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@article{Ndiaye:2017:10.1016/j.molmet.2017.03.011,
author = {Ndiaye, FK and Ortalli, A and Canouil, M and Huyvaert, M and Salazar-Cardozo, C and Lecoeur, C and Verbanck, M and Pawlowski, V and Boutry, R and Durand, E and Rabearivelo, I and Sand, O and Marselli, L and Kerr-Conte, J and Chandra, V and Scharfmann, R and Poulain-Godefroy, O and Marchetti, P and Pattou, F and Abderrahmani, A and Froguel, P and Bonnefond, A},
doi = {10.1016/j.molmet.2017.03.011},
journal = {MOLECULAR METABOLISM},
pages = {459--470},
title = {Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion},
url = {http://dx.doi.org/10.1016/j.molmet.2017.03.011},
volume = {6},
year = {2017}
}

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TY  - JOUR
AB  - Objectives:Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells.Methods:The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-βH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-βH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function.Results:We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-βH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-βH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression
AU  - Ndiaye,FK
AU  - Ortalli,A
AU  - Canouil,M
AU  - Huyvaert,M
AU  - Salazar-Cardozo,C
AU  - Lecoeur,C
AU  - Verbanck,M
AU  - Pawlowski,V
AU  - Boutry,R
AU  - Durand,E
AU  - Rabearivelo,I
AU  - Sand,O
AU  - Marselli,L
AU  - Kerr-Conte,J
AU  - Chandra,V
AU  - Scharfmann,R
AU  - Poulain-Godefroy,O
AU  - Marchetti,P
AU  - Pattou,F
AU  - Abderrahmani,A
AU  - Froguel,P
AU  - Bonnefond,A
DO  - 10.1016/j.molmet.2017.03.011
EP  - 470
PY  - 2017///
SN  - 2212-8778
SP  - 459
TI  - Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion
T2  - MOLECULAR METABOLISM
UR  - http://dx.doi.org/10.1016/j.molmet.2017.03.011
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000405453000001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/49379
VL  - 6
ER  -

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