Hypoglycemic effect of protopanaxadiol-type ginsenosides and compound K on Type 2 diabetes mice induced by high-fat diet combining with streptozotocin via suppression of hepatic gluconeogenesis

Compound K (CK) is a final intestinal metabolite of protopanaxadiol-type ginsenosides (PDG) from Panax ginseng. Although anti-diabetic activity of CK have been reported with genetic mouse models (db/db mice) in recent years, the therapeutic usefulness of CK and PDG in type 2 diabetes, a more prevalent form of diabetes, remains unclear. In the present investigation, we developed a mouse of non-insulin-dependent diabetes mellitus that closely simulated the metabolic abnormalities of the human disease. For this purpose, type 2 diabetes was induced in male ICR mice by combining of streptozotocin. The male ICR mice fed with HFD for 4 weeks received 100 mg/kg of STZ injected intraperitoneally. After 4 weeks, mice with fasting (12 h) blood glucose levels (FBG) above 7.8 mmol/L were divided into 3 groups (n = 12) and treated with vehicle (diabetes model, DM), 300 mg/kg/day of PDG and 30 mg/kg/day of CK for 4 weeks while continuing on the high-fat diet. Hypoglycemic effects of CK and PDG were consistently demonstrated by FBG levels, and insulin-sensitizing effects were seen during oral glucose tolerance testing (OGTT). Moreover, the mechanism of hypoglycemic effect in type 2 diabetic mice was examined. Gluconeogenic genes, Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), were decreased in two treatment groups with CK showing greater effects. These findings demonstrated the hypoglycemic and insulin-sensitizing capabilities of CK on type 2 diabetes induced by HFD/STZ via down-regulation of PEPCK and G6Pase expression in liver.     

Fucoidan regulate blood glucose homeostasis in C57BL/KSJ m+/+db and C57BL/KSJ db/db mice

Type 2 diabetes mellitus is a multisystem disease that is characterized by hyperglycemia and is associated with the dysfunction and failure of various organs. The control of postprandial hyperglycemia is important in the prevention and intervention of type 2 diabetes. Fucoidan has several biological activities in vitro and in vivo. However, the effect of fucoidan on hyperglycemia in non-diabetic and diabetic mice has not been investigated. This study was undertaken to study the effects of different molecular weight forms (5 kilodalton (k), 5-30 k and crude) of fucoidan on oral glucose tolerance tests in non-diabetic mice and on food intake, weight gain, fasting blood glucose and blood biochemistry of db/db mice. Treatment with 200 mg/mL 5 k, 5-30 k and crude fucoidan substantially prevented hyperglycemia according to oral glucose tolerance tests in non-diabetic mice. In addition, fucoidan fractions significantly reduced blood glucose levels in diabetic mice.     

Type 2 antidiabetic activity of bergenin from the roots of Caesalpinia digyna Rottler

Bergenin, a major constituent of Caesalpinia digyna Rottler (Leguminosae) was isolated from its roots and was characterized by comparing its melting point and spectroscopic data (IR, (1)H, (13)C, Mass Spectra) with standard bergenin. Isolated bergenin was then evaluated for antidiabetic (Type 2) activity in streptozotocin (STZ)-nicotinamide induced diabetic rats. Bergenin was administered at doses of 2.5, 5, and 10 mg/kg; p.o. to normal rats which were subjected to oral glucose tolerance test (OGTT). Bergenin at same dose level was given to diabetic rats and fasting blood glucose level was estimated on 0th, 7th and 14th day of treatment while plasma lipids, antioxidant enzymes and liver glycogen level in diabetic rats were estimated on 14th day of treatment followed by histopathological studies of pancreas. Bergenin at 10mg/kg; p.o. was found to reduce blood glucose level significantly in OGTT (P<0.01) while it showed a significant reduction in fasting blood glucose level in diabetic rats at same dose level only on 14th day of treatment. Bergenin in all dose levels reversed plasma lipid (reduced elevated TC, LDL-C and increased HDL-C level) profile to normal values except TG. However, bergenin showed no significant effect on liver glycogen at all dose level. The decrease in lipid peroxides and increase in superoxide dismutase (SOD) and catalase (CAT) in liver illustrated the antioxidant potential of bergenin. Histopathological studies demonstrated the regenerative effect of bergenin on pancreatic β cells. Hence, bergenin isolated from C. digyna possesses significant antidiabetic, hypolipidemic and antioxidant activity in Type 2 diabetic rats.     

