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A point mutation in the Pdia6 gene results in loss of pancreatic β-cell identity causing overt diabetes.
Mol. Metab. 54:101334 (2021)
OBJECTIVE: Protein disulfide isomerases (PDIs) are oxidoreductases that are involved in catalyzing the formation and rearrangement of disulfide bonds during protein folding. One of the PDI members is the PDI-associated 6 (PDIA6) protein, which has been shown to carry a vital role in β-cell dysfunction and diabetes. However, very little is known about the function of this protein in β-cells in vivo. This study aimed to describe the consequences of a point mutation in Pdia6 on β-cell development and function. METHODS: We generated an ENU mouse model carrying a missense mutation (Phe175Ser) in the second thioredoxin domain of the Pdia6 gene. Using biochemical and molecular tools, we determined the effects of the mutation on the β-cell development at embryonic day (E)18.5 and β-cell identity as well as function at postnatal stages. RESULTS: Mice homozygous for the Phe175Ser (F175S) mutation were mildly hyperglycemic at weaning and subsequently became hypoinsulinemic and overtly diabetic at the adult stage. Although, no developmental phenotype was detected during embryogenesis, mutant mice displayed reduced insulin-expressing β-cells at P14 and P21 without any changes in the rate of cell death and proliferation. Further analysis revealed an increase in BiP as well as PDI family member PDIA4, however without any concomitant apoptosis and cell death. Instead, the expression of prominent markers of β-cell maturation and function, such as Ins2, Mafa and Slc2a2 along with increased expression of α-cell markers, Mafb and glucagon was observed in adult mice, suggesting loss of β-cell identity. CONCLUSIONS: The data demonstrates that a global Pdia6 mutation renders mice hypoinsulinemic and hyperglycemic. This occurs due to the loss of pancreatic β-cell function and identity, suggesting a critical role of PDIA6 specifically for β-cells.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Er-stress ; Pdia6 ; Diabetes ; Insulin ; Islets; Protein Disulfide-isomerase; Mouse Model; Mice; Dedifferentiation; Pdia6
ISSN (print) / ISBN
2212-8778
e-ISSN
2212-8778
Zeitschrift
Molecular Metabolism
Quellenangaben
Band: 54,
Artikelnummer: 101334
Verlag
Elsevier
Verlagsort
Amsterdam
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Experimental Genetics (IEG)
Institute of Diabetes and Regeneration Research (IDR)
CF Comparative Medicine (CF-Comparative Medicine)
Institute of Human Genetics (IHG)
Research Unit Analytical Pathology (AAP)
Institute of Diabetes and Regeneration Research (IDR)
CF Comparative Medicine (CF-Comparative Medicine)
Institute of Human Genetics (IHG)
Research Unit Analytical Pathology (AAP)
Förderungen
German Center for Diabetes Research (DZD)
German Federal Ministry of Education and Research
NGFNplus grants from the Bundesministerium fur Bildung und Forschung
Nationales Genomforschungsnetz (NGFN)
BMBF OSTEOPATH
German Federal Ministry of Education and Research
NGFNplus grants from the Bundesministerium fur Bildung und Forschung
Nationales Genomforschungsnetz (NGFN)
BMBF OSTEOPATH