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Harten, A. ; Schmidtke, M. ; Giesert, F. ; Skerrett-Byrne, D.A. ; Teperino, R. ; Przemeck, G.K.H. ; Hrabě de Angelis, M.

MODY PDX1P33T: A mouse model reveals phenotypic divergence from human disease.

Front. Endocrin. 16:1680893 (2025)
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INTRODUCTION: Maturity-onset Diabetes of the Young (MODY) is a rare form of diabetes and arises from mutations in key regulatory genes of the pancreatic beta cell, leading to their functional impairment and early-onset diabetes. Research into PDX1-MODY, a form of MODY caused by mutations in the PDX1 gene, enhances understanding of gene-specific mechanisms underlying glucose dysregulation and provides insights into possible approaches to restore normal metabolic function. However, no currently published mouse model accurately depicts the genetic cause of PDX1-MODY in human patients. METHODS: Using CRISPR-Cas9 technology, we generated the first mouse model carrying one of the most prevalent pathological PDX1 point mutation found in human patients, P33T, and conducted an 18-week in vivo phenotyping experiment assessing homozygous PDX1P33T and wild-type littermates on both chow and high fat diet (HFD). Additionally, transcriptomic and proteomic analyses were performed on isolated pancreatic islets. Islet architecture was investigated via fluorescent microscopy. RESULT: Contrary to expectations, our comprehensive phenotypic analysis of the mouse model carrying the homozygous PDX1P33T mutation revealed no significant differences in metabolic parameters compared to wild-type controls, and no pathological outcomes were observed as seen in human patients. Notably, male PDX1P33T mice exhibited an increase in islet size and number on chow diet, with omics analyses suggesting reprogramming toward stress resilience, but failed to adapt respectively on HFD. DISCUSSION: Our work indicates substantial differences between mouse and human PDX1 function in the pancreas. Further refinement of animal models is necessary to better elucidate the pathophysiology of PDX1-MODY.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mody ; Mody4 ; Pdx1 ; Diabetes Mellitus ; Mouse Model ; Phenotypic Divergence ; Point Mutation; Pancreatic Beta-cells; Insulin-resistance; Diabetes-mellitus; Genome-wide; Alpha-cells; Pdx1; Transcription; Expression; Type-2; Inactivation
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 1664-2392
e-ISSN 1664-2392
Journal Frontiers in Endocrinology
Quellenangaben Volume: 16, Issue: , Pages: , Article Number: 1680893 Supplement: ,
Publisher Frontiers
Publishing Place Lausanne
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
Institute of Stem Cell Research (ISF)
POF-Topic(s) 30201 - Metabolic Health
30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
Stem Cell and Neuroscience
PSP Element(s) G-500600-001
G-500600-003
G-500800-001
G-500693-001
Grants National Health and Medical Research Council (NHMRC) Emerging Leadership Fellowship
Helmholtz Association - Initiative and Networking Fund (IVF) as part of the International Helmholtz Research School for Diabetes (HRD)
German Center for Diabetes Research (DZD)
DOI 10.3389/fendo.2025.1680893
WOS ID 001607341200001
Scopus ID 105021018935
PubMed ID 41199860
Erfassungsdatum 2025-11-11
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