SARAVANANG,PONMURUGANP,DEEPA MA,et al.Modulatory effects of diosgenin on attenuating the key enzymes activities of carbohydrate metabolism and glycogen content in Streptozotocin-induced diabetic rats[J].Can J Diabetes,2014,38(6):409-414.
Fenugreek and its active compound diosgenin are ancient herbal medicines recommended by the World Health Organization. In this study, the effect of diosgenin on changes in carbohydrate metabolic enzymes and glycogen content in muscle and kidneys of streptozotocin-induced diabetes rats were evaluated. Diabetes was induced in male albino Wistar rats by intraperitoneal administration of streptozotocin. The diosgenin at different doses (15, 30 and 60 mg/kg body weight) was administered orally to normal and streptozotocin-diabetic rats for 45 days. Streptozotocin intoxication led to a significant increase (p<0.05) in blood glucose and a decrease in insulin levels. The carbohydrate metabolic enzymes and glycogen content were also altered. The daily oral administration of diosgenin at different doses (15, 30 and 60 mg/kg body weight) to diabetic rats for 45 days resulted a significant (p<0.05) decline in blood glucose level and a significant increase in plasma insulin level. The altered activities of carbohydrate metabolic key enzymes in muscle and kidneys of diabetic rats were significantly (p<0.05) reverted to near normal level by the administration of diosgenin. The obtained results were compared with glibenclamide, a standard oral hypoglycemia drug. The modulatory effects of diosgenin on attenuating the activities of carbohydrate metabolic enzymes afford a promise for persistent use for the treatment of diabetes in the future, even though clinical studies to evaluate this possibility may be warranted.
RAFAELAR,VICTORIAJ,MIWONA,et al.Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver[J].J Biol Chem,2014,289(9):5510-5517.
Abstract Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor that regulates genes in the de novo lipogenesis and glycolysis pathways. The levels of SREBP-1 are significantly elevated in obese patients and in animal models of obesity and type 2 diabetes, and a vast number of studies have implicated this transcription factor as a contributor to hepatic lipid accumulation and insulin resistance. However, its role in regulating carbohydrate metabolism is poorly understood. Here we have addressed whether SREBP-1 is needed for regulating glucose homeostasis. Using RNAi and a new generation of adenoviral vector, we have silenced hepatic SREBP-1 in normal and obese mice. In normal animals, SREBP-1 deficiency increased Pck1 and reduced glycogen deposition during fed conditions, providing evidence that SREBP-1 is necessary to regulate carbohydrate metabolism during the fed state. Knocking SREBP-1 down in db/db mice resulted in a significant reduction in triglyceride accumulation, as anticipated. However, mice remained hyperglycemic, which was associated with up-regulation of gluconeogenesis gene expression as well as decreased glycolysis and glycogen synthesis gene expression. Furthermore, glycogen synthase activity and glycogen accumulation were significantly reduced. In conclusion, silencing both isoforms of SREBP-1 leads to significant changes in carbohydrate metabolism and does not improve insulin resistance despite reducing steatosis in an animal model of obesity and type 2 diabetes.
XIAX,YANJ,SHEN Y et al.Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis[J].PLoS One,2011,6(2):e16556.
Berberine (BBR) is a compound originally identified in a Chinese herbal medicine Huanglian (Coptis chinensis French). It improves glucose metabolism in type 2 diabetic patients. The mechanisms involve in activation of adenosine monophosphate activated protein kinase (AMPK) and improvement of insulin sensitivity. However, it is not clear if BBR reduces blood glucose through other mechanism. In this study, we addressed this issue by examining liver response to BBR in diabetic rats, in which hyperglycemia was induced in Sprague-Dawley rats by high fat diet. We observed that BBR decreased fasting glucose significantly. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in liver by BBR. Hepatic steatosis was also reduced by BBR and expression of fatty acid synthase (FAS) was inhibited in liver. Activities of transcription factors including Forkhead transcription factor O1 (FoxO1), sterol regulatory element-binding protein 1c (SREBP1) and carbohydrate responsive element-binding protein (ChREBP) were decreased. Insulin signaling pathway was not altered in the liver. In cultured hepatocytes, BBR inhibited oxygen consumption and reduced intracellular adenosine triphosphate (ATP) level. The data suggest that BBR improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by BBR. The observation supports that BBR improves glucose metabolism through an insulin-independent pathway.
