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

Bacos, Karl LU orcid ; Perfilyev, Alexander LU orcid ; Karagiannopoulos, Alexandros LU orcid ; Cowan, Elaine LU orcid ; Ofori, Jones K LU ; Bertonnier-Brouty, Ludivine LU ; Rönn, Tina LU ; Lindqvist, Andreas LU ; Luan, Cheng LU and Ruhrmann, Sabrina LU , et al. (2023) In The Journal of clinical investigation 133(4).
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.... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of clinical investigation
volume
133
issue
4
article number
e163612
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:85148113921
  • pmid:36656641
ISSN
0021-9738
DOI
10.1172/JCI163612
language
English
LU publication?
yes
id
6e29db61-7b25-42ca-a53e-bc86861342ac
date added to LUP
2023-02-09 11:14:10
date last changed
2024-04-18 18:43:00
@article{6e29db61-7b25-42ca-a53e-bc86861342ac,
  abstract     = {{<p>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.</p>}},
  author       = {{Bacos, Karl and Perfilyev, Alexander and Karagiannopoulos, Alexandros and Cowan, Elaine and Ofori, Jones K and Bertonnier-Brouty, Ludivine and Rönn, Tina and Lindqvist, Andreas and Luan, Cheng and Ruhrmann, Sabrina and Ngara, Mtakai and Nilsson, Åsa and Gheibi, Sevda and Lyons, Claire L and Lagerstedt, Jens O and Barghouth, Mohammad and Esguerra, Jonathan Ls and Volkov, Petr and Fex, Malin and Mulder, Hindrik and Wierup, Nils and Krus, Ulrika and Artner, Isabella and Eliasson, Lena and Prasad, Rashmi B and Cataldo, Luis Rodrigo and Ling, Charlotte}},
  issn         = {{0021-9738}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{4}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{The Journal of clinical investigation}},
  title        = {{Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets}},
  url          = {{http://dx.doi.org/10.1172/JCI163612}},
  doi          = {{10.1172/JCI163612}},
  volume       = {{133}},
  year         = {{2023}},
}