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Träfflista för sökning "WFRF:(Lagerstedt Jens O.) ;lar1:(ki)"

Sökning: WFRF:(Lagerstedt Jens O.) > Karolinska Institutet

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  • Bacos, Karl, et al. (författare)
  • Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets
  • 2023
  • Ingår i: The Journal of clinical investigation. - 0021-9738 .- 1558-8238. ; 133:4
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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