GPBA is a G protein-coupled receptor that is activated by bile acids. Because activation of GPBA leads to increased cAMP levels and secretion of incretins and insulin, GPBA has been proposed as a promising drug target for the treatment of metabolic syndrome. Previously, we have developed a ligand-screening system to identify novel agonists of GPBA by means of a fusion protein of GPBA with G protein stimulatory a subunit (Gs alpha) and by a [S-35] GTP gamma S-binding assay. To express the GPBA-Gs alpha fusion protein, transgenic silkworms were employed in this study, and cell membrane fractions were prepared from their fat body or pupae. We applied them to the screening of a chemical library that contains 10,625 compounds from the RIKEN Natural Products Depository (NPDepo). Eventually, a unique partial agonist, GUM2, was successfully identified. Our results indicated that the GPCR-G alpha fusion proteins were beneficial for ligand identification and that the transgenic silkworms were useful for large-scale production of GPCRs. In HEK293 cells transiently expressing GPBA, GUM2 showed 50% effective concentration (EC50) of 3.5 +/- 2.4 mu M and induced GPBA internalization as effectively as did an endogenous agonist, TLC. We also confirmed that GUM2 stimulates insulin secretion in MIN6 cells. Moreover, a single 2 mg/kg dose of GUM2 significantly reduced blood glucose levels in mice during an intraperitoneal glucose tolerance test even though GUM2 is only a partial agonist with a low intrinsic activity. We concluded that GUM2 is a good candidate for research on GPBA signaling under physiological conditions and for the development of GPBA-targeting therapeutic compounds.