KUMARM,RAWATP,KHAN MF,et al.Phenolic glycosides from dodecadeniagrandiflora and their glucose-6-phosphatase inhibitory activity[J].Fitoterapia,2010,81(6):475-479.
Three new compounds were isolated from D. grandiflora leaves, these compounds exhibited significant glucose-6-phosphatase inhibitory activity.
LEONIDK,MANAMLEYN,SNYDERW,et al.AMG 151 (ARRY-403),a novel glucokinase activator,decreases fasting and postprandial glycemia in patients with type 2 diabetes[J].Diabetes Obes Metab,2015,18:245-252.
Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose–effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33–35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 20065mg twice daily, AMG 151 at 100, 200 or 40065mg once daily or matching placebo for 2865days. A significant linear dose–effect trend was observed with the twice-daily regimen (p65=650.004) for change in FPG to day6528. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.
LYUL,WU SY,WANG GF,et al.Effect of astragaloside IV on hepatic glucose-regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin[J].Phytother Res,2010,24(2) :219-223.
Abstract Aim: Hepatic glycogen phosphorylase (GP) and glucose-6-phosphatase (G6Pase) are important in control of blood glucose homeostasis, and are considered to be potential targets for antidiabetic drugs. Astragaloside IV has been reported to have a hypoglycemic effect. However, the biochemical mechanisms by which astragaloside IV regulates hepatic glucose-metabolizing enzymes remain unknown. The present study examines whether GP and G6Pase mediate the hypoglycemic effect of astragaloside IV. Methods: Type 2 diabetic mice were treated with astragaloside IV for 2 weeks. Blood glucose and insulin levels were measured by a glucometer and the ELISA method, respectively. Total cholesterol (TC) and triglyceride (TG) levels were determined using Labassay TM kits. Activities of hepatic GP and G6Pase were measured by the glucose-6-phosphate dehydrogenase-coupled reaction. The mRNA and protein levels of both enzymes were determined by real-time RT-PCR and Western blotting. Results: Astragaloside IV at 25 and 50鈥塵g/kg significally decreased the blood glucose, TG and insulin levels, and inhibited the mRNA and protein expression as well as enzyme activity of GP and G6Pase in diabetic mice. Conclusions: Astragaloside IV exhibited a hypoglycemic effect in diabetic mice. The hypoglycemic effect of this compound may be explained, in part, by its inhibition of hepatic GP and G6Pase activities. Copyright 漏 2009 John Wiley & Sons, Ltd.
LIUQ,YUZ,LINZ,et al.Danshen extract 15,16-dihydrotanshinone I functions as a potential modulator against metabolic syndrome through multi-target pathways[J].J Steroid Biochem,2010,120(4/5):155-163.
Hypertension is a common complication of type 2 diabetes mellitus (T2DM), and is the main cause for T2DM-associated mortality. Although the stringent control of blood pressure is known to be beneficial in reducing the cardiovascular mortality of T2DM patients, drugs with both anti-hypertensive and anti-hyperglycemic effects are seldom reported. The traditional Chinese medicine danshen has long been used for lowering both blood pressure and blood glucose in T2DM patients, shedding lights on the development of such medication. However, the molecular mechanism and active component remain unclear. Here, we report that the lipophilic component, 15,16-dihydrotanshinone I (DHTH) from danshen potently antagonized both mineralocorticoid and glucocorticoid receptors, and efficiently inhibited the expression of their target genes like Na+/K+ ATPase, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK). In addition, DHTH increased AMPK伪 phosphorylation and regulated its downstream pathways, including increasing acetyl-CoA carboxylase (ACC) phosphorylation, inhibiting transducer of regulated CREB activity 2 (TORC2) translocation and promoting glucose uptake. Such discovered multi-target effects of DHTH are expected to have provided additional understandings on the molecular basis of the therapeutic effects of danshen against the metabolic syndrome.
WU SY,WANG GF,LIU ZQ,et al.Effect of geniposide,a hypoglycemic glucoside,on hepatic regulating enzymes in diabetic mice induced by a high-fat diet and Streptozotocin[J].Acta Pharmacol Sin,2009,30(2):202-207.
