TAS1R3 is dually required for GTPase signaling in human islet β-cells and skeletal muscle cells

The taste receptor type 1 member 3 (TAS1R3), a G protein coupled receptor, is required for whole body glucose homeostasis. However, the molecular mechanism of TAS1R3 function in islet β-cells and skeletal muscle to control glucose homeostasis remains unknown.

Objective

We questioned whether activation of endogenous TAS1R3 in human islets or clonal human β-cells or human skeletal muscle cells are necessary for glucose stimulated insulin secretion and insulin stimulated glucose uptake respectively via activation of small GTPases.

Methods and Results

We found that pharmacological TAS1R3 inhibition (lactisole) in human islets and a human β-cell line diminished glucose-stimulated insulin secretion, attenuated Src family tyrosine kinase signaling, and small GTPase Cdc42 activation. In human skeletal muscle cell lines, lactisole treatment reduced insulin-stimulated glucose uptake, and impaired small GTPase Rac1-dependent non-canonical insulin signaling. We excluded the requirement for the G protein Gαq/11 in TAS1R3 signaling by using the Gαq/11-specific YM-254890 inhibitor in β-cells and skeletal muscle. Notably, the significant reduction of TAS1R3 mRNA and protein levels in human type 2 diabetes pancreatic islets and skeletal muscle, reductions which could be replicated in otherwise healthy cells exposed to diabetogenic stimuli, indicates that the TAS1R3 deficit may be a consequence of diabetogenic stimuli.

Conclusion

Overall, our results suggest that TAS1R3 plays an essential role in GTPase signaling in islet β-cells and human skeletal muscle cells, adding to the growing list of proteins that play a vital role in multiple tissues as therapeutic targets in type 2 diabetes.

ARTICLE HIGHLIGHTS

• Human type 2 diabetic pancreatic islets and skeletal muscle show reduced TAS1R3 levels (> 50%). Exposure of healthy cells to diabetogenic stimuli simulates this reduction, indicating that diabetogenic stimuli may cause TAS1R3 deficit.

• TAS1R3 plays an important role in GTPase signaling in human islets, islet β-cells and human skeletal muscle myotube cells to control glucose homeostasis.

• TAS1R3 is a putative therapeutic target to remediate islet and skeletal muscle defects associated with type 2 diabetes.