Genkwanin glycosides from the Phaleria nisidai extract improve glucose homeostasis by stimulating insulin-independent glucose uptake.

Abstract Natural remedies are used as stand-alone treatments or as additives to modern medicine to control hyperglycemia. Here, we investigate the antidiabetic potential of the Palauan traditional leaf decoction of Phaleria nisidai (PNe) using a reverse pharmacology approach. In diet induced obese mice, dietary supplementation with PNe improves insulin sensitivity and promotes glucose uptake into adipose depots. In vitro, PNe triggers insulin-independent glucose disposal into murine and human adipocytes by upregulating Glut1 expression via PKC-ERK1/2 signaling. To identify PNe active principle(s), bioactivity-guided fractionations were performed. We decipher the genkwanin flavone glycosides as active principles found in PNe and demonstrate that the aglycone genkwanin (GE) improves insulin resistance to a comparable extent to metformin. We present GE as promising glucoregulatory phytochemical, which stimulates baseline glucose uptake into metabolically active adipocytes, thus dampening systemic glucose load and restoring insulin sensitivity.