PARIL,SANKARANARAYANANC.Beneficial effects of thymoquinone on hepatic key enzymes in Streptozotocin-nicotinamide induced diabetic rats[J].Life Sci,2009,85(s23-26):830-834.
The present study was designed to evaluate the antihyperglycemic potential of thymoquinone (TQ), major constituent of Nigella sativa seeds on the activities of key enzymes of carbohydrate metabolism in streptozotocin (STZ)-nicotinamide (NA)-induced diabetic rats. Diabetes was induced in experimental rats weighing 180鈥220 g, by a single intraperitoneal (i.p) injection of STZ (45 mg/kg b.w), 15 min after the i.p administration of NA (110 mg/kg b.w). Diabetic rats were administered TQ intragastrically at 20, 40, 80 mg/kg b.w for 45 days. The levels of plasma glucose, insulin, glycated hemoglobin (HbA 1C) and hemoglobin (Hb) were measured. The activities of hexokinase, glucose 6-phosphate dehydrogenase, glucose 6-phosphatase and fructose 1,6-bisphosphatase were assayed in liver homogenates. Oral administration of TQ for 45 days, dose dependently improved the glycemic status in STZ-NA induced diabetic rats. The levels of insulin, Hb increased with significant decrease in glucose and HbA 1C levels. The altered activities of carbohydrate metabolic enzymes were restored to near normal. No significant changes were noticed in normal rats treated with TQ. These results show that TQ at 80 mg/kg b.w is associated with beneficial changes in hepatic enzyme activities and thereby exerts potential antihyperglycemic effects.
YOSHINARIO,IGARASHIK.Anti-diabetic effect of trigonelline and nicotinic acid,on KK-A(y) mice[J].Curr Med Chem,2010,17(20):2196-2202.
Trigonelline (TRG) and nicotinic acid (NA), in which the former but not the latter improved the blood glucose level in the oral glucose tolerance test (OGTT) in Goto-Kakizaki (GK) rats were tested for anti-diabetic effects in mellitus models of KK-Ay obese mice that had type 2 diabetes. <br/> Blood glucose level in OGTT carried out on day 22-23 was lowered after feeding in mice fed TRG and NA than that of the control mice not fed these compounds, indicating that both TRG and NA have sufficient activity to improve glucose tolerance in diabetes with obesity. The serum insulin levels at fasting showed significantly lower levels in mice fed TRG, and a lower tendency in mice fed NA, compared with the control mice. The triglyceride (TG) levels in the liver and adipose tissue in mice fed TRG and NA showed lower values or a lower tendency than those of the control mice, indicating that TRG and NA were also effective to improve the changes in lipid levels accompanied with diabetes. Higher values or a higher tendency of the glucokinase (GLK) / glucose-6-phosphatase (G6Pase) ratio in the liver and lower levels of the serum tumor necrosis factor (TNF) -脦卤 in the TRG- and NA-fed mice, compared to the control mice, suggested that the regulation of GLK and G6Pase, and TNF-脦卤 production by TRG and NA are closely related in suppressing the progression of diabetes in the KK-Ay mice.
SOARES AF,CARVALHO RA,VEIGA FJ,et al.Restoration of direct pathway glycogen synthesis flux in the STZ-diabetes rat model by insulin administration[J].Am J Physiol-Endoc M,2012,303(7):875-885.
Abstract Type 1 diabetes subjects are characterized by impaired direct pathway synthesis of hepatic glycogen that is unresponsive to insulin therapy. Since it is not known whether this is an irreversible defect of insulin-dependent diabetes, direct and indirect pathway glycogen fluxes were quantified in streptozotocin (STZ)-induced diabetic rats and compared with STZ rats that received subcutaneous or intraperitoneal insulin (I-SC or I-IP). Three groups of STZ rats were studied at 18 days post-STZ treatment. One group was administered I-SC and another I-IP as two daily injections of short-acting insulin at the start of each light and dark period for days 9-18. A third group did not receive any insulin, and a fourth group of nondiabetic rats was used as control. Glycogen synthesis via direct and indirect pathways, de novo lipogenesis, and gluconeogenesis were determined over the nocturnal feeding period using deuterated water. Direct pathway was residual in STZ rats, and glucokinase activity was also reduced significantly from control levels. Insulin administration restored both net glycogen synthesis via the direct pathway and glucokinase activity to nondiabetic control levels and improved the lipogenic pathway despite an inefficient normalization of the gluconeogenic pathway. We conclude that the reduced direct pathway flux is not an irreversible defect of insulin-dependent diabetes.
