The Role of GPR 21 in Insulin resistance and Type 2 Diabetes


Given the rapid escalation of type 2 diabetes (T2D), an effective strategy that will delay disease progression is urgent. At present, an old compound, Metformin, solely or in combination with later-stage therapies, is the principal small molecule treatment. Many are uncomfortable with its use. Therefore, a new target or a more effective and specific alternative is necessary.

This project examines whether GPR21 is such a target. This protein is a member of the largest family of membrane receptors, G protein coupled receptors (GPCRs), many of which have been successfully addressed by molecular therapies. The promise of GPR21 lies in the observation that knocking out the protein in mice gives rise to increased insulin sensitivity and resistance to type 2 diabetes induced by high fat diets.

GPR21 remains an orphan and is particularly interesting in that it is suggested to be constitutively active, which shall be further examined here. A ligand which blocks the constitutive activity of GPR21 could be a very powerful therapy. We are employing our expertise in modelling and in silico screening to discover small molecule ligands for GPR21. They will serve as tools to understand the mechanism of action whereby GPR21 generates insulin resistance.

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