Identification de loci suppresseurs du phénotype diabétique lié à la déficience en Hnf1a chez la souris

Hnf1a-/- mice exhibit a severe diabetes mellitus due to a drastic defect in insulin secretion that closely resembles to the phenotype presented by MODY3 (Maturity Onset Diabetes of the Young type 3) patients. The molecular mechanisms responsible for the diabetes are still poorly understood. Here we show that congenic mice of different genetic backgrounds carrying the same Hnf1a deletion presented with drastically different phenotypes. Hnf1a-deficiency led to severe diabetes when introgressed into 129, B6, BALB/C or A/J genetic backgrounds (sensitive strains). Conversely, when the same null mutation was introgressed into CBA or C3H genetic backgrounds (resistant strains), the diabetic phenotype was suppressed. In sensitive strains, pancreatic islets did not increase in size compared to control animals and on the other hand average islet-size growth was normal in resistant strains. The genetic variations naturally present in these two resistant strains acted in a dominant way and a genome scan analysis led to the identification of a major suppressor locus on chromosome 3 that accounted for more than 60% of the variance of glycemia. The major locus contained 11 genes with non-synonymous SNPs changes and it interacted with 5 additional ancillary loci on chromosomes 4, 11 and 18. Our study demonstrated that the naturally occurring genetic variation present in distinct mouse laboratory strains is able to suppress the phenotype of a monogenic disorder.Les souris invalidées pour Hnf1a présentent un diabète sévère avec défaut d’insulino-sécrétion proche du phénotype observé chez les patients MODY3 (Maturity Onset Diabetes of te Young). Les mécanismes moléculaires responsables du diabète lié à la déficience en Hnf1a ne sont pas clairement compris. Dans ce travail, nous avons montré que des souris congéniques présentant la même délétion de Hnf1a dans des fonds génétiques différents présentent des phénotypes radicalement opposés. En effet, la déficience en Hnf1a conduit à un diabète sévère dans la plupart des lignées telles que 129, B6, BALB/c ou AJ (lignées sensibles). Mais à l’inverse, aucun diabète n’est observé chez les souris congéniques des lignées CBA et C3H malgré le défaut d’expression de Hnf1a (lignées résistantes). Les souris sensibles présentent une altération de leurs îlots de Langerhans avec notamment une diminution de taille de ces îlots. A l’inverse les souris résistantes présentent des îlots beta de taille normale malgré la déficience en Hnf1a. Nous avons pu montrer que le ou les variants génétiques présents dans les deux lignées résistantes agissent de façon dominante et, par un balayage du génome, nous avons identifié un locus majeur suppresseur du phénotype diabétique au niveau du chromosome 3. Ce locus majeur contient 11 gènes présentant des variations de SNP non synonymes et il interagit avec cinq autres loci ancillaires au niveau des chromosomes 4, 11 et 18. Notre travail montre finalement que les variations génétiques naturellement présentes dans les lignées de souris de laboratoire peuvent supprimer le phénotype diabétique lié à la déficience en Hnf1a

Variations de l'expression des gènes de l'inflammation dans le tissu adipeux chez des sujets obèses soumis à une restriction calorique

PARIS-BIUM (751062103) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Time of Bariatric Surgery and Hospitalization for SARS-CoV-2: a Nationwide Study

International audienc

For a better estimation of gamma heating in nuclear material-testing reactors and associated devices: status and work plan from calculation methods to nuclear data

International audienc

Impact Study on the Methodology used for Photon-Heating Calculations in Material-Testing Reactors

ANIMMA Conference, Lisbon, PORTUGAL, 2015International audienceDetermination of photon heating by calculation is an important issue for the Jules Horowitz Reactor (JHR), the next international Material-Testing Reactor (MTR) under construction in the south of France. Accurate knowledge of photon heating in structure materials and irradiation devices is necessary for JHR design and safety studies. In this paper, we quantify the impact of different photon-heating calculation routes by comparing absorbed dose and KERMA calculations (Kinetic Energy Released per MAss) from two different Monte Carlo codes, TRIPOLI-4.9 and MCNP (Monte Carlo N-Particle transport code). These calculations are carried out in JHR-representative geometries with the nuclear-data library JEFF3.1.1 and the photon-data library EPDL97. Discrepancies amounting to up to 18% between absorbed dose and KERMA are found in JHR irradiation devices and are linked to charged-particle transport effects taking place in heterogeneous materials of small dimensions. In a JHR-assembly cell, discrepancies of about 1% on photon KERMA and of about 3% on absorbed dose are highlighted between the two Monte Carlo codes. These latter discrepancies are small compared to typical sources of uncertainty for Monte Carlo calculation (for instance, nuclear data uncertainty) and are supposed to be due to differences in the processing of gamma-production data by neutron interactions and to differences in electromagnetic-shower models and implementation between the two codes

RYGB and Drug Disposition: How to Do Better? Analysis of Pharmacokinetic Studies and Recommendations for Clinical Practice

International audienc

Spin occurs in bariatric surgery randomized controlled trials with a statistically nonsignificant primary outcome: A systematic review

Objectives: To systematically identify the strategy and frequency of spin in reports of bariatric surgery randomized controlled trials (RCTs) with statistically nonsignificant primary endpoint. Study design and Setting: The use of specific reporting strategies to highlight the beneficial effect of an experimental treatment can affect the reader interpretation of trial results, particularly when the primary endpoint is not statistically significant. A literature search was performed to identify RCTs publications assessing the impact of bariatric surgery on obesity-related comorbidities published over the past 10 years (from January 2020 till December 2020) in MEDLINE and EMBASE. RCTs publications with statistically non-significant primary outcomes were included. Results: Of 46 576 reports screened for title and abstract inclusion, 29 RCT reports met the inclusion criteria for spin analysis. In total, 16 abstracts (55%) and 18 main texts (62%) were classified as having a spin. In abstract results and conclusion sections, the spin was identified in 69% of reports. In main text results, discussion, and conclusion sections, the spin was recognized in 37%, 72%, and 76% of reports respectively. The spin consisted mainly of focusing on within-group improvements and the interpretation of statistically nonsignificant results as showing treatment equivalence. Conclusion: Spin occurred in a high proportion of bariatric surgery RCTs with a statistically nonsignificant primary endpoint

Health care use by adults with obesity: A French cohort study

International audienceObjective: Studies on obesity costs have focused on global costs of people with obesity but scarcely investigated their precise use of health care. The aim of this study is to document real-life health care use across obesity classes.Methods: Data of participants with obesity and enrolled in the CONSTANCES cohort were analyzed. Health care use was defined as ≥1 visit to general practitioners, specialists, emergency departments, and inpatient hospital admissions versus none over a 3-year period prior to enrollment and was obtained from the Universal Health Insurance database. Multivariate regression models were conducted and adjusted for comorbidities and social deprivation markers with medical visits as the outcome variables and compared people with class II and III obesity versus class I obesity.Results: Out of the 10,774 participants with obesity, 613 (5.7%) had class III obesity, and 2,076 (19.3%) had class II obesity. Compared with participants with class I obesity, class III obesity participants had higher odds of visiting emergency departments (OR = 1.31; 95% CI: 1.07-1.61) and various specialist physicians (pneumologists, endocrinologists, cardiologists) but lower odds of visiting gynecologists (OR = 0.69; 95% CI 0.55-0.87). Participants with class II obesity had lower odds of visiting general practitioners, dentists, and psychiatrists. There was no difference with regard to hospital admissions.Conclusion: Health care use by people with obesity differs across classes