Dissertationen zum Thema „Diabètes – Génétique“
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Dubois-Laforgue, Danièle. „Déterminisme génétique de l'expression phénotypique du diabète de type 1“. Paris 5, 2002. http://www.theses.fr/2002PA05N112.
Der volle Inhalt der QuelleThe genetics of type 1 diabetes (DT1) remains elusive. About twenty susceptibility regions have been localized by genome scans, of wich a minority have been confirmed. Moreover, causal genes remain to be characterized. Association studies have been more contributive, since they demonstrated the implication of HLA genes and of the insulin VNTR and suggested that of CTLA4 and IL-12B. One of the difficulties in studying genetics of DT1 relies in the phenotypic heterogeneity of the disease. We studied the genetics of type 1 diabetes and of its phenotypic expression through the study of three genes, SDF-1, PARP and NOTC, which constitue putative candidates because of their function and their localization in regions. .
Prevost, Gaëtan. „L'implication du Récepteur des Produits Avancés de Glycation (RAGE) dans les complications du diabète : approches génétique et pharmacologique“. Lille 2, 2006. http://www.theses.fr/2006LIL2S040.
Der volle Inhalt der QuelleAdvanced glycation endproducts (AGE) are implicated in diabetic micro- but also macrovascular complications of diabetes mellitus. AGE toxicity is partially mediated via receptor dependant pathway especially via the RAGE (Receptor for Advanced Glycation Endproducts). The RAGE implication in the genetic of diabetic nephropathy and in the endothelial dysfunction has been investigated. First, the polymorphisms of exon 3 has been analysed by Denaturant Gradient Gel Electrophoresis. Although no association of this RAGE gene polymorphisms with type 1 diabetes susceptibility was found, we reported a strong linkage disequilibrium between the variant carrying the serine amino acid at position 82 and HLA class II genes. Finally, in a case control study, we reported an association between the 82 serine variant and advanced nephropathy in type I diabetic patients. This suggests that some RAGE gene polymorphisms may be associated with progression to diabetic advanced nephropathy in Caucasian type 1 diabetic patients. Thus, AGE have been implicated in diabetic endothelial dysfunction as vascular hyperpermeability and procoagulant and inflammatory states. However, the link between AGE and the endothelium dependent vasorelaxation impairment is still controversial. Vascular relaxation response to acetylcholine was tested in isolated segments of phenylephrine precontracted mice aorta at several stages of streptozotocin-induced diabetes. Blood levels of AGE (ELISA) and aortic tissue RAGE expression (Western Blot) were simultaneously quantified. Compared to control mice, significant impairment of endothelium dependant relaxation occurred four weeks after diabetes induction (-24% vs control, P<0,01) and was more severe eight weeks later. Simultaneously, blood AGE concentrations and RAGE aortic expression were significantly increased. Moreover, vasorelaxation impairment was associated with induced diabetic structural changes in the wall of aorta : intima-media thickening, disorganization of elastin lamina and actin network, increased amount and disorganization of the type III collagen. Four weeks after diabetes induction, aminoguanidine, AGE inhibitor, completely prevented the diabetes-induced decrease of relaxation to acetylcholine by decreasing AGE blood levels and RAGE expression. Moreover, aminoguanidine treatment significantly improves the induced diabetic structural changes. In conclusion, our work is in favour of a strong implication of the AGE pathway both in diabetic complications as nephropathy and vasorelaxation impairment. The use of anti AGE or AGE-RAGE inhibitors could be attractive therapeutics
Boulard, Olivier. „Contrôle génétique de l'auto-immunité chez la souris Nonobese Diabetic (NOD). Les locus IDD5 et IDD 16 de susceptibilité au diabète“. Paris 5, 2002. http://www.theses.fr/2002PA05N119.
Der volle Inhalt der QuelleNonobese diabetic (NOD) mice is a reference strain for autoimmue diabetes. We have analized more precisely one of the susceptibility loci, Idd5 on chromosome 1. This locus is of special interest because the corresponding genetic region include candidate genes like Ctla4 or Icos. Moreover, the human synteny on chromosome 2q is also a susceptibility region for human diabetes (IDDM 12 locus) and include CTLA4. The Idd5 locus has been investigated using congenic recombinant strains of mice. We have also characterized the genetic control of autoimmune phenotypes associated to NOD mice diabetes, like the inducible thyroi͏̈ditis of chronic evolution and spontaneous infiltration of salivary glands
Ghoussaini, Maya. „Utilisation des approches de gènes candidats positionnels et physiologiques dans l'identification des variants de susceptibilité à l'obésité et au diabète de type 2“. Lille 2, 2006. http://www.theses.fr/2006LIL2S024.
Der volle Inhalt der QuelleWe recently conducted a genome-wide scan for childhood obesity in the French population, the strongest evidence of linkage was detected on chromosome 6q16-23. The study of the positional candidate genes, ENPP, MCHR2 and SIM1 was the purpose of this PhD work. The ENPP1 gene encodes an inhibitor of the insulin receptor. The genetic study for the ENPP1 gene in 6,147 subjects, showed significant association of the allele risk haplotype of the variants (K121Q, IVS20delT-11 et A>G +1044 TGA, QdelTG) with childhood obesity (Odd Ratio (OR)=1. 69, p=0. 0006), moderate or morbid obesity in adults (OR=1. 37, p=0. 02; OR=1. 50, P=0. 006 respectively) and type 2 diabetes (T2D) (OR=1. 56, p=0. 00002). This haplotype is also associated with higher levels of the circulating forms of ENPP1. In contrast to other isoforms of ENPP1 that show ubiquitary expression, the long isoform of ENPP1 including the SNP A>G +1044 TGA had a specific expression in liver, adipocytes and pancreas, three key organs involved in glucose homeostasis. This haplotype also partially contributed to observed linkage with childhood obesity on chromosome 6q. Our results suggest a causative role of the ANPP1 haplotype in the insulin resistance in children which could further predisposes to the development of obesity and T2D. The MCHR2 encodes a receptor for the MCH (Melanin Concentrating Hormone), an orexigenic neuropeptide. Case/control analysis performed in 1,993 subjects showed an association between A76A T/C variant (p0. 03, OR=0. 75) and childhood obesity. Analysis of 645 trios with childhood obesity supproted the association and showed an over-transmission of the at risk T allele to obese children (59. 0%, p=0. 01), especially with severe obesity (67. 0%, p=0. 003). The risk allele was also over-transmitted in children with higher appetite during meals (62. 0%,p=0. 01) and with snacking habits (60. 0%, p=0. 03). None of the MCHR2 variants, including the A76A T/C SNP, showed association with adult class III obesity (BMI>40), although there was a trend for association of the T allele of this variant with disinhibition for food (p=0. 06) and with higher hunger (p=0. 09). Moreover, the A76A T/C SNP did not provide any evidence for participation to the linkage observed on the 6q locus. Our results altogether suggest that MCHR2 gene is not a major contributor to polygenic forms of obesity but supported a modest effect of the A76A T/C SNP on food intake abnormalities particularly in childhood. These results should be confirmed in additional populations. The SIM1 encodes a transcription factor highly expressed in the paraventricular nucleus (PVN). Sim1 (+/-) mice develop early onset of obesity and hyperphagia. Using direct sequencing, we identified 38 polymorphisms in the human gene SIM1. Case/control studies of frequent variants (>5%) in 2,474 French Caucasians showed significant association of three polymorphisms P352T, +2004 -/insT TGA, et +2215 TGA A/G with severe forms of childhood and/or adulthood obesity (1,19A. Functional analysis of the –767delGG deletion showed an alteration of the expression of the SIM1 gene. Our data suggest that severe hyperphagia could be a consequence of the dysfunction of the PVN which could be the result of mutations that affect the function and the expression of the SIM1 gene. Finally, we studied the Pro12A1a variant of the physiological candidate gene PPAR2. PPAR2 encodes a transcription factor essential for the diferenciation of adipocytes. Case/control studies encompassing 3,479 subjects found significant association between the Pro12A1a polymorphism and T2D (p=0. 04, OR=1. 37), which was stronger when the T2D cohort was stratified according to the obesity status (p=0. 03, OR=1. 81 in obese T2D subjects). In contrast, there was no association between the Pro12A1a and childhood and adulthood abesity. In normal glucose tolerant obese adults, allele Pro12 was associated with a significant increase in fasting insulin levels (p=0. 01) and insullin resistance (p=0. 003). We also found a borderline interaction of the Pro12A1a variant and obesity status on insulin resistance (p=0. 06) in normal glucose tolerant adults. In the study, we confirmed a contribution of the Pro12 allele in the genetic risk for T2D, especially in obese subjects, where this allele worsens insulin resistance and increases fasting insulin levels. These studies bring new insights into the implication of the feeding behaviour central patways and insulin pathways in the regulation of energy homeostasis
Populaire, Céline. „Etude des déterminants génétiques du diabète de type 2 de la fonction bêta pancréatique : combinaison des approches de la génétique inverse dans deux populations, japonaise et française“. Lille 2, 2004. http://www.theses.fr/2004LIL2S031.
