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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.

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