SEKAR DS,SIVAGNANAM KS.Antidiabetic activity of Momordicacharantia seeds on Streptozotocin induced diabetic rats[J].Pharmazie,2005,60(5):383-387.
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WEN XA,LIUJ,ZHANG LY,et al.Synthesis and biological evaluation of arjunolic acid,bayogenin,hederagonic acid and 4-epihederagonic acid as glycogen phosphorylase inhibitors[J].Chin J Nat Med,2010,8(6):441-448.
AIM: To study glycogen phosphorylase inhibitory activity of natural pentacyclic triterpenes bearing 23-hydroxy or 24-hydroxy. METHODS: Arjunolic acid, bayogenin, hederagonic acid and 4-epi-hederagonic acid were synthesized from oleanolic acid as the starting material and biologically evaluated as glycogen phosphorylase inhibitors. RESULTS: Arjunolic acid, bayogenin, hederagonic acid and 4-epi-hederagonic acid were successfully semi-synthesized by multiple steps. The synthesis of arjunolic acid was via 11 steps in about 10% overall yield, and bayogenin via 14 steps in about 12% overall yield. Biological evaluation indicated that arjunolic acid, bayogenin, hederagonic acid and 4-epi-hederagonic acid showed moderate potency of glycogen phosphorylase inhibition with IC50 of 53-103 渭mol路L?1. CONCLUSION: Arjunolic acid, bayogenin, hederagonic acid and 4-epi-hederagonic acid are gly-cogen phosphorylase inhibitors with moderate potency. Insert of 23-hydroxy or 24-hydroxy to oleanane skeleton has a tendency to be unfavorable to GP inhibition.
PUNITHAVATHI VR,PRINCE P S M,KUMAR R,et al.Antihyperglycaemic,antilipidperoxidative and antioxidant effects of gallic acid on Streptozotocin induced diabetic Wistar rats[J].Eur J Pharmacol,2011,650(1):465-471.
The present study aims to evaluate the antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic male Wistar rats. To induce diabetes mellitus, rats were injected with streptozotocin intraperitoneally at a single dose of 4002mg/kg. Streptozotocin induced diabetic rats showed significant ( P 02<020.05) increase in the levels of blood glucose, glycosylated haemoglobin and significant ( P 02<020.05) decrease in the levels of plasma insulin, body weight and total haemoglobin. Diabetic rats also showed significant ( P 02<020.05) decrease in the activity of hepatic hexokinase and significant ( P 02<020.05) increase in the activities of glucose-6-phosphatase and fructose-1, 6-bisphosphatase. The pancreatic thiobarbituric acid reactive substances and lipid hydroperoxides were significantly ( P 02<020.05) increased and the activities of pancreatic superoxide dismutase, catalase and glutathione peroxidase were significantly ( P 02<020.05) decreased in diabetic rats. Oral treatment with gallic acid (10 and 2002mg/kg) daily for a period of 2102days showed significant ( P 02<020.05) protective effects on all the biochemical parameters studied. Histopathology of pancreas confirmed the protective effects of gallic acid in diabetic rats. In vitro study also revealed the potent antioxidant effect of gallic acid. Thus, the study shows the antihyperglycaemic, antilipid peroxidative and antioxidant effects of gallic acid on streptozotocin induced diabetic rats. The effect exerted by 20mg/kg body weight of gallic acid was more effective than 1002mg/kg body weight of gallic acid.
WU SY,WANG GF,LIU ZQ,et al.Effect of geniposide,a hypoglycemic glucoside,on hepatic regulating enzymes in diabetic mice induced by a high-fat diet and Streptozotocin[J].Acta Pharmacol Sin,2009,30(2):202-208.
LIUJ,WANGX,CHEN YP,et al.Maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase[J].Chin J Nat Med,2014,12(4):259-265.
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KIM J JY,TANY,XIAOL,et al.Green tea polyphenol epigallocatechin-3-gallate enhance glycogen synthesis and inhibit lipogenesis in hepatocytes[J].Biomed Res Int,2013,2013(3):920128-920129.
