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J. Biol. Chem., Vol. 279, Issue 40, 41361-41367, October 1, 2004

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A Novel Insulin-releasing Substance, Phanoside, from the Plant Gynostemma pentaphyllum^*

Åke Norberg, Nguyen Khanh Hoa¶||, Edvards Liepinsh, Dao Van Phan||, Nguyen Duy Thuan**, Hans Jörnvall, Rannar Sillard, and Claes-Göran Östenson¶

From the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden, ^¶Department of Molecular Medicine, Karolinska Hospital, SE-171 76 Stockholm, Sweden, ^||Department of Pharmacology, Hanoi Medical University, Hanoi, Vietnam, and ^**Institute of Material Medica, Hanoi, Vietnam

Extracts from Gynostemma pentaphyllum Makino (Cucurbitaceae), a Southeast Asian herb, has been reported to affect numerous activities resulting in antitumor, cholesterol-lowering, immunopotentiating, antioxidant, and hypoglycemic effects. We have isolated one active compound by ethanol extraction, distribution in n-butyl alcohol/water, solid phase extraction/separation, and several rounds of reverse phase high pressure liquid chromatography. We have shown by NMR and mass spectrometry that this active compound is a novel saponin, a gypenoside, which we have named phanoside (21-,23-epoxy-,3-,20-,21-trihydroxydammar-24-ene-3-O-([-D-rhamnopyranosyl(12)]-[-D-glycopyranosyl(13)]--D-lyxopyranoside)), with a molecular mass of 914.5 Da. Phanoside is a dammarane-type saponin, and four stereoisomers differing in configurations at positions 21 and 23 were identified, each of which were found to stimulate insulin release from isolated rat pancreatic islets. We have also found that the stereoisomers are interconvertible. Dose-dependent insulin-releasing activities at 3.3 and 16.7 mM glucose levels were determined for the racemic mixture containing all four stereoisomers. Phanoside at 500 µM stimulates insulin release in vitro 10-fold at 3.3 mM glucose and potentiates the release almost 4-fold at 16.7 mM glucose. At these glucose levels, 2 µM glibenclamide stimulates insulin release only 2-fold. Interestingly, -cell sensitivity to phanoside is higher at 16.7 mM than at 3.3 mM glucose, although insulin responses were significantly increased by phanoside below 125 µM only at high glucose levels. Also when given orally to rats, phanoside (40 and 80 mg/ml) improved glucose tolerance and enhanced plasma insulin levels at hyperglycemia.

Received for publication, March 29, 2004 , and in revised form, June 18, 2004.

^* This study was supported by grants from the Swedish International Development Cooperation Agency, Swedish Diabetes Association, Swedish Research Council, and Karolinska Institutet. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental appendix.

These authors contributed equally to this study.

To whom correspondence should be addressed. Tel.: 46-8-52487011; Fax: 46-8-319497; E-mail: rannar{at}ki.se.

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