽  
Β Cells ◽  
Human Pancreatic Islets ◽  
Reverse Transcription Pcr ◽  
Vp1 Capsid Protein

ABSTRACT The interactions of coxsackievirus B3 (CVB3), CVB4E2 (diabetogenic), and CVB4JBV (nondiabetogenic) strains with human pancreatic islets from eight adult brain-dead donors were investigated. Persistent replication of viruses in human islets was proved by detection of viral RNA by in situ hybridization, VP1 capsid protein by immunofluorescence (IF) staining, negative-strand viral RNA by reverse transcription-PCR in extracted RNA from islets, and release of infectious particles up to 30 days after infection without obvious cytolysis. By double IF staining, glucagon-containing α cells and insulin-containing β cells were shown to be susceptible to CVB. The persistence of CVB3 and CVB4 in islet cells was associated with the chronic synthesis of alpha interferon (IFN-α), as evidenced by the detection of IFN-α mRNA and immunoreactive IFN-α with antiviral activity. By double IF staining, IFN-α was detected in insulin-producing β cells only. Experiments with neutralizing anti-coxsackievirus and adenovirus receptor (CAR) antibodies provided evidence that CAR was expressed by α and β cells and that it played a role in the infection of these cells with CVB and the consecutive IFN-α expression in β cells. The viral replication and the expression of IFN-α in islets were not restricted to the CVB4E2 diabetogenic strain and did not depend on the genetic background of the host. The neutralization of endogenous IFN-α significantly enhanced the CVB replication in islet cells and resulted in rapid destruction of islets. Thus, human β cells can harbor a persistent CVB infection, and CVB-induced IFN-α plays a role in the initiation and/or maintenance of chronic CVB infection in human islets.

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