Der volle Inhalt der QuelleThe pathogenesis of type 2 diabetes (T2D) is complex, with two distinct mechanisms: insulin resistance and insulin deficiency. These abnormalities are due to genetic and environmental factors. To allow a better understanding of T2D aetiology, we have undertaken the identification of genetic variants implied in the development of the disease, using 2 approaches: - a genome wide scan for T2D in diabetic Japanese sib-pairs revealed 2 linked regions at loci 3q26-q28 and 15q13-q21 where are located respectively APM1 and CX36 genes - genetic studies of KCNJ11, encoding the sub-unit of the channel Kir6. 2, and PDX-1, b cell pancreatic specific transcription factor were investigated in different French diabetic groups. We found activating mutations responsible for a neonatal form of diabetes and frequent variants implicated in mechanisms leading to an ordinary T2D
Abderrahmani, Amar. „Le diabète de type MODY : rôle des facteurs nucléaires hépatiques HNF1 alpha et HNF bêta“. Lille 1, 1999. https://pepite-depot.univ-lille.fr/LIBRE/Th_Num/1999/50376-1999-393.pdf.
Der volle Inhalt der QuelleCheyssac, Claire. „Etude de deux gènes candidats du DT2 : EIF4A2 : candidat positionnel au locus 3Q27 et PTPN1/PTP1B : cible pharmacologique dans la sensibilité à l'insuline“. Lille 2, 2006. http://www.theses.fr/2006LIL2S009.
Der volle Inhalt der QuelleType 2 diabetes (T2D) is the most common form of diabetes affecting more than 170 million people worldwide. The T2D pathophysiological mechanisms are characterized by defects of insulin secretion and insulin action leading to chronic hyperglycaemia determined by interactions between genetic and environmental risk factors. Although many genes responsible for monogenic forms of diabetes were identified, genetic determinants influencing T2D predisposition are still largely unknown. To identify new susceptibility variants, we used two approaches : - a familial association study of positional candidate gene variants at the 3q27 locus in falilies showing linkage to T2D with onset before 45 years ; and the exploration of a physiological candidate gene, PTPN1, through case-control analyses in different groups of subjects with type 2 diabetes or obesity. The analysis of the 3q27 locus in French families with strong T2D aggregation (432 diabetes subjects and 129 normoglycaemic subjects) confirmed of a genetic linkage with T2D age-of-onset. Two genes were investigated : KNG1, coding for kininogen, the bradykinin precursor, and EIF4A2 coding for the Eukaryotic Translation Initiation Factor 4 alpha 2, a translation initiation factor involved in protein synthesis which is down-regulated by glucose in rat pancreatic beta cells (INS832/13). A variant (rs266714), located upstream of the EIF4A2 gene showed association with T2D and T2D age-of-onset in the families. Affected sib-pairs sharing at least one at risk T allele showed a LOD-score of 5. 24 which could explain the T2D linkage. Moreover, this variant partly explains the age-of-onset linkage. The rs266714 SNP could modify the expression level of the eIF4A2 factor which modulates mRNA translation and protein synthesis rates in pancreatic beta cells. The PTPN1 gene codes for the protein tyrosine phosphatase 1B, a negative regulator of the insulin and leptin signalling pathways. An association with T2D and moderate obesity is observed for a variant at the PTPN1 gene locus. In 736 normoglycaemic non obese subjects, 2 intronic SNPs associate with variations of quantitative traits of glucose and lipid metabolism : increased HOMA-B and triglycerides, decreased HDL-cholesterol, which suggests a possible role in metabolic syndrome. This genetics approach contributes to an improved understanding of the pathways involved in the development of T2D and to propose new therapeutic targets
Dupont, Sophie. „Etude des déterminants génétiques du diabète de type 2 dans la population française“. Lille 1, 2000. https://pepite-depot.univ-lille.fr/RESTREINT/Th_Num/2000/50376-2000-308.pdf.
Der volle Inhalt der QuelleBouatia, Naji Nabila. „Implication des voies métaboliques associées à l'insuline dans la susceptibilité aux formes polygéniques d'obésité : études des gènes candidats ACDC/Adiponectine et ENPP1/PC-1“. Lille 2, 2006. http://www.theses.fr/2006LIL2S001.
Der volle Inhalt der QuelleObesity in an expected result of the obesogenic environment, defined by higher food intake and lower energy expenditure. Obesity is also a metabolic disorder that highly predisposes to type 2 diabetes (T2D) and cardiovascular diseases and its prevalence is constantly increasing in children. Genetic background contributes to individual's capacity of fat storage, insulin resistance and T2D. Here we describe genetic studies of ENPP1/ PC-1 and ACDC / adiponectin genes, both implicated in insulin associated metabolic pathways, and describe a rôle of their genetic variants in polygenic forms of obesity. A genome-wide scan study has described a childhood obesity susceptibility locus on chromosome 6q16-q23. The ENPP1/ PC-1 gene encoding an insulin receptor inhibitor was located in this interval. Analysis of ENPP1/ PC-1 in 6,147 subjects showed association between a three-allele risk haplotype QdelTG of SNPs K121Q, IVS20delT-11 and A>G+1044TGA and childhood obesity (OR=1. 69 ; p=0. 0006) and contribution of this haplotype to linkage with chidhood obesity on 6q. Haplotyoe QdelTG was also associated with morbid obesity (BMI ≥ 40) (OR=1. 50 ; p=0. 0006), moderate obesity (30 ≤ BMI < 40) (OR=1. 37 ; p=0. 02) and T2D (OR=1. 56 ; p=0. 00002). In children, this haplotype was associated with higher levels of circulating forms of ENPP1/ PC-1. Interestingly, long form of mRNA of ENPP1/ PC-1 that includes SNP A>G+1044TGA is specifically expressed in three tissues (pancreas, liver and adipose tissue) mainly involved in energy homeostasis. Our findings suggest that SNPs in ENPP1/ PC-1 gene may be a precursor to mediating insulin resistance and to the development of obesity and TD2. The second part of this study was dedicated to the candidate gene ACDC / adiponectin. Adiponectin is an adipokine with insulin sensitizing and anti-atherogenic properties. Several SNPs of the ACDC / adiponectin gene has been associated with insulin resistance and T2D. We describe the rôle of SNPs -11377C>g, -11391G>A, +45T>G and +276G>T of the ACDC locus in genetic susceptibility to severe forms of obesity like chidhood obesity and adults morbid obesity. Case/ controls analysis and familial association studies (TDT) showed that alleles -11,377C and +276T are associated with severe obesity in our populations individually and as a haplotype (0. 001 ≤p< 0. 10 ; 1. 19 ≤ OR ≤ 1. 24). Previously, the alternative alleles of these SNPs (-11,377G and +276G) were associated with higher risk of hypoadiponectinemia and T2D. In the general population, familial association (QTDT) of adiponectinemia showed evidence of association between the obesity risk haplotype and higher adiponectin levels (p=0. 03). Our findings suggest a rôle of adiponectin in weight gain. Several physiological and molecular results indicate that insulin sensitivity in adipose tissue is important for fat storage. Thus, ACDC / adiponectin SNPs predispose to severe forms of obesity and enhance insulin sensitivity which may in term, protect against insulin resistance and T2D. In summary, our studies reflect the complex rôle that insulin plays in energy homeostasis. Both insulin resistance and insulin sensitivity may favor weight gain depending on the target tissue of its action
Lacquemant, Corinne. „Étude génétique de l'insulino-résistance, du diabète et de leurs complications cardio-vasculaires“. Lille 1, 2000. https://pepite-depot.univ-lille.fr/LIBRE/Th_Num/2000/50376-2000-322-323.pdf.
