ABSTRACT
Catalpol, a major bioactive component from Rehmannia glutinosa, which has been used to treat diabetes. The present study was designed to elucidate the anti-diabetic effect and mechanism of action for catalpol in db/db mice. The db/db mice were randomly divided into six groups (10/group) according to their blood glucose levels: db/db control, metformin (positive control), and four dose levels of catalpol treatment (25, 50, 100, and 200 mg·kg), and 10 db/m mice were used as the normal control. All the groups were administered orally for 8 weeks. The levels of fasting blood glucose (FBG), random blood glucose (RBG), glucose tolerance, insulin tolerance, and glycated serum protein (GSP) and the globe gene expression in liver tissues were analyzed. Our results showed that catalpol treatment obviously reduced water intake and food intake in a dose-dependent manner. Catalpol treatment also remarkably reduce fasting blood glucose (FBG) and random blood glucose (RBG) in a dose-dependent manner. The RBG-lowering effect of catalpol was better than that of metformin. Furthermore, catalpol significantly improved glucose tolerance and insulin tolerance via increasing insulin sensitivity. Catalpol treatment significantly decreased GSP level. The comparisons of gene expression in liver tissues among normal control mice, db/db mice and catalpol treated mice (200 and 100 mg·kg) indicated that there were significant increases in the expressions of 287 genes, whichwere mainly involved in lipid metabolism, response to stress, energy metabolism, and cellular processes, and significant decreases in the expressions of 520 genes, which were mainly involved in cell growth, death, immune system, and response to stress. Four genes expressed differentially were linked to glucose metabolism or insulin signaling pathways, including Irs1 (insulin receptor substrate 1), Idh2 (isocitrate dehydrogenase 2 (NADP), mitochondrial), G6pd2 (glucose-6-phosphate dehydrogenase 2), and SOCS3 (suppressor of cytokine signaling 3). In conclusion, catalpol ecerted significant hypoglycemic effect and remarkable therapeutic effect in db/db mice via modulating various gene expressions.
Subject(s)
Animals , Humans , Male , Mice , Blood Glucose , Metabolism , Diabetes Mellitus, Experimental , Drug Therapy , Genetics , Metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drugs, Chinese Herbal , Gene Expression , Glucosephosphate Dehydrogenase , Genetics , Metabolism , Hypoglycemic Agents , Insulin , Metabolism , Insulin Receptor Substrate Proteins , Genetics , Metabolism , Iridoid Glucosides , Isocitrate Dehydrogenase , Genetics , Metabolism , Liver , Metabolism , Mice, Inbred C57BL , Rehmannia , Chemistry , Suppressor of Cytokine Signaling 3 Protein , Genetics , MetabolismABSTRACT
Catalpol, a major bioactive component from Rehmannia glutinosa, which has been used to treat diabetes. The present study was designed to elucidate the anti-diabetic effect and mechanism of action for catalpol in db/db mice. The db/db mice were randomly divided into six groups (10/group) according to their blood glucose levels: db/db control, metformin (positive control), and four dose levels of catalpol treatment (25, 50, 100, and 200 mg·kg), and 10 db/m mice were used as the normal control. All the groups were administered orally for 8 weeks. The levels of fasting blood glucose (FBG), random blood glucose (RBG), glucose tolerance, insulin tolerance, and glycated serum protein (GSP) and the globe gene expression in liver tissues were analyzed. Our results showed that catalpol treatment obviously reduced water intake and food intake in a dose-dependent manner. Catalpol treatment also remarkably reduce fasting blood glucose (FBG) and random blood glucose (RBG) in a dose-dependent manner. The RBG-lowering effect of catalpol was better than that of metformin. Furthermore, catalpol significantly improved glucose tolerance and insulin tolerance via increasing insulin sensitivity. Catalpol treatment significantly decreased GSP level. The comparisons of gene expression in liver tissues among normal control mice, db/db mice and catalpol treated mice (200 and 100 mg·kg) indicated that there were significant increases in the expressions of 287 genes, whichwere mainly involved in lipid metabolism, response to stress, energy metabolism, and cellular processes, and significant decreases in the expressions of 520 genes, which were mainly involved in cell growth, death, immune system, and response to stress. Four genes expressed differentially were linked to glucose metabolism or insulin signaling pathways, including Irs1 (insulin receptor substrate 1), Idh2 (isocitrate dehydrogenase 2 (NADP), mitochondrial), G6pd2 (glucose-6-phosphate dehydrogenase 2), and SOCS3 (suppressor of cytokine signaling 3). In conclusion, catalpol ecerted significant hypoglycemic effect and remarkable therapeutic effect in db/db mice via modulating various gene expressions.
Subject(s)
Animals , Humans , Male , Mice , Blood Glucose , Metabolism , Diabetes Mellitus, Experimental , Drug Therapy , Genetics , Metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drugs, Chinese Herbal , Gene Expression , Glucosephosphate Dehydrogenase , Genetics , Metabolism , Hypoglycemic Agents , Insulin , Metabolism , Insulin Receptor Substrate Proteins , Genetics , Metabolism , Iridoid Glucosides , Isocitrate Dehydrogenase , Genetics , Metabolism , Liver , Metabolism , Mice, Inbred C57BL , Rehmannia , Chemistry , Suppressor of Cytokine Signaling 3 Protein , Genetics , MetabolismABSTRACT
Objective To establish a sensitive, simple and accurate HPLC-MS/MS method to quantify glycyrrhetic acid(glycyrrhetinic acid)in mice blood, and to further study pharmacokinetic profiles of glycyrrhetic acid after oral administration of glycyrrhizin and Bu- Zhong- Yi- Qi- Wan (BY). Methods Rats were intragastric administered of glycyrrhizin(glycyrrhizic acid, 61.5 mg/kg) and BY extract(3 g/kg, with the same mole of glycyrrhizin moiety), respectively. Plasma samples were collected after administration and extracted with liquid-liquid extraction, then by separated by liquid chromatography on a C8 reversion phase chromatographic column with gradient elution. Concentration of glycyrrhetic acid was detected by the validated HPLC-MS/MS. Non-compartmental pharmacokinetic profiles were constructed using the software of Das 2.0 software(Shanghai, China), and the pharmacokinetic parameters were compared using unpaired Student’s t-test. Results This bioanalytical method was fully validated and showed good linearity(r> 0.99), wide dynamic range(5-1000 ng/ml), and favorable accuracy and precision. Compared with the glycyrrhizin pure form group, BY significantly reduced the Cmax and AUC0-t of glycyrrhetic acid by 56% and 76%, respectively. Whereas no significant differences in Tmax, T1/2 and MRT were observed between the two groups. Conclusion The constituents in the BY prescription have significantly reduced the oral bioavailability of glycyrrhetic acid in rats than those in the glycyrrhizin pure form and the results indicate that some components in the BY have an inhibition effect on the absorption process of glycyrrhizin in the gut.