This impressive single cell study profiled every stage of beta cell development (from embryonic stem cells to mature beta cells) and beautifully demonstrates that many GWAS identified T2D genes are expressed only at specific developmental stage. https://twitter.com/FulaiJin/status/1333466144091435008
The authors studied expression profile of one gene in particular: TCF7L2, one of the most replicated T2D risk genes. TCFL2 is expressed only during specific developmental stages as visualised in this lineage tree
Previous studies showed the GWAS risk variant is an eQTL and increases the TCF7L2 expression in pancreatic beta cells. Deleting a developmental stage specific enhancer (which is in LD with GWAS locus) results in reduced TCFL2 expression and increased endocrine differentiation.
So this means the possible mechanism of TC7L2 GWAS variant is : increased TCF7L2 expression (during specific developmental stages), which resulting in reduced endocrine differentiation and so decreased insulin production.
This means that TCFL2 is a potential drug target and TC7L2 inhibitors might help to treat T2D by enhancing beta cell production in pancreas.
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