Der volle Inhalt der QuellePar contre, l'incidence des maladies athérosclereuses prématurées a considérablement augmenté ces dernières années a l'île Maurice. Les facteurs de risque généralement associés à cette pathologie sont les anomalies du métabolisme du glucose, des lipides et des facteurs de la coagulation, l'hyperinsulinisme, l'obésité centrale et l'hypertension artérielle. Ce syndrome d'insulinorésistance à une forte composante héréditaire en raison de l'existence d'une forte prévalence de diabète et de maladie coronarienne. L'analyse familiale de liaison dans la population mauricienne nous a permis de détecter des régions liées aux différents facteurs de l'insulinorésistance. D'autres étapes seront nécessaires pour identifier et valider les gènes de prédisposition au développement de ces différentes pathologies
Barros, Monteiro Janice. „Déterminants génétiques de la résistance à l'insuline et du diabète sucré : exploration par SNP (single nucleotide polymorphism) de la calpai͏̈ne-10 et d'autres gènes candidats dans la population amazonienne du Brésil“. Montpellier 1, 2004. http://www.theses.fr/2004MON1T016.
Der volle Inhalt der QuelleBonnefond, Amélie. „Etude génétique du contrôle glycémique“. Phd thesis, Université du Droit et de la Santé - Lille II, 2010. http://tel.archives-ouvertes.fr/tel-00590624.
Der volle Inhalt der QuelleCarpentier, Rodolphe. „Partenaires d'interaction, gènes cibles et rôles potentiels du récepteur nucléaire orphelin Nurr1“. Lille 2, 2007. http://www.theses.fr/2007LIL2S026.
Der volle Inhalt der QuelleLamri, Amel. „Interaction entre variabilité génétique et consommation de lipides dans la survenue du diabète de type 2“. Paris 7, 2013. http://www.theses.fr/2013PA077012.
Der volle Inhalt der QuelleThe detection of the genes associated with type 2 diabetes risk is essential for a better comprehension of the etiology of the disease. To date, more than sixty loci have been associated with the onset of type 2 diabetes. Nevertheless, these loci explain only a small part of the heritability of the disease. The study of interactions between gene and nutrition could help to reveal new genes involved in the onset of type 2 diabetes. The objective of our work was to estimate the interaction between dietary fat intake and the genotype of polymorphisms of candidate genes on type 2 diabetes incidence in a large cohort drawn from the French general population (the D. E. S. I. R study). Given the data available for this cohort (DNA, nutritional habits, glyceamic status) the interactions genotype-fat intake were analyzed for polymorphisms of two groups of genes:Lipid sensor genes, encoding for proteins whose activity is regulated by fatty acidssuch as the nuclear receptors PPARa, y, and the G protein coupled receptor GPR120. Reverse cholesterol transport genes, such as ABCA1, CETP, hepatic and endothelial lipases (LIPC and LIPG) whose implication in the onset of type 2 diabetes needs to be clarified. Our results revealed different associations between polymorphisms of PPARA, PPARG, GPR120, ABCA1 and LIPC on the risk of type 2 diabetes. These effects were detected only when dietary fat intake was considered. These results highlight the importance of gene-environment interactions in the onset of complex diseases such as type 2 diabetes
Weil, Robert. „Distribution des anomalies fonctionnelles du récepteur à l'insuline érythrocytaire dans une famille de diabétiques non insulino-dépendants“. Montpellier 1, 1992. http://www.theses.fr/1992MON11045.
Der volle Inhalt der QuelleAït, El Mkadem Samira. „Déterminisme génétique de la résistance à l'insuline : identification de défauts moléculaires dans le syndrome des ovaires polykistiques, l'obésité et le diabète sucré“. Saint-Etienne, 2000. http://www.theses.fr/2000STET004T.
Der volle Inhalt der QuelleFajardy, Isabelle. „Facteurs de prédisposition au diabète insulino-dépendant : typage du codon HLA-DQB1 57“. Paris 5, 1990. http://www.theses.fr/1990PA05P206.
Der volle Inhalt der QuelleNowak, Maxime. „Rôle du facteur de transcription USF dans la régulation du gène de l'apolipoprotéine A5 par l'insuline et le glucose“. Lille 2, 2005. http://www.theses.fr/2005LIL2S009.
Der volle Inhalt der QuelleDyslipidemia such as hypertriglyceridemia and hypercholesterolemia are important risk factors for cardiovascular diseases and are often associated with metabolic pathologies like diabetes or obesity. The recently discovered apolipoprotein A5 (APOA5) is inversely correlated with plasmatic triglyceride levels. The aim of the study was to investigate the role of APOA5 in the glucido-lipidic metabolism by studying its regulation by insulin and glucose. We showed that insulin decreases APOA5 gene expression in hepatocytes. The plasma apoA-V level in humans and the apoa5 gene expression in mice are decreased after an induced-hyperinsulinemia. We showed that insulin-mediated down-regulation occurs through a phosphorylation / dephosphorylation mechanism and involves the phosphatidylinositol 3-kinase (PI3K) and P70S6 kinases pathway. Unlike insulin, glucose increases APOA5 gene expression in vitro in hepatocytes. This glucose-mediated induction involves a protein phosphatase 2A (PP2A)-dependent phosphorylation / dephosphorylation mechanism. However, we showed that apoA-V protein level in plasma from type 2 diabetic patients are decreased. Moreover, apoa5 gene expression is decreased in ZDF rats, a type 2 diabetes model. In vitro extensive studies allow us to demonstrate the involvement of the transcription factor USF in the APOA5 gene regulation. Indeed, the binding of USF to the promoter is needed to induce the APOA5 expression. The fixation of USF is decreased after a treatment with insulin and is increased after a treatment with glucose. This binding seems to be dependent of the USF phosphorylation state. The importance of these findings and the elucidation of the mechanism involved in this regulation allow, in fine, to in part explain the metabolic perturbations associated with diabetes
Daures, Mathilde. „Identification de gènes à contribution monogénique dans le diabète : Approches bio-informatiques“. Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC049.
