TAS1R3 Regulates GTPase Signaling in Human Skeletal Muscle Cells for Glucose Uptake

Taste receptor type 1 member 3 (TAS1R3) is a class C G protein-coupled receptor (GPCR) traditionally associated with taste perception. While its role in insulin secretion is established, its contribution to skeletal muscle glucose uptake, a process responsible for 70-80% of postprandial glucose disposal, remains unclear. TAS1R3 expression was assessed in skeletal muscle biopsies from non-diabetic and type 2 diabetes (T2D) donors using qPCR and immunoblotting. Functional studies in human LHCN-M2 myotubes involved TAS1R3 inhibition with lactisole or siRNA-mediated knockdown, followed by the measurement of insulin-stimulated glucose uptake using radiolabeled glucose assays. Rac1 activation and phospho-cofilin were analyzed by G-LISA and Western blotting, and Gαq/11 involvement was tested using YM-254890. TAS1R3 mRNA and protein levels were significantly reduced in T2D skeletal muscle. Pharmacological inhibition or the knockdown of TAS1R3 impaired insulin-stimulated glucose uptake in myotubes. TAS1R3 regulates skeletal muscle glucose uptake through a non-canonical insulin signaling pathway involving Rac1 and phospho-cofilin, independent of IRS1-AKT and Gαq/11 signaling. These findings identify TAS1R3 as a key determinant of Rac1-mediated glucose uptake and a potential therapeutic target for improving insulin sensitivity in T2D.