title: 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 potential of a leaf extract and flavonoids from Sedum dendroideum (SD). Additionally, our goals were to establish a possible structure/activity relationship between these flavonoids and to assess the most active flavonoid on the glycolytic enzyme 6-phosphofructo-1-kinase (PFK). SD juice (LJ), a flavonoid-rich fraction (BF), and separately five flavonoids were evaluated intraperitoneally for their acute hypoglycemic activity in normal and streptozotocin-induced diabetic mice. First, the major flavonoids kaempferol 3,7-dirhamnoside or kaempferitrin (1), kaempferol 3-glucoside-7-rhamnoside (2), and kaempferol 3-neohesperidoside-7-rhamnoside (3) were tested. Then, the monoglycosides kaempferol 7-rhamnoside (5) and kaempferol 3-rhamnoside (6) were assayed to establish their structure/activity relationship. The effect of 1 on PFK was evaluated in skeletal muscle, liver, and adipose tissue from treated mice. LJ (400 mg/kg), BF (40 mg/kg), and flavonoid 1 (4 mg/kg) reduced glycemia in diabetic mice (120 min) by 52, 53, and 61%, respectively. Flavonoids 2, 3, 5, and 6 were inactive or showed little activity, suggesting that the two rhamnosyl moieties in kaempferitrin are important requirements. Kaempferitrin enhanced the PFK activity chiefly in hepatic tissue, suggesting that it is able to stimulate tissue glucose utilization. This result is confirmed testing kaempferitrin on C2C12 cell line, where it enhanced glucose consumption, lactate production, and the key regulatory glycolytic enzymes. The hypoglycemic activity of kaempferitrin depends on the presence of both rhamnosyl residues in the flavonoid structure when intraperitoneally administered. Our findings show for the first time that a flavonoid is capable of stimulating PFK in a model of diabetes and that kaempferitrin stimulates glucose-metabolizing enzymes. This study contributes to the knowledge of the mechanisms by which this flavonoid exerts its hypoglycemic activity.
authors.affiliation: Laboratório de Enzimologia e Controle do Metabolismo (LabECoM), BioTecFar, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Da Silva
authors.forename: Livia Marques
authors.initials: LM
authors.lastname: Casanova
authors.forename: Mariah Celestino
authors.initials: MC
authors.lastname: Marcondes
authors.forename: Jair Machado
authors.initials: JM
authors.lastname: Espindola-Netto
authors.forename: Larissa Pereira
authors.initials: LP
authors.lastname: Paixão
authors.forename: Giany Oliveira
authors.initials: GO
authors.lastname: De Melo
authors.forename: Patricia
authors.initials: P
authors.lastname: Zancan
authors.forename: Mauro
authors.initials: M
authors.lastname: Sola-Penna
authors.forename: Sônia Soares
authors.initials: SS
authors.lastname: Costa
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D007004:Hypoglycemic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000201:enzymology; D044949:Kaempferols / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D032446:Myoblasts / Q000378:metabolism; D025221:Phosphofructokinases / Q000378:metabolism*; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D031963:Sedum / Q000737:chemistry*
chemical_list: D007004:Hypoglycemic Agents; D044949:Kaempferols; D010936:Plant Extracts; D025221:Phosphofructokinases; C042728:lespenefril
keywords: PFK; Sedum dendroideum; diabetes; flavonoids; kaempferitrin