Der volle Inhalt der QuelleDiabetes mellitus represents an heterogeneous group of metabolic disorders characterized by a dysfunction of glycaemia regulation. Common forms are type 1 (T1D) and type 2 diabetes. A large number of susceptibility loci associated with T1D have been identified by genetic studies, however those loci only explain a small part of the genetic contribution to T1D. Our hypothesis is that part of this missing heritability may be explained by genes with a monogenic effect. To identify these rare monogenic forms, my PhD project strategy is to study selected individuals (patients and familles enriched in monogenic forms), integrating whole exome sequencing and linkage analysis results together with available clinical data to identify the responsible genes and mutations. I developped a software to analyze human exome sequencing data. To facilitate the identification of mutations and genes causing monogenic diseases (or with a strong genetic effect) : filtering variants to identify the ones fitting the genetic model, recovering additional information on these variants from public and private databases, computing a prioritization score for each remaining variant and comparing variants between individuals or groups of individuals. This software is available as open-source code We used this software to analyze exome sequencing data from 211 selected diabetic patients. With this analysis we identified several causal mutations in genes already known as monogenic diabetes genes and in several new genes, that are currently at different stages of genetic and functional validation in our laboratory
Vigé, Alexandre. „Epigénomique nutritionnelle du syndrome métabolique“. Paris 5, 2007. http://www.theses.fr/2007PA05P602.
Der volle Inhalt der QuelleEpigenetic changes associated with DNA methylation and histone modifications leading to chromatin remodeling and regulation of gene expression underlie the developmental programming of obesity, type 2 diabetes, cardiovascular diseases and metabolic syndrome. This review focuses on converging data supporting the hypothesis that, in addition to "thrifty genotype" inheritance, individuals with obesity, type 2 diabetes, and metabolic syndrome (MetS) with an increased risk of cardiovascular diseases have suffered improper "epigenetic programming" during their fetal/postnatal development due to maternal inadequate nutrition and metabolic disturbances and also during their lifetime, that could even be transmitted to the next generation(s). We highlight the susceptibility of epigenetic mechanisms controlling gene expression to environmental influences due to their inherent malleability, emphasizing the participation of transposable elements and the potential role of imprinted genes during critical time windows in epigenetic programming, from the very beginning of development, throughout life. Increasing our understanding on epigenetic patterns significance and their role in development, evolution and adaptation and on small molecules (nutrients, drugs) that reverse epigenetic (in)activation should provide us with the means to "unlock" silenced (enhanced) genes, and to "convert" the obsolete human thrifty genotype into a "squandering" phenotype
Le, Collen Lauriane. „Médecine de précision du diabète de type 2 et des obésités génétiques“. Electronic Thesis or Diss., Université de Lille (2022-....), 2023. http://www.theses.fr/2023ULILS042.
Der volle Inhalt der QuelleThis scientific thesis delves deeply into critical health issues, specifically diabetes, obesity, and rare familial lipodystrophies. These health concerns hold immense importance due to their substantial medical and financial implications, impacting individuals, healthcare systems, and national economies. The central aim of this research was to harness the capabilities of next-generation sequencing (NGS), such as exome sequencing, to detect genetic mutations within genes already associated with these conditions in diagnostically challenging patients. It is now established that up to 2% of cases of type 2 diabetes can be attributed to pathogenic variants in genes related to Maturity-Onset Diabetes of the Young (MODY). This study sought to enhance the diagnostic process and optimize therapeutic management for these complex conditions while demonstrating the effectiveness of the sequencing approach in comprehensive disease management.In a first case, we showcased the significance of this approach by examining a patient with an atypical syndromic form of diabetes. Through in-depth genetic analysis using NGS, we identified a pathogenic heterozygous variant in the WFS1 gene inherited from the diabetic father. This discovery had a profound impact on the patient's treatment, highlighting the effectiveness of GLP1 analog therapy in optimizing diabetes management. Furthermore, our study investigated the impact of a de novo deletion in 16q24.2, which had the potential to affect the regulation of a neighboring gene, FOXC2, implicated in lymphedema-distichiasis syndrome. This case also raised questions about neurodevelopmental disorders, potentially linked to this deletion and a variant located in USP9X inherited from the patient's mother. These results underscore the critical importance of precise diagnosis in selecting appropriate treatments.In a second article, our research focused on the PDX1 gene, responsible for MODY 4, by analyzing heterozygous carriers of pathogenic variants. Our investigations revealed complete penetrance of diabetes, an increase in body mass index, and an elevated risk of pancreatic insufficiency in these individuals. Once again, the judicious use of GLP1 analogs proved beneficial in optimizing glycemic control.Next, we explored the case of a patient suffering from morbid obesity, presenting with combined pituitary deficiency and composite heterozygosity in POMC. This observation challenged the previous notion that heterozygosity in POMC could cause monogenic obesity. This reconsideration raises crucial questions about the effectiveness of targeted treatment with MC4R agonists in POMC heterozygotes, posing significant financial challenges for its use in this indication.Finally, we studied a large family with a severe metabolic syndrome associated with partial lipodystrophy. Genetic analysis revealed a variant in the ZMPSTE24 gene, previously identified in the same geographic region, raising the question of a founder variant. However, the contribution of this heterozygous variant to partial lipodystrophy remains to be confirmed, necessitating further studies to definitively establish its role.In conclusion, this thesis has highlighted the remarkable efficacy of next-generation sequencing in elucidating complex cases of atypical diabetes and obesity, shedding light on monogenic forms of these conditions. Moreover, this research expanded its investigations to the broader population through comprehensive literature reviews and analysis of various databases, including the Human Gene Mutation Database, RaDIO, and UK Biobank. We hope that these compelling results will encourage wider adoption of genetic sequencing, paving the way for increased customization of treatments based on patients' genotypes in the near future
Macari, Françoise. „Déterminisme génétique de la résistance à l'insuline : identification de défauts moléculaires dans les syndromes de type A, d'Alström et des ovaires polykystiques“. Montpellier 1, 1999. http://www.theses.fr/1999MON13505.
Der volle Inhalt der QuelleLagouge, Marie. „Identification of cofactor network, including SIRT1 and SRC-3, which converges on energy expenditure through PGC-1α“. Université Louis Pasteur (Strasbourg) (1971-2008), 2008. https://publication-theses.unistra.fr/restreint/theses_doctorat/2008/LAGOUGE_Marie_2008.pdf.
