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

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Standard

Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets. / Bacos, Karl; Perfilyev, Alexander; Karagiannopoulos, Alexandros; Cowan, Elaine; Ofori, Jones K.; Bertonnier-Brouty, Ludivine; Rönn, Tina; Lindqvist, Andreas; Luan, Cheng; Ruhrmann, Sabrina; Ngara, Mtakai; Nilsson, Åsa; Gheibi, Sevda; Lyons, Claire L.; Lagerstedt, Jens O.; Barghouth, Mohammad; Esguerra, Jonathan L.S.; Volkov, Petr; Fex, Malin; Mulder, Hindrik; Wierup, Nils; Krus, Ulrika; Artner, Isabella; Eliasson, Lena; Prasad, Rashmi B.; Cataldo, Luis Rodrigo; Ling, Charlotte.

In: Journal of Clinical Investigation, Vol. 133, No. 4, e163612, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Bacos, K, Perfilyev, A, Karagiannopoulos, A, Cowan, E, Ofori, JK, Bertonnier-Brouty, L, Rönn, T, Lindqvist, A, Luan, C, Ruhrmann, S, Ngara, M, Nilsson, Å, Gheibi, S, Lyons, CL, Lagerstedt, JO, Barghouth, M, Esguerra, JLS, Volkov, P, Fex, M, Mulder, H, Wierup, N, Krus, U, Artner, I, Eliasson, L, Prasad, RB, Cataldo, LR & Ling, C 2023, 'Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets', Journal of Clinical Investigation, vol. 133, no. 4, e163612. https://doi.org/10.1172/JCI163612

APA

Bacos, K., Perfilyev, A., Karagiannopoulos, A., Cowan, E., Ofori, J. K., Bertonnier-Brouty, L., Rönn, T., Lindqvist, A., Luan, C., Ruhrmann, S., Ngara, M., Nilsson, Å., Gheibi, S., Lyons, C. L., Lagerstedt, J. O., Barghouth, M., Esguerra, J. L. S., Volkov, P., Fex, M., ... Ling, C. (2023). Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets. Journal of Clinical Investigation, 133(4), [e163612]. https://doi.org/10.1172/JCI163612

Vancouver

Bacos K, Perfilyev A, Karagiannopoulos A, Cowan E, Ofori JK, Bertonnier-Brouty L et al. Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets. Journal of Clinical Investigation. 2023;133(4). e163612. https://doi.org/10.1172/JCI163612

Author

Bacos, Karl ; Perfilyev, Alexander ; Karagiannopoulos, Alexandros ; Cowan, Elaine ; Ofori, Jones K. ; Bertonnier-Brouty, Ludivine ; Rönn, Tina ; Lindqvist, Andreas ; Luan, Cheng ; Ruhrmann, Sabrina ; Ngara, Mtakai ; Nilsson, Åsa ; Gheibi, Sevda ; Lyons, Claire L. ; Lagerstedt, Jens O. ; Barghouth, Mohammad ; Esguerra, Jonathan L.S. ; Volkov, Petr ; Fex, Malin ; Mulder, Hindrik ; Wierup, Nils ; Krus, Ulrika ; Artner, Isabella ; Eliasson, Lena ; Prasad, Rashmi B. ; Cataldo, Luis Rodrigo ; Ling, Charlotte. / Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets. In: Journal of Clinical Investigation. 2023 ; Vol. 133, No. 4.

Bibtex

@article{65aeaa9399f546a29fbf4138dd52d7c7,
title = "Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets",
abstract = "Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 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 expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes 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 have identified molecular alterations in human pancreatic islets that contribute to β cell dysfunction in T2D pathophysiology.",
author = "Karl Bacos and Alexander Perfilyev and Alexandros Karagiannopoulos and Elaine Cowan and Ofori, {Jones K.} and Ludivine Bertonnier-Brouty and Tina R{\"o}nn and Andreas Lindqvist and Cheng Luan and Sabrina Ruhrmann and Mtakai Ngara and {\AA}sa Nilsson and Sevda Gheibi and Lyons, {Claire L.} and Lagerstedt, {Jens O.} and Mohammad Barghouth and Esguerra, {Jonathan L.S.} and Petr Volkov and Malin Fex and Hindrik Mulder and Nils Wierup and Ulrika Krus and Isabella Artner and Lena Eliasson and Prasad, {Rashmi B.} and Cataldo, {Luis Rodrigo} and Charlotte Ling",
note = "Publisher Copyright: Copyright: {\textcopyright} 2023, Bacos et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2023",
doi = "10.1172/JCI163612",
language = "English",
volume = "133",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "4",

}

RIS

TY - JOUR

T1 - Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets

AU - Bacos, Karl

AU - Perfilyev, Alexander

AU - Karagiannopoulos, Alexandros

AU - Cowan, Elaine

AU - Ofori, Jones K.

AU - Bertonnier-Brouty, Ludivine

AU - Rönn, Tina

AU - Lindqvist, Andreas

AU - Luan, Cheng

AU - Ruhrmann, Sabrina

AU - Ngara, Mtakai

AU - Nilsson, Åsa

AU - Gheibi, Sevda

AU - Lyons, Claire L.

AU - Lagerstedt, Jens O.

AU - Barghouth, Mohammad

AU - Esguerra, Jonathan L.S.

AU - Volkov, Petr

AU - Fex, Malin

AU - Mulder, Hindrik

AU - Wierup, Nils

AU - Krus, Ulrika

AU - Artner, Isabella

AU - Eliasson, Lena

AU - Prasad, Rashmi B.

AU - Cataldo, Luis Rodrigo

AU - Ling, Charlotte

N1 - Publisher Copyright: Copyright: © 2023, Bacos et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

PY - 2023

Y1 - 2023

N2 - Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 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 expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes 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 have identified molecular alterations in human pancreatic islets that contribute to β cell dysfunction in T2D pathophysiology.

AB - Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 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 expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes 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 have identified molecular alterations in human pancreatic islets that contribute to β cell dysfunction in T2D pathophysiology.

U2 - 10.1172/JCI163612

DO - 10.1172/JCI163612

M3 - Journal article

C2 - 36656641

AN - SCOPUS:85148113921

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

M1 - e163612

ER -

ID: 357478318