Here, using high fat diet (HFD) mice as an experimental model of hyperinsulinemia, we demonstrated that treatment with TUDCA normalizes their plasma insulin concentrations by increasing insulin clearance. This effect is probably due to increased IDE expression in the liver. In vitro experiments, using hepatic human cell line HepG2, demonstrated that TUDCA also increases IDE expression, by a mechanism dependent on the interaction of TUDCA with the S1PR2 receptor, via the insulin signaling pathway. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of hyperinsulinemia in obese pre-diabetic individuals.