Genkwanin glycosides are major active compounds in Phaleria nisidai extract mediating improved glucose homeostasis by stimulating glucose uptake into adipose tissues

Carla Horvath, Joëlle Houriet, Alexandra Kellenberger, Caroline Moser, Lucia Balazova, Miroslav Balaz, Hua Dong, Aron Horvath, Isabel Reinisch, Vissarion Efthymiou, Adriano Rutz, Laurence Marcourt, Christopher Kitalong, Bertrand Graz, Victor Yano, Emerson Ferreira Queiroz, Jean-Luc Wolfender () and Christian Wolfrum ()
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Carla Horvath: ETH Zurich
Joëlle Houriet: University of Geneva, CMU
Alexandra Kellenberger: ETH Zurich
Caroline Moser: ETH Zurich
Lucia Balazova: ETH Zurich
Miroslav Balaz: ETH Zurich
Hua Dong: Stanford University School of Medicine
Aron Horvath: Balgrist Campus
Isabel Reinisch: ETH Zurich
Vissarion Efthymiou: ETH Zurich
Adriano Rutz: University of Geneva, CMU
Laurence Marcourt: University of Geneva, CMU
Christopher Kitalong: Balgrist Campus
Bertrand Graz: University of Geneva, CMU
Victor Yano: Pacific Academic Institute for Research
Emerson Ferreira Queiroz: University of Geneva, CMU
Jean-Luc Wolfender: University of Geneva, CMU
Christian Wolfrum: ETH Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: Abstract Natural remedies are used as standalone treatments or complementary to modern medicine to control type 2 diabetes. In Palau, the traditional leaf decoction of Phaleria nisidai (PNe) is selected to treat hyperglycemia and its efficacy has been supported by a small clinical trial. As part of a reverse pharmacology approach, we here investigated the anti-diabetic potential of PNe and its bioactive compounds to alleviate insulin resistance in diet-induced obese, male mice. Dietary supplementation with PNe improves insulin sensitivity and promotes glucose uptake into adipose depots. In vitro, PNe triggers glucose disposal into murine and human adipocytes by upregulating Glut1 expression through PKC-ERK1/2 signaling. To identify active constituents in PNe, we conducted bioactivity-guided fractionations and deciphered genkwanin flavone glycosides as bioactive principles. Moreover, we demonstrate that the aglycone genkwanin (GE) improves insulin resistance to a comparable extent to the anti-diabetic drug, metformin. Our findings present GE as promising glucoregulatory phytochemical that facilitates glucose uptake into adipocytes, thereby reducing systemic glucose load and enhancing insulin sensitivity.

Date: 2025
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DOI: 10.1038/s41467-025-62689-8

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