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TCF7L2 is a master regulator of insulin production and processing.

Zhou, Yuedan LU ; Park, Soo-Young; Su, Jing; Bailey, Kathleen; Ottosson Laakso, Emilia LU ; Shcherbina, Liliya LU ; Oskolkov, Nikolay LU ; Zhang, Enming LU ; Thevenin, Thomas LU and Fadista, Joao LU , et al. (2014) In Human Molecular Genetics 23(24). p.6419-6431
Abstract
Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and... (More)
Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D. (Less)
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Contribution to journal
publication status
published
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Human Molecular Genetics
volume
23
issue
24
pages
6419 - 6431
publisher
Oxford University Press
external identifiers
  • pmid:25015099
  • wos:000347921900001
  • scopus:84965091713
ISSN
0964-6906
DOI
10.1093/hmg/ddu359
language
English
LU publication?
yes
id
87f6ebc1-f1b7-4d1f-b82a-46e7b35bb0ae (old id 4582504)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25015099?dopt=Abstract
date added to LUP
2014-08-07 20:48:06
date last changed
2017-10-22 03:22:07
@article{87f6ebc1-f1b7-4d1f-b82a-46e7b35bb0ae,
  abstract     = {Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.},
  author       = {Zhou, Yuedan and Park, Soo-Young and Su, Jing and Bailey, Kathleen and Ottosson Laakso, Emilia and Shcherbina, Liliya and Oskolkov, Nikolay and Zhang, Enming and Thevenin, Thomas and Fadista, Joao and Bennet, Hedvig and Vikman, Petter and Wierup, Nils and Fex, Malin and Rung, Johan and Wollheim, Claes and Nobrega, Marcelo and Renström, Erik and Groop, Leif and Hansson, Ola},
  issn         = {0964-6906},
  language     = {eng},
  number       = {24},
  pages        = {6419--6431},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {TCF7L2 is a master regulator of insulin production and processing.},
  url          = {http://dx.doi.org/10.1093/hmg/ddu359},
  volume       = {23},
  year         = {2014},
}