Virus-like infection induces human β cell dedifferentiation

Oshima, Masaya; Knoch, K. P.; Diedisheim, Marc; Petzold, A; Cattan, Pierre; Bugliani, Marco; Marchetti, Piero; Choudhary, Pratik; Huang, Guo Cai; Bornstein, Stefan R.; Solimena, Michele; Albagli-Curiel, Olivier; Scharfmann, Raphaël

doi:10.1172/jci.insight.97732

Cited by 60 publications

(75 citation statements)

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“…EndoC-βH1 cells were treated with 5 μmol/l thapsigargin for 24 h (Sigma-Aldrich, Saint Quentin Fallavier, France). EndoC-βH1 cells were passaged and transfected using Lipofectamine RNAiMAX (Life Technologies, Saint Aubin, France) 24 h later as described [32,33]. SMARTpool siRNAs for human ELOVL6 (L-008861-01-0005), SCD (L-005061-00-0020), SCD5 (L-008416-00-0005) or SOX9 (M-021507-00-0020), or ON-TARGETplus non-targeting control pool siRNA (siCTRL, D-001810-01-20) were used (Dharmacon, GE Healthcare Life Sciences, Velizy-Villacoublay, France) at a final concentration of 80 nmol/l.…”

Section: Methodsmentioning

confidence: 99%

Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

et al. 2019

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Aims/hypothesis During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment. Methods EndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity. Results EndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion. Conclusions/interpretation The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity. Data availability Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.

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Section: Methodsmentioning

confidence: 99%

Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

et al. 2019

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“…§: Multiple SNPs in the MHC gene class regions are significant, so a single SNP with the lowest marginal epistatic p-value is reported as the most extreme. There are three subregions that divide the MHC region: the class I region (29. ≈ 0 (rs6475502) -- [106,107]…”

Section: Discussionmentioning

confidence: 99%

“…For HT, the cis-window version of LT-MAPIT identified significant variants near the gene PSAT1, whose low expression levels serve as a biomarker of decreased serine biosynthesis pathway activity and increased risk for pulmonary hypertension [102,103]. Similarly, IFNB1 has been validated as a gene that affects immunity in T1D [104][105][106] and is a key member of the inflammatory signature for progressive diabetic nephropathy in T2D [106,107].…”

Section: Practical Application To Wtccc Datamentioning

confidence: 99%

Genome-wide Marginal Epistatic Association Mapping in Case-Control Studies

Crawford

Zhou

2018

Preprint

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Epistasis, commonly defined as the interaction between genetic loci, is an important contributor to the genetic architecture underlying many complex traits and common diseases. Most existing epistatic mapping methods in genome-wide association studies explicitly search over all pairwise or higher-order interactions. However, due to the potentially large search space and the resulting multiple testing burden, these conventional approaches often suffer from heavy computational cost and low statistical power. A recently proposed attractive alternative for mapping epistasis focuses instead on detecting marginal epistasis, which is defined as the combined pairwise interaction effects between a given variant and all other variants. By searching for marginal epistatic effects, one can identify genetic variants that are involved in epistasis without the need to identify the exact partners with which the variants interact -thus, potentially alleviating much of the statistical and computational burden associated with conventional epistatic mapping procedures. However, previous marginal epistatic mapping methods are based on quantitative trait models. As we will show here, these lack statistical power in case-control studies. Here, we develop a liability threshold mixed model that extends marginal epistatic mapping to case-control studies. Our method properly accounts for case-control ascertainment and the binary nature of casecontrol data. We refer to this method as the liability threshold marginal epistasis test (LT-MAPIT). With simulations, we illustrate the benefits of LT-MAPIT in terms of providing effective type I error control, and being more powerful than both existing marginal epistatic mapping methods and conventional explicit search-based approaches in case-control data. We finally apply LT-MAPIT to identify both marginal and pairwise epistasis in seven complex diseases from the Wellcome Trust Case Control Consortium (WTCCC) 1 study.

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“…Peptidomic-based approaches have also used the human β cell lines to identify target epitopes processed and presented by β cells, thereby providing the first HLA-I peptidome catalog of human β cells (84). Finally, our group used EndoC-βH1 cells to develop models and identify markers of human β cell dedifferentiation (85,86). All of the above examples depended on experiments that would have been difficult to perform with human islets because of limitations in cell purity or cell number and that would have produced different results in rodent β cell lines because of species differences.…”

Section: Human β Cell Lines: From Rodent To Humanmentioning

confidence: 99%