TCF7L2 is a master regulator of insulin production and processing

BioRxiv : the Preprint Server for Biology
Yuedan ZhouOla Hansson

Abstract

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.

Related Concepts

Diabetes Mellitus, Non-Insulin-Dependent
Genes
Insulin
Islets of Langerhans
Proinsulin
Rodent
T-Lymphocyte
Transcription Factor 7-Like 2
Insulin Secretion
Regulation of Biological Process

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