Dokument: Identification and functional investigation of novel disease genes of a susceptibility locus for type 2 diabetes mellitus

Titel:	Identification and functional investigation of novel disease genes of a susceptibility locus for type 2 diabetes mellitus
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=63835
URN (NBN):	urn:nbn:de:hbz:061-20231009-111342-9
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Görigk, Sarah Annemarie [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 4,69 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 06.10.2023 / geändert 06.10.2023
Beitragende:	Prof. Dr. Hadi Al Hasani [Gutachter] Prof. Dr. Prömel, Simone [Gutachter]
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 540 Chemie
Beschreibung:	The development of type 2 diabetes mellitus (T2D) due to genetic predisposition is a complex field in metabolic research. In the past, genome-wide linkage analyses of mouse inbred strains have identified almost 200 quantitative trait loci (QTL) for diabetes-related traits. However, identification of the causal gene variants remains challenging and many of them account for only a small percentage of the total heritability. To enhance the efficiency of gene discovery, a collective diabetes cross project was initiated which combined different crossbreeding approaches of inbred mouse strains that vary in their T2D susceptibilities. Among other loci, a novel QTL was previously identified on chromosome 4 (Nbg4; NZO blood glucose on chromosome 4) within a backcross of obese and T2D-prone New Zealand Obese (NZO) and lean, diabetes-resistant 129P2/OlaHsd (Ola) mice. Initial investigations revealed major linkage of this locus with blood glucose levels (LOD 7.1) where heterozygous NZO/Ola-allele carriers displayed strikingly elevated blood glucose levels compared to NZO/NZO-allele carriers. The aim of the present study was to investigate the metabolic features of the Nbg4 locus to filter for causal gene variants. Phenotypical characterization of congenic mice confirmed the diabetogenic effect in mice carrying the proximal region of Nbg4 (Nbg4p; 40-77 Mb), thereby reducing the critical fragment to a size of 37 Mb. As expected, homozygous Ola-allele carriers of Nbg4p (Nbg4pO/O) showed a strikingly elevated diabetes prevalence, presumably due to reduced whole-body glucose tolerance. Moreover, investigations of the adipose tissue revealed an early-onset insulin resistance phenotype in Nbg4pO/O mice, which was characterized by significantly reduced fat tissue-specific glucose uptake and endogenous GLUT4 protein abundance. Furthermore, Nbg4pO/O mice displayed an increase in hepatic glucose production, indicating that Nbg4p regulates insulin sensitivity in both, adipose tissue and the liver. Finally, a combination of haplotype and gene expression analyses was used to select potential candidate genes that may contribute to the diabetogenic effects of Nbg4p. As a second aim of this study, novel candidate genes, which were identified within two independent approaches of the collective diabetes cross project, were investigated for their potential impact on T2D development. With this, a potential causal relationship of the gene Alad with Nbg4p was confirmed by its impact on glucose uptake in adipocytes. Moreover, a potential contribution of the gene Nudt19 on Nbg7, another blood glucose QTL, was confirmed in cultured liver cells by its regulation of the hepatic lipid metabolism. Future studies will focus on the detailed mechanisms by which these genes contribute to hyperglycemia and the development of T2D.
Lizenz:	Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät
Dokument erstellt am:	09.10.2023
Dateien geändert am:	09.10.2023
Promotionsantrag am:	10.07.2023
Datum der Promotion:	28.09.2023