The incretin hormone glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) are central regulators of glucose-stimulated insulin secretion and major targets in type 2 diabetes. 6-Gingerol, the principal bioactive constituent of ginger, has a reported insulinotropic action that depends on GLP-1 in vivo, but whether this reflects GLP-1 secretion from intestinal L-cells or signaling at the β-cell GLP-1R is unresolved. Using NCI-H716 and STC-1 L-cells and MIN6 β-cells, we examined whether 6-Gingerol acts as a GLP-1 secretagogue or at the β-cell. 6-Gingerol did not stimulate GLP-1 secretion. It had no effect in NCI-H716 cells and reduced secretion in STC-1 cells at concentrations that did not reduce viability. In MIN6 β-cells, 6-Gingerol potentiated insulin secretion in a bell-shaped manner. This effect was abolished by two mechanistically distinct GLP-1R antagonists and by protein kinase A inhibition and was accompanied by a GLP-1R-dependent rise in cAMP. MIN6 cells expressed Glp1r transcript, and Exendin-4 confirmed a functional receptor response. These findings suggest that 6-Gingerol acts at the β-cell through GLP-1R-, cAMP-, and PKA-dependent mechanisms and not as an L-cell GLP-1 secretagogue. At the pharmacological concentration used, these results suggest an in vitro mechanism rather than a physiological dietary effect, and in vivo validation is needed.