The beneficial effects of green tea polyphenols (GTP) against metabolic syndrome and type 2 diabetes by suppressing appetite and nutrient absorption have been well reported. However the direct effects and mechanisms of GTP on glucose and lipid metabolism remain to be elucidated. Since the liver is an important organ involved in glucose and lipid metabolism, we examined the effects and mechanisms of GTP on glycogen synthesis and lipogenesis in HepG2 cells. Concentrations of GTP containing 68% naturally occurring (???)-epigallocatechin-3-gallate (EGCG) were incubated in HepG2 cells with high glucose (30???mM) under 100???nM of insulin stimulation for 24???h. GTP enhanced glycogen synthesis in a dose-dependent manner. 10?????M of EGCG significantly increased glycogen synthesis by 2fold (P<0.05) compared with insulin alone. Western blotting revealed that phosphorylation of Ser9 glycogen synthase kinase 3?? and Ser641 glycogen synthase was significantly increased in GTP-treated HepG2 cells compared with nontreated cells. 10?????M of EGCG also significantly inhibited lipogenesis (P<0.01). We further demonstrated that this mechanism involves enhanced expression of phosphorylated AMP-activated protein kinase ?? and acetyl-CoA carboxylase in HepG2 cells. Our results showed that GTP is capable of enhancing insulin-mediated glucose and lipid metabolism by regulating enzymes involved in glycogen synthesis and lipogenesis.
KIM KM,LEE KS,LEE GY,et al.Anti-diabetic efficacy of KICG1338,a novel glycogen synthase kinase-3β inhibitor,and its molecular characterization in animal models of type 2 diabetes and insulin resistance[J].Mol Cell Endocrinol,2015,11(3):4-21.
Selective inhibition of glycogen synthase kinase-3 (GSK3) has been targeted as a novel therapeutic strategy for diabetes mellitus. We investigated the anti-diabetic efficacy and molecular mechanisms of KICG1338 (2-(4-fluoro-phenyl)-3 H -imidazo[4,5-b]pyridine-7-carboxylic acid(4-methyl-pyridin-3-yl)-amide), a GSK3尾 inhibitor, in three animal models: Otsuka Long-Evans Tokushima Fatty (OLETF) rats, leptin receptors-deficient db / db mice, and diet-induced obese (DIO) mice. Biochemical parameters including glucose tolerance tests and gene expressions associated with glucose metabolism were investigated. Glucose excursion decreased significantly by KICG1338-treated OLETF rats, accompanied by increase in insulin receptor substrate-1 and glucose transporter (GLUT)-4 expressions in muscle and decreased GLUT-2 expression in liver. Glucose-lowering effects were similarly observed in KICG1338-treated db / db and DIO mice. KICG1338 treatment increased adiponectin levels and decreased TNF-伪 levels. KICG1338 therapy also led to greater 尾-cell preservation and less hepatic fat infiltration with decreased expressions of genes involved in inflammation and endoplasmic reticulum stress. These data demonstrate anti-diabetic efficacy of KICG1338, a novel GSK3尾 inhibitor.
JANG SM,KIM MJ,CHOI MS,et al.Inhibitory effects of ursolic acid on hepatic polyol pathway and glucose production in Streptozotocin-induced diabetic mice[J].Metabolism,2010,59(4):512-519.
The effects of ursolic acid on the polyol pathway and glucose homeostasis鈥搑elated metabolism were examined in the livers of streptozotocin (STZ)-induced diabetic mice fed a high-fat (37% calories from fat) diet for 4 weeks. Male mice were divided into nondiabetic, diabetic control, and diabetic鈥搖rsolic acid (0.05% wt/wt) groups. Diabetes was induced by the injection of STZ (200 mg/kg body weight, intraperitoneally). Although an ursolic acid supplement lowered the blood glucose level, it did not affect the plasma leptin and adiponectin levels. The present study shows that the blood glucose levels have a positive correlation with the hepatic sorbitol dehydrogenase activities ( r = 0.39, P < .05). Ursolic acid significantly inhibited sorbitol dehydrogenase activity as well as aldose reductase activity in the liver. The supplementation of ursolic acid significantly increased glucokinase activity, while decreasing glucose-6-phosphatase activity in the livers of STZ-induced diabetic mice. Ursolic acid significantly elevated the hepatic glycogen content compared with the diabetic control group. Supplementation with ursolic acid significantly lowered the plasma total cholesterol, free fatty acid, and triglyceride concentrations compared with the diabetic control group, whereas it normalized hepatic triglyceride concentration. A negative correlation was found between the hepatic triglyceride concentration and blood glucose levels ( r = 鈭0.50, P < .01) in regard to insulin-dependent diabetic mice. The hepatic fatty acid synthase activity was significantly lower in the ursolic acid group than in the diabetic control group, whereas hepatic fatty acid 尾-oxidation and carnitine palmitoyltransferase activities were significantly higher. These results indicate that ursolic acid may be beneficial in preventing diabetic complications by improving the polyol pathway as well as the lipid metabolism and that it can function as a potential modulator of hepatic glucose production, which is partly mediated by up-regulating glucose utilization and glycogen storage and down-regulating glyconeogenesis in the liver.
