A public domain small molecule inhibitor of ABHD6 was found to inhibit the hydrolysis of MAG (the natural ligand of ABHD6), thereby reducing the levels of the most common hydrolysis products as well as increasing GSIS. Other experiments involving knockdown, knockout or overexpression of ABHD6 in islet cell and in mice confirmed its importance in controlling insulin secretion. Also, in animal models following a standard oral glucose tolerance test, the molecule enhanced insulin secretion in control mice, whereas in streptozotocin (STZ) treated mice, the compound lowered glycemia, improved glucose tolerance and restored GSIS.
The project will focus on SAR work to find ABHD6-specific inhibitors. These will then be tested in several cellular assays leading to an acute and a chronic DIO mouse model experiments.