Der volle Inhalt der QuelleOrganisms respond to variations in hormonal, metabolic, and nutritional signaling by altering the expression of their genetic information, allowing metabolic adaptation. Transcriptional control is achieved through an interwoven and redundant molecular circuitry that involves individual transcription factors, the basal transcriptional machinery, and multiprotein coregulator complexes, which fine-tune metabolic homeostasis. Most of the coregulators interact directly with transcription factors and can either repress or enhance their transcriptional activities. Aberrant signaling by coregulators is known to generate abnormalities of cellular metabolism, and hence can contribute to abnormalities of systemic metabolic pathways and to the pathogenesis of several common disorders, such as obesity and type 2 diabetes. We first demonstrated that an in vivo pharmacological activation of SIRT1, a member of the evolutionary conserved family of NAD-dependant deacetylases named sirtuins, protects the mice against the development of obesity and linked pathophysiologies, through an increased energy expenditure. At the molecular level, the in vivo effects of the sirtuinactivating compounds were associated with an induction of the expression of genes involved in mitochondrial biogenesis, oxidative phosphorylation and fatty acid oxidation in metabolic tissues such as the skeletal muscle and the brown adipose tissue and were explained by a the SIRT1-mediated deacetylation, and subsequent activation, of PGC-1α, a master regulator of mitochondrial function. In parallel, through a genetical approach, we demonstrated that not only deacetylases but also acetyltransferases impact in a major fashion on energy homeostasis. In fact, we have shown that, through promoting the expression the PGC-1α acetyltransferase GCN5, SRC-3 facilitates PGC-1α acetylation in muscle and brown adipose tissue and consequently inhibits PGC-1α activity. Interestingly, the expression levels of SIRT1, the major PGC-1α deacetylase, mirror those of SRC-3 and GCN5 in various physiological situations such as fasting and high fat feeding. This results in a convergent regulation of PGC-1α acetylation by both acetyltransferases and deacetylases and lead us to consider theses enzymes as members of coregulator network that informs PGC-1α about the cellular energy status, which then adapts cellular energy production through its commanding role of master regulator of mitochondrial function. It is therefore tempting to speculate that this converging cofactor network, including SRC-3, GCN5 and SIRT1 can be exploited to design new preventive and therapeutic strategies to combat obesity and associated metabolic disorders such as type 2 diabetes
Joannes, Marie-Odile. „Recherche de polymorphysmes génétiques associés à des complications majeures de pathologies prédominantes en Martinique et en Guadeloupe : la drépanocytose et le diabète“. Antilles-Guyane, 2009. http://www.theses.fr/2009AGUY0269.
Der volle Inhalt der QuelleSICKLE CELL DISEASE (SCD) AND DIABETES MELLlTUS ARE LEADING CAUSES OF MORBIDITY IN MARTINIQUE AND GUADElOUPE. BECAUSE OF THE ASSOCIATION OF SOME GENETIC POLYMORPHISMS AND PATHOlOGIES, WE WONDERED IF SOME GENETIC POLYMORPHISMS COULD PREDICT COMPLICATIONS IN SICKLE CELL PATIENTS AND TYPE 2 DIABETIC WE INVESTIGATED POLYMORPHISM OF GENES INVOLVED IN THE IMMUNE SYSTEM (MYELOPEROXYDASE, HLA, TNF ALPHA, IFN GAMMA, IL6 AND IL10) AS MODULATORS OF INFECTIOUS COMPLICATIONS IN SCD. WE ALSO TRIED TO FIND AN ASSOCIATION BETWEEN FABP2 POLYMORPHISM, METABOLIC SYNDROME AND CARDIOVASCULAR COMPLICATIONS IN T2D SUBJECTS. OUR RESULTS REVEALED AN ASSOCIATION BETWEEN MYELOPEROXIDASE POLYMORPHISM AND INFECTIOUS COMPLICATIONS IN SICKLE CELL PATIENTS JUST AS IFNr POLYMORPHISM. ON THE OTHER HAND, HLA-DRB1*11 COULD HAVE A PROTECTIVE EFFECT AGAINST INFECTIONS. MOREOVER, OUR RESULTS HIGHLIGHTED A PREDOMINANT COMBINATION OF DYSLlPIDEMIA AND OBESITY IN T2D PATIENTS CARRYING THE THREONINE VARIANT OF FABP2
Courivaud, Cécile. „Influence de variants génétiques de l'immunité innée sur la survenue de complications inflammatoires chroniques après transplantation rénale“. Besançon, 2010. http://www.theses.fr/2010BESA0011.
Der volle Inhalt der QuelleAtherosclerosis, new-onset diabetes after transplantation (NODAT), cancer and chronic graft dysfunction are serious long term complications of kidney transplantation. It is now well established that all these complications are chronic inflammatory diseases with an important impact on patient's morbidity and mortality. The innate immune system is implied in all these complications. We studied the influence of 4 genes polymorphisms, all involved in inflammatory process : IL-6, Cyclooxygénase-2 (COX-2), CX3CR1 (CX3CL1 or Fractalkine receptor) and NOD2. We showed that IL-6 gene promoteur polymorphism is associated with NODAT. COX-2 gene promoter polymorphism is associated with chronic graft dysfuntion and CX3CR1 gene polymorphisms are associated with cancer. Finally, we showed that genetics variants of innate immunity contribute to inflammatory response and play a role in long term complications of kidney transplantation
Cao, Huibi. „La paraoxonase associée aux HDL : polymorphisme génétique et impact sur l'inhibition de la péroxydation des lipoprotéines“. Lyon 1, 1999. http://www.theses.fr/1999LYO1T281.
Der volle Inhalt der QuelleDentin, Renaud. „Rôle du facteur de transcription ChREBP dans la régulation transcriptionnelle par le glucose des gènes de la glycolyse et de la lipogenèse dans le foie : implication dans la physiopathologie de l'obésité et/ ou du diabète de type 2“. Paris 7, 2006. http://www.theses.fr/2006PA077093.
Der volle Inhalt der QuelleIn the liver, the regulation of glycolytic and lipogenic gènes like L-pyruvate kinase (L-PK), acetyl-CoA carboxilase (ACC) and fatty acid synthase (FAS), which catalyze fatty acid synthesis from glucose, requires both high glucose and insulin concentration. Recently, the transcription factor ChREBP (Carbohydrate Responsive Element Binding Protein) has emergea has a major mediator of glucose action on L-PK gene expression. However, in the beginning of this work, its role in the regulation of lipogenic gene was unknown. In this context, we clearly show that decreased ChREBP gene expression, achieved using small interfering RNA, results in a loss of glucose effect on endogenous L-PK, FAS, and ACC gene expression, thereby demonstrating the direct implication of ChREBP in glucose action in liver. The present study also reveals that ChREBP gene expression as well as ChREBP nuclear protein content are significantly increased in liver of ob/ob mice, and that liver-specific inhibition of ChREBP in ob/ob mice markedly improved hepatic steatosis by decreasing lipogenic rates. As consequence, overall glucose tolerance and insulin sensitivity were restored in ob/ob mice. Taken together, our results demonstrate that ChREBP is central for the regulation of lipogenesis in vivo and plays a determinant role in the development of the hepatic steatosis and of insulin resistance in ob/ob mice. Finally, we demonstrate that polyunsaturated fatty acid, by preventing ChREBP gene expression and ChREBP nuclear translocation, decrease glycolytic and lipogenic gene expression and could prevent the development of the hepatic steatosis observed in the pathology of obesity and insulin resistance
Bour, Sandy. „Rôle des amines oxydases du tissu adipeux : implications dans le diabète et l'obésité“. Toulouse 3, 2006. http://www.theses.fr/2006TOU30172.
Der volle Inhalt der QuelleSemicarbazide-sensitive amine oxidase (SSAO) and monoamine oxidase (MAO) are expressed in adipocytes and their expression is increased during adipogenesis in man. We wanted to explore their implication in diabetes and obesity in vivo. Acute or chronic benzylamine administration improves glucose tolerance in rodents. MAO and SSAO inhibition reduces adiposity in rats ; semicarbazide alone displaying the same effect in mice in opposition to BTT 2052, a new SSAO inhibitor. Furthermore, phenotype of mice invalidated for SSAO was analysed. They exhibit increased weight, adiposity and LDL-cholesterol. Finally, SSAO invalidation reduces lymphocytes and macrophages amount in adipose tissue. Since amine oxidases substrates exert insulin-like effects, they could be antidiabetic agents and or control adipose tissue physiology
Nicolas, Anthony. „Polymorphismes du gène de la t-cadhérine (CDH13), récepteur de l'adiponectine, dans les diabètes et leurs complications“. Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066232/document.
