Antidiabetic Activity of Sedum dendroideum: Metabolic Enzymes as Putative Targets for the Bioactive Flavonoid Kaempferitrin

Abstract

The aim of this study was to evaluate the antidiabetic potentialof a leaf extract and flavonoids fromSedum dendroideum(SD). Additionally, our goals were to establish a possible struc-ture/activity relationship between these flavonoids and toassess the most active flavonoid on the glycolytic enzyme 6-phosphofructo-1-kinase (PFK). SD juice (LJ), a flavonoid-richfraction (BF), and separately five flavonoids were evaluatedintraperitoneally for their acute hypoglycemic activity in normaland streptozotocin-induced diabetic mice. First, the majorflavonoids kaempferol 3,7-dirhamnoside or kaempferitrin (1),kaempferol 3-glucoside-7-rhamnoside (2), and kaempferol 3-neohesperidoside-7-rhamnoside (3) were tested. Then, themonoglycosides kaempferol 7-rhamnoside (5) and kaempferol3-rhamnoside (6) were assayed to establish their structure/activ-ity relationship. The effect of 1 on PFK was evaluated in skeletalmuscle, liver, and adipose tissue from treated mice. LJ (400mg/kg), BF (40 mg/kg), and flavonoid 1 (4 mg/kg) reduced gly-cemia in diabetic mice (120 min) by 52, 53, and 61%, respec-tively. Flavonoids 2, 3, 5, and 6 were inactive or showed littleactivity, suggesting that the two rhamnosyl moieties in kaemp-feritrin are important requirements. Kaempferitrin enhanced thePFK activity chiefly in hepatic tissue, suggesting that it is ableto stimulate tissue glucose utilization. This result is confirmedtesting kaempferitrin on C2C12 cell line, where it enhanced glu-cose consumption, lactate production, and the key regulatoryglycolytic enzymes. The hypoglycemic activity of kaempferitrindepends on the presence of both rhamnosyl residues in the fla-vonoid structure when intraperitoneally administered. Our find-ings show for the first time that a flavonoid is capable ofstimulating PFK in a model of diabetes and that kaempferitrinstimulates glucose-metabolizing enzymes. This study contrib-utes to the knowledge of the mechanisms by which this flavo-noid exerts its hypoglycemic activity.