Loss of Sugar Detection by GLUT2 Affects Glucose Homeostasis in Mice

International audienceBACKGROUND: Mammals must sense the amount of sugar available to them and respond appropriately. For many years attention has focused on intracellular glucose sensing derived from glucose metabolism. Here, we studied the detection of extracellular glucose concentrations in vivo by invalidating the transduction pathway downstream from the transporter-detector GLUT2 and measured the physiological impact of this pathway. METHODOLOGY/PRINCIPAL FINDINGS: We produced mice that ubiquitously express the largest cytoplasmic loop of GLUT2, blocking glucose-mediated gene expression in vitro without affecting glucose metabolism. Impairment of GLUT2-mediated sugar detection transiently protected transgenic mice against starvation and streptozotocin-induced diabetes, suggesting that both low- and high-glucose concentrations were not detected. Transgenic mice favored lipid oxidation, and oral glucose was slowly cleared from blood due to low insulin production, despite massive urinary glucose excretion. Kidney adaptation was characterized by a lower rate of glucose reabsorption, whereas pancreatic adaptation was associated with a larger number of small islets. CONCLUSIONS/SIGNIFICANCE: Molecular invalidation of sugar sensing in GLUT2-loop transgenic mice changed multiple aspects of glucose homeostasis, highlighting by a top-down approach, the role of membrane glucose receptors as potential therapeutic targets

La mise en marque des villes et des régions en France : la gouvernance comme facteur-clé de succès

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La mise en marque des villes et des régions en France : la gouvernance comme facteur clé de succès

Nombreux sont les territoires en France qui ont organisé ces dernières années la gestion de l’image officielle d’un territoire à l’échelle des métropoles ou des régions. Plusieurs ont échoué, mais d’autres sont parvenus à les lancer grâce à la gouvernance mise en place autour de l’objet « marque ». Il reste à pérenniser ces marques, outil de dynamisation collective des parties prenantes qui deviennent acteurs territoriaux. Cet article décrit la dimension relationnelle d’agents économiques, culturels ou sociaux, accompagnés par les services publics de l’administration locale et qui ont comme point commun la quête d’une dynamique territoriale.In recent years, many territories in France have organized the management of the official image of metropolises or regions. Several failed, but others managed to launch them thanks to the governance set up around the Brand. The perpetuation of these brands, as a tool for collective empowerment of stakeholders, is an important challenge based on good governance. This article describes the relational dimension of economic, cultural or social agents, accompanied by the public services of the local administration and which share the quest for a territorial mobilization

Dissecting Highly Mutagenic Processing of Complex Clustered DNA Damage in Yeast Saccharomyces cerevisiae

International audienceClusters of DNA damage, also called multiply damaged sites (MDS), are a signature of ionizing radiation exposure. They are defined as two or more lesions within one or two helix turns, which are created by the passage of a single radiation track. It has been shown that the clustering of DNA damage compromises their repair. Unresolved repair may lead to the formation of double-strand breaks (DSB) or the induction of mutation. We engineered three complex MDS, comprised of oxidatively damaged bases and a one-nucleotide (1 nt) gap (or not), in order to investigate the processing and the outcome of these MDS in yeast Saccharomyces cerevisiae. Such MDS could be caused by high linear energy transfer (LET) radiation. Using a whole-cell extract, deficient (or not) in base excision repair (BER), and a plasmid-based assay, we investigated in vitro excision/incision at the damaged bases and the mutations generated at MDS in wild-type, BER, and translesion synthesis-deficient cells. The processing of the studied MDS did not give rise to DSB (previously published). Our major finding is the extremely high mutation frequency that occurs at the MDS. The proposed processing of MDS is rather complex, and it largely depends on the nature and the distribution of the damaged bases relative to the 1 nt gap. Our results emphasize the deleterious consequences of MDS in eukaryotic cells

Myeloperoxidase: new polymorphisms and relation with lung cancer risk.