Der volle Inhalt der QuelleT-cadherin is a receptor of adiponectin, a protein involved in the pathophysiology of diabetes. In genome-wide association studies, T-cadherin gene (CDH13) polymorphisms are associated with adiponectin concentrations. The aim of our study was to deepen the relationship between polymorphisms of CDH13, plasma adiponectin, and the risk of diabetes and its complications. We selected two polymorphisms in CDH13. Genotyping was performed in D.E.S.I.R., cohort drawn from the French general population, DIABHYCAR (subjects with type 2 diabetes) and three cohorts of patients with type 1 diabetes, GENESIS, GENEDIAB and SURGENE. In the general population, CDH13 polymorphisms were associated with body mass index, HbA1c, Fatty Liver Index, an index of hepatic steatosis, and plasma adiponectin. In a case-control study between D.E.S.I.R. and DIABHYCAR, polymorphisms were associated with the risk of type 2 diabetes. These associations with clinical phenotypes could be due to the beneficial effects of adiponectin. In subjects with type 1 diabetes from GENESIS and GENEDIAB, we observed associations between polymorphisms of CDH13 and the prevalence and the incidence of kidney disease. The analysis in the SURGENE prospective study confirmed these associations. The direction of the relationships observed in this study is in favor of a deleterious role of adiponectin in diabetic nephropathy. In conclusion, these associations may be explained by variations in adiponectin and suggest a causal relationship
Saulnier, Pierre-Jean. „Étude des déterminants génétiques et environnementaux des complications du diabète de type 2“. Thesis, Poitiers, 2012. http://www.theses.fr/2012POIT1403/document.
Der volle Inhalt der QuelleType 2 diabetes (T2D) is a public health issue because of vascular and renal complications, which are complex diseases with interaction between genetic and environmental determinants.The objective of this work was to study these determinants in three independent populations of T2D patients by coupling cross-sectional (DIAB2NEPHROGENE) and longitudinal studies (SURDIAGENE and DIABHYCAR). Through a candidate-gene approach, we first focused on the natriuretic peptides system, NPR3 gene and sodium intake and then on the metabolic pathway of sex hormones, CYP19A1 gene (coding for aromatase) and sex steroid levels.Our first results showed that NPR3 rs2270915 G Allele was associated with high blood pressure (BP) and a reduced salt-sensitivity of BP. However, this SNP was not associated with any significant risk of cardio-vascular events (CVE) or death, at variance with rs6889608. Ultimately, CVE-free survival was impacted by salt intake with a reduced risk of morbi-mortality in those patients having the greatest intake, though a higher BP.In our second study, we confirmed that male gender was a risk factor for diabetic nephropathy (DN), but also for the occurrence of CVE. In men, we showed higher levels of estradiol (E2) associated with a higher prevalence of ND but without any significant increase in renal or CVE during follow-up. CYP19A1 variants were not associated with either E2 levels or the prevalence of ND. However, 2 SNPs tested, were significantly associated with the occurrence of end stage renal failure. Altogether, we have identified 2 different metabolic ways contributing to the genetic determinants of complications associated with T2D including a gene-environment interaction
Fournis, Véronique. „Polymorphisme de l'apoliprotéine A-IV humaine (codons 347 et 360) : moyens d'analyse génotypique ; fréquence et relations avec les paramètres du bilan lipidique chez le sujet diabétique“. Bordeaux 2, 1997. http://www.theses.fr/1997BOR2P073.
Der volle Inhalt der QuelleGeise, Mandy. „Localizing the Genetic : making sense of diabetes through research, care and public health in Mexico“. Thesis, Paris, EHESS, 2020. http://www.theses.fr/2020EHES0081.
Der volle Inhalt der QuelleThe gene is embedded in various domains of knowledge and practices in which doctors, scientists and public health experts make sense of diabetes, genetic disease, health and heredity in Mexico. Medical genetics in the (specialized pediatric) clinic, which deals with mostly single-gene disorders, congenital metabolic disorders and chromosomal abnormalities, takes up a marginalized/small place in health care policy or investments. The growing presence of diabetes as a pubic health problem has led to campaigns instructing people to eat better and exercise more. But it has also been at the heart of genomics research interested in the particular genomic makeup of Mexicans — made unique by ancestral contributions to a mestizo genome — and its relations/as an explanation for heightened predisposition to diabetes and other common chronic disorders. Recent work has proposed ways to explain the growing presence of diabetes in Mexico through a biosocial approach that considers the role of the (social) environment in the onset of disease. Epigenetics, in studying how environmental factors can influence gene expression, brings in new ways to think about genes and the articulation of these in relation to illness and heredity. As scientists combine biological data with inquiries into the social circumstances in the communities they study, epigenetics actively brings the environment in and gives scientists tools to think about how the environment becomes embodied. These studies provide room for biomedical and social scientists to (re)think how body and environment act together, opening the door to new ways to conceptualize genetic predisposition and disease
Snoussi, Chahira. „Effet du thé en décoction et ses dérivés polyphénoliques sur l'absorption intestinale des carbohydrates et des lipides“. Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC007.
Der volle Inhalt der QuelleTea containing polyphenols has been reported to exert anti-diabetic and anti-obesity effects but the impact of chronic consumption of tea decoction was poorly reported. The aim of this study was to explore in rat fed normal or high-fat diet, the effects of green tea decoction (GTD) or black tea decoction (BTD) on intestinal glucose and lipids absorption. We demonstrate that tea leaves cooked in water for only 15 min contain higher amounts of polyphenols compounds. The acute or chronic oral administration of GTD reduced intestinal SGLT1 :GLUT2 ratio. Consumption of GTD and BTD reduce intestinal absorption of lipids in rats fed high fat diet by enhancing their fecal excretion with a more pronounced effect of BTD. In conclusion, the tradional cooking of tea in Tunisia containing higher amounts of polyphenols compounds, a natural alternative in the prevention of obesity and diabetes
Acosta, Montalvo Ana. „The Role of Hepatocyte-Nuclear-Factor-1-A (HNF1A) in the Regulation of Glucose Homeostasis and Pancreatic Hormone Secretion“. Electronic Thesis or Diss., Université de Lille (2022-....), 2022. http://www.theses.fr/2022ULILS043.
