RT Journal Article
SR Electronic
T1 <em>TCF7L2</em> is a master regulator of insulin production and processing
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 003202
DO 10.1101/003202
A1 Yuedan Zhou
A1 Soo Young Park
A1 Jing Su
A1 Kathleen Bailey
A1 Emilia Ottosson-Laakso
A1 Liliya Shcherbina
A1 Nikolay Oskolkov
A1 Enming Zhang
A1 Thomas Thevenin
A1 João Fadista
A1 Hedvig Bennet
A1 Petter Vikman
A1 Nils Wierup
A1 Malin Fex
A1 Johan Rung
A1 Claes Wollheim
A1 Marcelo Nobrega
A1 Erik Renström
A1 Leif Groop
A1 Ola Hansson
YR 2014
UL http://biorxiv.org/content/early/2014/03/05/003202.abstract
AB Although variants in the T-cell factor 7-like 2 gene (TCF7L2) confer the strongest risk of type 2 diabetes (T2D) by presumed effects on islet function, the underlying mechanisms are not well understood. We have identified TCF7L2-target genes and described the regulatory network downstream of TCF7L2 responsible for its effect on insulin secretion in rodents and human pancreatic islets. ISL1 is a direct target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1 and PCSK2 and possibly clearance of proinsulin via SLC30A8. 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 in a genotype dependent manner. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing the strongest association with T2D.