International audienceMyeloperoxidase (MPO) is an haemoprotein that metabolizes tobacco smoke procarcinogens such as benzo(a)pyrene and aromatic amines into highly reactive intermediates. A polymorphism in the MPO promoter (-463G>A), resulting in lower expression, was previously associated with a decrease in lung cancer risk. In this study, the MPO gene was analysed for new polymorphisms by denaturing high-performance liquid chromatography and sequencing on a panel of 48 subjects. Subsequently, the association between newly described polymorphisms, the -463G>A single nucleotide polymorphism (SNP) and lung cancer risk was investigated in a case-control study comprising 245 Caucasian cases and 249 Caucasian controls. Genetic polymorphisms were found in exons 2 (V53F), 6 (M251T), 7 (A332V), 11 (I642L) and 12 (I717V), with allelic frequencies of 6.0%, 1.8%, 1.8%, 0.2% and 1.8%, respectively. A new polymorphism located in the intron 11 3' splice site was found (0.4%). The known -463G>A polymorphism (24.0%) and four new polymorphisms in promoter region were also detected. No correlation between these new polymorphisms and lung cancer risk was found. For the -463G>A polymorphism, no modification of lung cancer risk was observed for either the G/A genotype [odds ratio (OR) 1.19; 95% confidence interval (CI) 0.8-1.8] or the A/A genotype (OR 0.97; 95% CI 0.4-2.6). Linkage analysis showed a strong disequilibrium between -463G>A polymorphism and exonic SNPs. However, the distribution of reconstructed haplotypes did not differ significantly between cases and controls. Further studies need to be performed to investigate the role of these polymorphisms in others diseases

Performance of cervical phIGFBP-1 test alone or combined with short cervical length to predict spontaneous preterm birth in symptomatic women

Abstract We aimed to assess the accuracy of cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) test alone or in combination with cervical length (CL), to predict preterm birth (PTB) in symptomatic women. We performed a prospective cohort study from 2012 to 2015 including singleton pregnancies with symptoms of preterm labor, intact membranes and CL < 25 mm at 24–34 weeks of gestation. Studied outcome were spontaneous delivery within 7 and 14 days of testing and spontaneous PTB at <34 and <37 weeks of gestation. Among 180 women, 21 (11.7%) had a positive phIGFBP-1 test. Spontaneous PTB occurred within 7 days, 14 days of testing and before 34 weeks and 37 weeks in 7.8%, 10.6%, 12.9% and 28.8%, respectively. The phIGFBP-1 test had a low predictive performance for all studied outcomes varying for positive likelihood ratios (2.8 to 3.4) and negative likelihood ratios (0.8). Combining phIGFBP-1 and CL did not increase its predictive ability. After adjustment, positive phIGFBP-1 test was no more independently associated with a delivery within 7 days (p = 0.55), unlike CL < 15 mm (p = 0.04). In conclusion, phIGFBP-1 test alone or in combination with CL has a low predictive accuracy to predict PTB in symptomatic women

Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development

International audienceAbstract Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4 . The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex

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Kidney function in mice after impairment of extracellular sugar detection.

<p>A: Effect of a glucose-rich diet on gene expression in the kidney of transgenic (Tg) and wild-type (WT) mice fasted for 48 h and refed for 15 h. Levels of mRNA were analyzed by real-time PCR. Values are presented as means±S.E.M. (n = 3 to 4 mice/group). Statistical differences between refed and fasted mice are indicated as *P<0.05, **P<0.01 and ns non significant. B: GLUT2 protein levels in total membrane preparations of kidney from mice fed with a glucose-rich diet for five days. C: Structure, size and weight of kidneys from wild-type and transgenic mice shown by ultrasonic image (transverse cross section). D: Urine and blood glucose concentrations during an oral glucose tolerance test in fasted wild-type and transgenic mice (n = 3 mice per group). Statistical differences between transgenic and wild-type mice are indicated as **P<0.01 (two-way ANOVA) for the areas under the curves. E: Levels of SGLT mRNA were analyzed by real-time PCR. Values are presented as means±S.E.M. (n = 3 to 4 mice/group). Statistical differences between refed and fasted mice are indicated as **P<0.01 and ns non significant.</p