Der volle Inhalt der QuelleHepatocyte-nuclear-factor-1-alpha (HNF1A) is a key transcription factor that regulates the expression of numerous genes involved in several metabolic processes such as in the liver, intestine, kidney, and pancreas. Heterozygous mutations in the HNF1A gene causes the most frequent form of monogenic diabetes called Maturity-onset-diabetes-of-the-young (MODY), commonly referred to as HNF1A-MODY. HNF1A-MODY mutation carriers develop mild-hyperglycemia in childhood and diabetes later in life due to a progressive loss of beta cell function. However, since HNF1A is not only expressed in pancreatic beta cells, but also in alpha and delta cells, this thesis project was carried out to study the effect of HNF1A deficiency on intra-islet paracrine secretion, accompanied by alterations in genes encoding proteins that control glucose uptake and metabolism. To do so, I used cellular and mouse models of HNF1A-MODYdiabetes.The first cellular model I used was the beta-cell-derived rat insulinoma INS-1 cell line to conditionally overexpress the frameshift P291fsinsC mutation in the HNF1A gene(HNF1A-P291fsinsC), using a reverse tetracycline-dependent transactivator system. The expression of the P291fsinsC mutant protein was maximally induced to a significant level over that of endogenous Hnf1a by treating the cells with 500 ng/ml of doxycycline for (2 to 72 hrs). Non-induced INS-1 cells served as a control. Since INS-1 cells were previously reported to be bi-hormonal and did not express alpha cellmarkers, I utilized this model to study the effect of the HNF1A-P291fsinsC mutation on insulin and glucagon gene and protein expression and secretion. Cytometric and immunofluorescence analysis revealed that INS-1 cells comprised mostly of insulinpositivecells, whereas only a few cells co-expressed insulin and glucagon. However,both mature and immature beta cells secreted insulin and glucagon in response to glucose stimulation. Moreover, the overexpression of the HNF1A-P291fsinsC mutant protein increased proglucagon-derived peptide expression and glucagon secretion inresponse to high-glucose stimulation compared to non-induced INS-1 cells. These findings suggest that Hnf1A is essential to maintain beta cell maturation and function.Although INS-1 cells are a valuable tool to study beta-cell function, they do not resemble human islet cells in terms of paracrine signaling. Therefore, I developed an in vitro model by transfecting human islets with siRNAs targeting HNF1A (siHNF1A). I used islets deficient in HNF1A to investigate its effects on glucose transport and hormone secretion, simultaneously from the same donor islet preparations. siHNF1A transfections significantly decreased HNF1A protein levels compared to scrambled controls, observed by Western Blot analysis. siHNF1A also reduced insulin protein expression and secretion in response to high-glucose stimulation. This coincided with reduction in SGLT2 protein levels, with no changes in SGLT1, but a slight decrease inGLUT2. The decrease in SGLT2 was also associated with a significant increase inglucagon protein expression and secretion. These findings highlighted that HNF1A is also a key regulator of alpha cell function.Two HNF1A-MODY mouse models have previously been developed to study the pathogenesis of HNF1A-MODY in vivo. The first was a global Hnf1a-/- knock-out (KO) mouse and the second was a transgenic mouse that overexpresses the dominant-negative human mutant protein specifically in pancreatic beta cells, under the rat insulin promoter [...]
Mészáros, Gergő. „CaMK1D controls β-cell mass and glucose homeostasis“. Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ035.
Der volle Inhalt der QuelleType 2 diabetes mellitus (T2DM) is characterized by hyperglycemia resulting from defects in insulin secretion in combination with impaired insulin action. CaMK1D represents one potential candidate gene, the in vivo function remained elusive. In this work, I have found that CaMK1D plays a central role in blood glucose regulation. Pancreas-specific CaMK1D knockout mice display dramatically reduced fasting blood glucose levels leading to an overall improved glucose tolerance. CaMK1D knockout mice show markedly higher ad libitum and fasting insulin levels. Interestingly, pancreas-specific CaMK1D knockout mice display islet hyperplasia caused by beta-cell hypertrophy. Furthermore, conditional knockout mice are protected against high-fat feeding-induced hepatic steatosis. Overall, my work establishes an essential role of CaMK1D in pancreatic beta-cells and provides further understanding about its role in the development of T2DM
Abdelkarim, Mouaadh. „Rôle du récepteur nucléaire Farnesoid X : receptor (FXR) dans la différenciation et la fonction adipocytaire“. Lille 2, 2010. http://www.theses.fr/2010LIL2S005.
Der volle Inhalt der QuelleChèvre, Jean-Claude. „Etude des déterminants génétiques du diabète de type MODY“. Paris 6, 2000. http://www.theses.fr/2000PA066594.
Der volle Inhalt der QuelleGouty-Dufayet, de La Tour Dominique. „Na,K-ATPase et diabète : facteurs génétiques et environnementaux“. Aix-Marseille 2, 1998. http://theses.univ-amu.fr.lama.univ-amu.fr/1998AIX2666U.pdf.
Der volle Inhalt der QuelleSanyoura, May. „Contributions monogéniques dans le diabète insulino-dépendant au Liban“. Paris 7, 2013. http://www.theses.fr/2013PA077112.
Der volle Inhalt der QuelleDiabetes mellitus represents a heterogeneous group of metabolic disorders characterized by sustained high blood glucose concentrations. Disease etiology is still poorly understood but involves both genetic and environmental factors. The main aim of this thesis was to identify and study genes responsible for monogenic forms of juvenile-onset insulin-dependent diabetes (JOD) in the Lebanese population. Due to the high rate of consanguinity and intra-population endogamy, the Lebanese population is particularly well suited to address the question of the responsibility of monogenic contribution to JOD. Using a family-based genetic study, we identified evidence of linkage near the WFS1 gene, responsible for Wolfram syndrome. We identified one frameshift mutation, the WFS1LIB mutation, which was associated with a delayed onset of optic atrophy (OA). The delayed onset of OA in WFS1LIB homozygous patients was family dependent and suggested the role of a modifier variant. Our results suggest that one common variant located in the 5' regulatory region of the WFS1 gene is associated with delayed onset of OA and decreased expression of WFSL After excluding ail genetically explained families, we identified evidence of linkage on chromosome 11. We selected the most plausible candidate gene and identified 3 mutations. We then used a siRNA-mediated knockdown approach in dispersed islets, INS-1E, and purified bêta cells and showed that gene deficiency resulted in increased cell death and decreased insulin expression. The last study concerns the genetic investigation of a diabetic Lebanese patient initially diagnosed as Wolfram Syndrome. Using linkage study and sequencing, we selected ALMS1, responsible for Alström Syndrome, in which we identified a novel splice mutation. In conclusion, monogenic forms of diabetes are likely to represent a significant subset of JOD cases, generally diagnosed as T1D, particularly in highly consanguineous populations such as Lebanon
Marquez, Marcel. „Optimisation de la technique de BRET : étude de l’association des variants d’HMGA1 avec le diabète de type 2“. Thesis, Lille 2, 2011. http://www.theses.fr/2011LIL2S035.
Der volle Inhalt der QuelleThe BRET technique is based on resonance energy transfer has been described by Förster and is based on a luminescentdonor enzyme and a complementary acceptor fluorophore upon oxidation of a donor enzyme substrate. Unlike many techniquesfor the study of protein-protein interactions, the BRET is non-invasive and allows the dynamic study of interaction between twoproteins in living cells and the screening of molecules modulating this interaction.In our study, we sought to optimize the BRET technique for screening assay by selecting the best pair of donor / acceptor.Rluc8, a new donor, with superior light capabilities than Rluc, was tested in combination with two new acceptors, YPET, avariant of YFP optimized for energy transfer, and RGFP, a fluorophore from Renilla reniformis which is involved in theBREAT signal when in contact with Rluc. These new donors / acceptors were compared to the original Rluc / YFP combination,usually used in BRET1, in fusion proteins and in follow-up studies of protein-protein interactions involving GPCRs and βARR2in order to assess their capacity to improve the BRET technique. We were able to show that Rluc8, YPET and RGFP increasedthe sensitivity of the original BRET1 method by increasing at least 2-fold of the BRET signal. These results demonstrate theinterest of these new donors / acceptors in BRET technique and may help improving current follow-up studies of protein-proteininteractions
Gutierrez-Aguilar, Ruth. „Etudes génétiques des gènes de la famille KLF : analyse fonctionnelle d'un variant du promoteur de KLF11“. Lille 2, 2007. http://www.theses.fr/2007LIL2S019.
Der volle Inhalt der QuelleBouzekri, Nourdine. „Etude de polymorphismes génomiques chez l'homme ; application de leur étude à la génétique de populations et à la génétique du diabète insulino-dépendant“. Toulouse 3, 1997. http://www.theses.fr/1997TOU30157.
Der volle Inhalt der QuelleVambergue, Libbrecht Anne. „Anomalies de la tolérance au glucose au cours de la grossesse : du phénotype au génotype : expression de gènes placentaires associée à la macrosomie“. Lille 2, 2004. http://www.theses.fr/2004LIL2S003.