Abstract The extract of plant Shilianhua (SLH; Sinocrassula indica Berge) is a component in a commercial product for control of blood glucose. However, it remains to be investigated whether the SLH extract enhances insulin sensitivity in a model of type 2 diabetes. To address this question, the SLH crude extract was fractionated into four parts on the basis of polarity, and bioactivities of each part were tested in cells. One of the fractions, F100, exhibited a strong activity in the stimulation of glucose consumption in vitro. Glucose consumption was induced significantly by F100 in 3T3-L1 adipocytes, L6 myotubes, and H4IIE hepatocytes in the absence of insulin. F100 also increased insulin-stimulated glucose consumption in L6 myotubes and H4IIE hepatocytes. It increased insulin-independent glucose uptake in 3T3-L1 adipocytes and insulin-dependent glucose uptake in L6 cells. The glucose transporter-1 (GLUT1) protein was induced in 3T3-L1 cells, and the GLUT4 protein was induced in L6 cells by F100. Mechanism study indicated that F100 induced GSK-3beta phosphorylation, which was comparable with that induced by insulin. Additionally, the transcriptional activity of NF-kappaB was inhibited by F100. In RAW 264.7 macrophages, mRNA expression of NF-kappaB target genes (TNFalpha and MCP-1) was suppressed by F100. In KK.Cg-A(y)/+ mice, F100 decreased fasting insulin and blood glucose and improved insulin tolerance significantly. We conclude that the F100 may be a bioactive component in the SLH plant. It promotes glucose metabolism in vitro and in vivo. Inhibition of GSK-3beta and NF-kappaB may be the potential mechanism.
DO THIH,TRINH NAMT,TRAN THIH,et al.Selected compounds derived from Moutan Cortex stimulated glucose uptake and glycogen synthesis via AMPK activation in human HepG2 cells[J].J Ethnopharmacol,2011,47(47):209-216.
To evaluate the effect of selected compounds derived from Moutan Cortex on glucose uptake and glycogen synthesis associated with AMPK activation in insulin-resistant human HepG2 cell. The effect of isolated compounds ( 1– 16) on glucose uptake and glycogen synthesis was performed using HepG2 cells. The western blot was used to determine the expression of AMPK and its downstream substrates, ACC, p-ACC, and p-GSK-3β. The effects of the 16 compounds from Moutan Cortex on glucose metabolism in HepG2 cells under high glucose conditions were evaluated. Compounds 2, 3, and 6 displayed highly potent effects on the stimulation of glucose uptake and glycogen synthesis in human HepG2 cells under high glucose conditions. Compounds 2, 3, and 6 phosphorylate AMPK (AMP-activated protein kinase), and resulted in increased phosphorylation of GSK-3β and suppression of lipogenic expression (ACC and FAS) in a dose-dependent manner. Compounds 2, 3, and 6 also demonstrated interesting, strong eNOS phosphorylation in human umbilical vein endothelial cells (HUVECs). Compounds 1, 4, 5–12, and 14 displayed considerable effects on hepatic glucose production, AMPK activation, and phosphorylation of GSK-3β in HepG2 cells under high glucose conditions. These effects may indicate that the activation of AMPK by the active compounds from Moutan Cortex has considerable potential for reversing the metabolic abnormalities associated with type-2 diabetes.
Anti-diabetic efficacy of KICG1338,a novel glycogen synthase kinase-3β inhibitor,and its molecular characterization in animal models of type 2 diabetes and insulin resistance
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