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  • Bacos, KarlLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital (author)

Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2023

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:6e29db61-7b25-42ca-a53e-bc86861342ac
  • https://lup.lub.lu.se/record/6e29db61-7b25-42ca-a53e-bc86861342acURI
  • https://doi.org/10.1172/JCI163612DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:152724159URI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

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

Notes

  • Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β-cells. To identify candidates contributing to T2D pathophysiology, we studied human pancreatic islets from ~300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified islet expression changes may predispose to diabetes, as they associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β-cells based on single-cell RNA-sequencing data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D-SNPs. Mouse knock-out strains demonstrated that T2D-associated candidates regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing β-cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we identified molecular alterations in human pancreatic islets contributing to β-cell dysfunction in T2D pathophysiology.

Subject headings and genre

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

  • Perfilyev, AlexanderLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-apy (author)
  • Karagiannopoulos, AlexandrosLund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups,Skåne University Hospital(Swepub:lu)al6183ka (author)
  • Cowan, ElaineLund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups,Skåne University Hospital(Swepub:lu)el3560co (author)
  • Ofori, Jones KLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-joi (author)
  • Bertonnier-Brouty, LudivineLund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Endokrin Celldifferentiering,Forskargrupper vid Lunds universitet,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Endocrine Cell Differentiation and Function,Lund University Research Groups(Swepub:lu)lu4661be (author)
  • Rönn, TinaLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-tar (author)
  • Lindqvist, AndreasLund University,Lunds universitet,Neuroendokrin cellbiologi,Forskargrupper vid Lunds universitet,Neuroendocrine Cell Biology,Lund University Research Groups(Swepub:lu)medk-alt (author)
  • Luan, ChengLund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups(Swepub:lu)med-cgl (author)
  • Ruhrmann, SabrinaLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)sa4447ru (author)
  • Ngara, MtakaiKarolinska Institutet,Lund University,Lunds universitet,Neuroendokrin cellbiologi,Forskargrupper vid Lunds universitet,Neuroendocrine Cell Biology,Lund University Research Groups(Swepub:lu)mt1874ng (author)
  • Nilsson, ÅsaLund University,Lunds universitet,Diabetiska komplikationer,Forskargrupper vid Lunds universitet,Diabetic Complications,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-nna (author)
  • Gheibi, SevdaLund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Diabetes - Molecular Metabolism,Lund University Research Groups,Skåne University Hospital(Swepub:lu)se3645gh (author)
  • Lyons, Claire LLund University,Lunds universitet,Medicinsk proteinvetenskap,Forskargrupper vid Lunds universitet,Diabetes - molekylär metabolism,Medical Protein Science,Lund University Research Groups,Diabetes - Molecular Metabolism,Skåne University Hospital(Swepub:lu)cl6746ly (author)
  • Lagerstedt, Jens OLund University,Lunds universitet,Medicinsk proteinvetenskap,Forskargrupper vid Lunds universitet,Medical Protein Science,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-jls (author)
  • Barghouth, MohammadLund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups(Swepub:lu)mo4503ba (author)
  • Esguerra, Jonathan LsLund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-jer (author)
  • Volkov, PetrLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups(Swepub:lu)med-pvo (author)
  • Fex, MalinLund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Diabetes - Molecular Metabolism,Lund University Research Groups,Skåne University Hospital(Swepub:lu)medk-mf0 (author)
  • Mulder, HindrikLund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Diabetes - Molecular Metabolism,Lund University Research Groups,Skåne University Hospital(Swepub:lu)medk-hmu (author)
  • Wierup, NilsLund University,Lunds universitet,Neuroendokrin cellbiologi,Forskargrupper vid Lunds universitet,Neuroendocrine Cell Biology,Lund University Research Groups(Swepub:lu)mphy-nwi (author)
  • Krus, UlrikaLund University,Lunds universitet,Diabetiska komplikationer,Forskargrupper vid Lunds universitet,Diabetic Complications,Lund University Research Groups,Skåne University Hospital(Swepub:lu)medk-ufr (author)
  • Artner, IsabellaLund University,Lunds universitet,Endokrin Celldifferentiering,Forskargrupper vid Lunds universitet,Bildbehandlingsplattformen,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Endocrine Cell Differentiation and Function,Lund University Research Groups,Imaging,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)med-iba (author)
  • Eliasson, LenaLund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups,Skåne University Hospital(Swepub:lu)mphy-lel (author)
  • Prasad, Rashmi BLund University,Lunds universitet,Translationell muskelforskning,Forskargrupper vid Lunds universitet,Translational Muscle Research,Lund University Research Groups,University of Helsinki,Skåne University Hospital(Swepub:lu)med-rpa (author)
  • Cataldo, Luis RodrigoLund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Diabetes - Molecular Metabolism,Lund University Research Groups,University of Copenhagen,Skåne University Hospital(Swepub:lu)lu3583ca (author)
  • Ling, CharlotteLund University,Lunds universitet,Diabetes - epigenetik,Forskargrupper vid Lunds universitet,Diabetes - Epigenetics,Lund University Research Groups,Skåne University Hospital(Swepub:lu)endo-cl0 (author)
  • Diabetes - epigenetikForskargrupper vid Lunds universitet (creator_code:org_t)

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  • In:The Journal of clinical investigation133:40021-97381558-8238

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