Der volle Inhalt der QuelleGestational diabetes mellitus (GDM) is defined as glucose tolerance abnormalities during pregnancy. This pathology is characterized by a clinical heterogenecity with minors forms as mild gestational hyperglycaemia (MGH). In the two cases, the materno-foetal complication is most often a macrosomia. The clinical and metabolic data (insulin resistance and or abnormalities of insulin secretion) are in favour of a continuum. In addition, it appears that glycemic control is not the only factor allowing the control of macrosomia. This lets think that genetic components can play a part in the determinism of macrosomia. We initially were interested in GDM and MGH to the type 1 diabetes markers (IDDM1,IDDM2, IDDM12) and type 2 diabetes (Glucokinase HNF1α). The results are not in favour of an autoimmune diabetes but showed that there are differences in the in the allelic distribution primarily in the group MGH. Among the markers associated to the type 2 diabetes, we identified any polymorphism associated to a significant degree with these clinical entities. In a second time, we were interested in the locus of the insulin gene (IDDM2) like to close genes (IGF-II and H19) rather implied in the fœtal growth. These genes are under parental imprinting, so we had evoked the hypothesis of a loss of imprinting associated to fœtal macrosomia, non verified hypothesis in 11 informative families. This result does not exclude the imlplication from this area in the fœtal growth. At last, we analysed in a more total way the placental transcriptome in relation to macrosomia by microarrays (2200 genes). We highlighted a variation of some genes expression in relation to fœtal macrosomia. These preliminary results will be validated by others techniques such as quantitative RT-PCR and proteins analyses by Western blot
Blanchet, Emilie. „Rôle de E2F1 dans la sécrétion d'insuline, le métabolisme oxydatif, la néoglucogenèse et la lipogenèse. Implication dans le diabète, la dystrophie musculaire et le cancer“. Thesis, Montpellier 1, 2011. http://www.theses.fr/2011MON13506.
Der volle Inhalt der QuelleE2F1, a crucial regulator of metabolism in normal and cancer cells. Abstract: E2F1 is a key transcription factor involved in the control of the cell cycle. We and others have previously demonstrated a a major role for E2F1 in the control of glucose and lipid homeostasis. In this thesis, we showed bu using E2F1 null mice, that E2F1 plays a major role in the control of insulin secretion, oxidative metabolism, lipogenesis and gluconeogenesis. E2F1 controls insulin secretion through the modulation of Kir6.2 expression. Moreover, we demonstrated that E2F1 controls the expression of oxidative genes in BAT and muscle. In addition, we observed that E2F1 is involved in the control of lipogenesis and gluconeogenesis in the liver. E2F1regulates the expression of key lipogenic genes, such as Fas, and G6Pase, a gene involved in hepatic glucose production, through cooperation with foxo-1. Finally, we observed that the inhibition of gluconeogenesis upon E2f1 genetic ablation impaired the formation of lung metastases. These different results show that E2F1 is a key regulator of metabolism, and that modulating its activity could have High outcomes on diseases such as diabetes, obesity, muscular distrophies or cancers.Key words: E2F1, insulin secretion, oxidative metabolism, lipogenesis, gluocneogenesis, cancer
Lecompte, Sophie. „Etude du rôle du gène PROX1 dans le diabète de type 2“. Phd thesis, Université du Droit et de la Santé - Lille II, 2012. http://tel.archives-ouvertes.fr/tel-00790524.
Der volle Inhalt der QuelleCésari, Maya. „Les marqueurs génétiques associés au diabète insulino-dépendant dans la population réunionnaise : typage des gènes TAP et quantification des ARNm HLA DQ“. La Réunion, 1999. http://elgebar.univ-reunion.fr/login?url=http://thesesenligne.univ.run/99_09_Maya.pdf.
Der volle Inhalt der QuelleGonzales, Cristina. „Etude des déterminants génétiques de la vulnérabilité des cellules β pancréatiques de la souris non obese diabetic (NOD) : étude du rôle de la poly (ADP-ribose) polymérase-1 (PARP-1) dans le diabète et génétique moléculaire du diabète induit par la streptozotocine“. Paris 5, 2003. http://www.theses.fr/2003PA05N063.
Der volle Inhalt der QuelleThe Non Obese Diacitic (NOD) mouse develops a spontaneous auto-immune diabetes similar to human type 1 diabetes. Whereas a lot of studies analysed the dysregulation of the immune system of the NOD mouse, our purpose was to identify the genetic factors involved in the intrinsic vulnerability of the pancreactic beta cells to the immune destructive process, by using two complementary strategies. First, we studied the role of poly(ADP-ribose) polymerase-1 (PARP-1), an ADN repair enzyme whose activation is paradoxically deleterious for pancreatic beta cells, in NOD diabetes. Secondly, we attempted to localise the genetic loci involved in the extreme sensitivity of the NOD strain to streptozotocin-induced toxic diabetes
Taverna, Mariano Javier. „Rétinopathie diabétique humaine : aspects génétiques et physiopathologiques“. Paris 6, 2005. http://www.theses.fr/2005PA066113.
Der volle Inhalt der QuelleRouxel, Ophélie. „Rôles des cellules MAIT (Mucosal Associated Invariant T) dans la physiopathologie du diabète de type 1“. Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB114.
Der volle Inhalt der QuelleType 1 diabetes (T1D) is an auto-immune disease characterized by the selective destruction of pancreatic islet β cells resulting in hyperglycemia and requiring a life-long insulin replacement therapy. The physiopathology of T1D is complex and still not entirely understood. Both innate and adaptive immune cells are involved in the pathogenesis and the regulation of T1D. While diabetes development can clearly be associated with genetic inheritance, environmental factors were also implicated in this autoimmune diseases. Recent studies have highlighted the role of the intestinal microbiota in the development or protection against T1D. Gut microbiota analyses in patients have shown differences before the onset of T1D. Moreover, several studies also described gut mucosa alterations in NOD mice and in T1D patients. MAIT (Mucosal Associated Invariant T) cells are innate-like T cells recognizing the MR1 molecule and expressing a semi-invariant receptor Vα chain (Vα7.2-Jα33 and Vα19-Jα33 in mice). MAIT cells are activated by bacterial metabolites, derived from the synthesis of riboflavin. Their particularity is to rapidly produce various cytokines such as TNF-α IFN-γ, IL-17 and granzyme B. The localization and the function of MAIT cells suggest that they could exert a key role in the maintenance of gut integrity, thereby controlling the development of autoimmune responses against pancreatic β cells. To summarize, our results in T1D patients and in NOD mice indicate an abnormal MAIT cell activation in this pathology, which occurs before disease onset. The analysis of peripheral tissues from NOD mice highlights the role of MAIT cells in two tissues, the pancreas and the gut mucosa. In the pancreas, MAIT cells frequency is elevated and they could participate to the β cells death. In contrast to the pancreas, in the gut mucosa MAIT cells could play a protective role through their cytokines production of IL-22 and IL-17. Our data in Mr1-/- NOD mice, lacking MAIT cells, reveal that these cells play a protective role against diabetes development and in the maintenance of gut mucosa integrity. Moreover, the presence of gut alteration as T1D progress in NOD mice underscores the importance of MAIT cells in maintaining gut mucosa homeostasis. Interestingly, MAIT cells could represent a new biomarker towards T1D progression and open new avenues for innovative therapeutic strategies based on their local triggering
Caillier, Bertrand. „Effets modulateurs du diabète, de l'obésité et de la génétique sur l'électrophysiologie des médicaments prolongeant l'intervalle QT“. Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/28614/28614.pdf.
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