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  • Mattis, Katia KOxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. (author)

Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023-01-12
  • Springer Nature,2023
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-495953
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-495953URI
  • https://doi.org/10.1007/s00125-022-05856-6DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • AIMS/HYPOTHESIS: Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk.METHODS: A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 type 2 diabetes risk alleles.RESULTS: CRISPR/Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression and glucose levels. Loss of RREB1 also reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of type 2 diabetes risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with a role for RREB1 in regulating islet cell function.CONCLUSIONS/INTERPRETATION: Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Krentz, Nicole A JWellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (author)
  • Metzendorf, ChristophUppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)chmet515 (author)
  • Abaitua, FernandoWellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (author)
  • Spigelman, Aliya FDepartment of Pharmacology, University of Alberta, Edmonton, AB, Canada. (author)
  • Sun, HanDivision of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA. (author)
  • Ikle, Jennifer MDivision of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA. (author)
  • Thaman, SwarajDivision of Endocrinology, Department of Pediatrics, Stanford School of Medicine, Stanford University, Stanford, CA, USA. (author)
  • Rottner, Antje KOxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. (author)
  • Bautista, AustinDepartment of Pharmacology, University of Alberta, Edmonton, AB, Canada. (author)
  • Mazzaferro, EugeniaUppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)eugma242 (author)
  • Perez-Alcantara, MartaWellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (author)
  • Manning Fox, Jocelyn EDepartment of Pharmacology, University of Alberta, Edmonton, AB, Canada. (author)
  • Torres, Jason MWellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (author)
  • Wesolowska-Andersen, AgataWellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (author)
  • Yu, Grace ZOxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. (author)
  • Mahajan, AnubhaWellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (author)
  • Larsson, AndersUppsala universitet,Klinisk kemi(Swepub:uu)andlarss (author)
  • MacDonald, Patrick EDepartment of Pharmacology, University of Alberta, Edmonton, AB, Canada. (author)
  • Davies, BenjaminWellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (author)
  • den Hoed, Marcel,1980-Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)marde358 (author)
  • Gloyn, Anna LOxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK. (author)
  • Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. (creator_code:org_t)

Related titles

  • In:Diabetologia: Springer Nature66:4, s. 674-6940012-186X1432-0428

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