MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

Richards, Pamela Spence; Rachdi, Latif; Oshima, Masaya; Marchetti, Piero; Bugliani, Marco; Armanet, Mathieu; Postic, Catherine; Guilmeau, Sandra; Scharfmann, Raphaël

doi:10.2337/db17-0595

Cited by 39 publications

(46 citation statements)

References 41 publications

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“…To further investigate the function of the GABA B receptor in ECN90, we searched for genes whose induction by forskolin would be blunted upon pretreatment with baclofen (16 h, 100 µM). Forskolin treatment induced a robust increase in MAFA, PCSK1, PAX4, IGFBP3 and the non-coding long RNA Linc00473, as previously shown in our microarray analyses from forskolin treated human EndoC-βH1 cells 20 . This induction was blunted upon pretreatment with baclofen ( Fig.…”

Section: Ecn90 Expresses Both Subunits Of the Metabotropic Gaba B Recsupporting

confidence: 86%

Regulated expression and function of the GABAB receptor in human pancreatic beta cell line and islets

Rachdi

Maugein

Pechberty

et al. 2020

Sci Rep

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G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes. they constitute a large protein family of receptors with almost 300 members detected in human pancreatic islet preparations. However, the functional role of these receptors in pancreatic islets is unknown in most cases. We generated a new stable human beta cell line from neonatal pancreas. This cell line, named ECN90 expresses both subunits (GABBR1 and GABBR2) of the metabotropic GABA B receptor compared to human islet. In ECN90 cells, baclofen, a specific GABA B receptor agonist, inhibits cAMp signaling causing decreased expression of beta cellspecific genes such as MAFA and PCSK1, and reduced insulin secretion. We next demonstrated that in primary human islets, GABBR2 mRnA expression is strongly induced under cAMp signaling, while GABBR1 mRnA is constitutively expressed. We also found that induction and activation of the GABA B receptor in human islets modulates insulin secretion. Type 2 diabetes mellitus (T2DM) is the most common metabolic disease worldwide, affecting more than 350 million people. It is a multigenic disease showing increased insulin resistance progressively weakening pancreatic beta cell response. In patients with T2DM, both beta cell function and beta cell mass are decreased. Thus, understanding the regulation of beta cell function is critical to identify mechanisms underlying the development of T2DM 1. G protein-coupled receptors (GPCRs), which modulate a variety of physiological responses, are potential targets for anti-diabetic compounds 2. These seven transmembrane receptors are coupled to heterotrimeric G proteins, such as Gα s , Gα i/o , Gα q/11 and Gα 12/13. GPCR coupling to Gα s stimulates adenylyl cyclase, which increases cyclic AMP levels while coupling through Gα i/o inhibits adenylyl cyclase activation 3,4. Gamma aminobutyric acid (GABA) is an inhibitory neurotransmitter that acts in an autocrine and/or paracrine manner by activating GABA A and GABA B receptors at the plasma membrane. The GABA A receptor is a five-subunits chloride ion channel whereas the GABA B receptor (also known as the metabotropic receptor) is a GPCR heterodimer composed of two subunits, GABBR1 and GABBR2. The GABBR1 subunit binds GABA, whereas the GABBR2 subunit is responsible for Gα i/o-protein-coupled activation, leading to inhibition of adenylyl cyclase and consequently, to decreased cAMP signaling. Previous studies demonstrated that the presence of both subunits is necessary for GABA-induced signaling in individual cells 5,6. GABA plays major roles in the brain. Interestingly, beta cells express glutamic acid decarboxylase (GAD1/GAD67 in mice and GAD2/GAD65 in human) the enzyme involved in the synthesis of GABA from glutamate 7. However, how GABA signals in islets and particularly in human beta cells has not been fully explored. Whereas the expression of GABA A receptors in human islets and their altered expression and sensitivity in islets from T2DM patients has been re...

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Section: Ecn90 Expresses Both Subunits Of the Metabotropic Gaba B Recsupporting

confidence: 86%

Regulated expression and function of the GABAB receptor in human pancreatic beta cell line and islets

Rachdi

Maugein

Pechberty

et al. 2020

Sci Rep

Self Cite

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“…the deleterious effects of combined elevated glucose and NEFA concentrations, prompted us to study EndoC-βH1 cell viability following both high glucose and NEFA exposure. The efficiency of HG (30 mmol/l) treatment was validated by TXNIP mRNA upregulation ( [39] and data not shown). Remarkably, we did not observe cell toxicity after palmitate incubation at low glucose (5.6 mmol/l) or HG ( Fig.…”

Section: Resultsmentioning

confidence: 96%

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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“…Previous studies have reported a close relationship between glucose metabolism and MA. [ 30 ] Accordingly, MLXIP play a role in gene regulation in response to cellular glucose levels; [ 31 ] C1QTNF12 regulates glucose metabolism in liver and adipose tissues; [ 32 ] and CREM is associated with Type 1 diabetes mellitus. [ 33 ] For FGR, C FGR‐A (Table S10, Supporting Information) included CD63 , which is involved in different levels of platelet activation in preeclamptic, normotensive pregnant, and non‐pregnant women.…”

Section: Discussionmentioning

confidence: 99%

Whole‐Genome Promoter Profiling of Plasma DNA Exhibits Diagnostic Value for Placenta‐Origin Pregnancy Complications

et al. 2020

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Placenta‐origin pregnancy complications, including preeclampsia (PE), gestational diabetes mellitus (GDM), fetal growth restriction (FGR), and macrosomia (MA) are common occurrences in pregnancy, resulting in significant morbidity and mortality for both mother and fetus. However, despite their frequency, there are no reliable methods for the early diagnosis of these complications. Since cfDNA is mainly derived from placental trophoblasts and maternal hematopoietic cells, it might have information for gene expression which can be used for disease prediction. Here, low coverage whole‐genome sequencing on plasma DNA from 2,199 pregnancies is performed based on retrospective cohorts of 3,200 pregnant women. Read depth in the promoter regions is examined to define read‐depth distribution patterns of promoters for pregnancy complications and controls. Using machine learning methods, classifiers for predicting pregnancy complications are developed. Using these classifiers, complications are successfully predicted with an accuracy of 80.3%, 78.9%, 72.1%, and 83.0% for MA, FGR, GDM, and PE, respectively. The findings suggest that promoter profiling of cfDNA may be used as a biological biomarker for predicting pregnancy complications at early gestational age.

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MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells

Cited by 39 publications

References 41 publications

Regulated expression and function of the GABAB receptor in human pancreatic beta cell line and islets

Regulated expression and function of the GABAB receptor in human pancreatic beta cell line and islets

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

Whole‐Genome Promoter Profiling of Plasma DNA Exhibits Diagnostic Value for Placenta‐Origin Pregnancy Complications

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