Antihyperglycemic and antioxidant activities of total alkaloids from Catharanthus roseus in streptozotocin-induced diabetic rats

We evaluated the hypoglycemic and antioxidant effects of the total alkaloids of leaves and twigs of Catharanthus roseus Linn.(CTA) in streptozotocin(STZ)-induced diabetic rats. The hypoglycemic effect was measured by blood glucose and plasma insulin level. Oxidative stress was measured in heart, liver and kidney by levels of antioxidant markers, free radical scavengers and lipid peroxides i.e. superoxide dismutase(SOD), catalase(CAT), glutathione(GSH) and thiobarbituric acid reactive substances(TBARS). Biochemical parameters, i.e. aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphate(ALP) were observed in diabetic control and treated rats. Oral administration of CTA for30 days was followed by a significant(P \ 0.05) decrease in fasting blood glucose and increase in insulin level as compared with untreated diabetic rats. Also it significantly(P \ 0.05) reduced ALT, AST and ALP. The treatment also resulted in significant(P \ 0.05) reductions in GSH,SOD, CAT, and decrease in TBARS in the heart, liver and kidney of diabetic rats. The results suggest that CTA can effectively normalize the impaired antioxidant status in STZ-induced diabetes in a dose-dependent manner.CTA exerted rapid protective effects against lipid peroxidation by scavenging of free radicals and reducing the risk of diabetic complications.     

Comparative pharmacokinetics of baicalin in normal and the type 2 diabetic rats after oral administration of the Radix scutellariae extract

Radix scutellariae was used alone or in combination with other medicinal herbs in the treatment of type 2 diabetes mellitus in China. At present, the pharmacokinetics of baicalin in type 2 diabetic rats following oral administration of Radix scutellariae extract was investigated. The results showed that the pharmacokinetics (especially AUC) of baicalin in type 2 diabetic rats after oral administration of Radix scutellariae extract was remarkably different from that in normal rats. Then the mechanism which resulted in the increased AUC of baicalin in diabetic rats was investigated from system clearance and presystemic metabolism. And it was found that the increased AUC of baicalin in diabetic rats at least partly resulted from higher production of baicalein in the intestinal tract of type 2 diabetic rats. Moreover, the activity of β-glucuronidase in intestinal mucosa of type 2 diabetic rats was demonstrated to be higher than that in normal rats, which confirmed the results above. In conclusion, the pharmacokinetic behavior of baicalin was significantly altered in type 2 diabetic rats after orally administrated Radix scutellariae extract, which may partly result from the increased activity of intestinal β-glucuronidase under the pathological state of type 2 diabetes mellitus.     

Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy

Diabetes mellitus is a serious debilitating epidemic affecting all social strata in developing as well as developed countries. Diabetic neuropathy is most common of secondary complications associated with diabetes mellitus and is characterized by slowing of nerve conduction velocity, elevated pain, sensory loss and nerve fiber degeneration. The aim of the present investigation was to evaluate the neuroprotective effect of naringin against streptozotocin (STZ) induced diabetic neuropathic pain in laboratory rats. Four weeks after intraperitoneal injection of STZ resulted in significant decrease in mechano-tactile allodynia, mechanical hyperalgesia, thermal hyperalgesia and motor nerve conduction velocity. Activity of endogenous antioxidant like superoxide dismutase as well as membrane bound inorganic phosphate enzyme was also found to be significantly decreased. It not only caused neural cell apoptosis but also enhanced lipid peroxide, nitrite, and inflammatory mediators' (TNF-α) level. Chronic treatment with naringin (40 and 80mg/kg) for 4 weeks significantly and dose dependently attenuated the decrease in level of nociceptive threshold, endogenous antioxidant and membrane bound inorganic phosphate enzyme. It also decreased the elevated levels of oxidative-nitrosative stress, inflammatory mediators as well as apoptosis in neural cells significantly and dose dependently. The important finding of the study is that, the naringin-insulin combination not only attenuated the diabetic condition but also reversed the neuropathic pain, whereas insulin or naringin alone only improved hyperglycemia but partially reversed the pain response in diabetic rats. Thus, naringin is a potential flavonone bearing antioxidant, antiapoptotic and disease modifying property acting via modulation of endogenous biomarker to inhibit diabetes induced neuropathic pain.     

Pre-treatment of Syndrex® protects mice from becoming diabetic after streptozotocin injection

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to either insufficiency of insulin or inability of cells to respond to insulin. Many clinical and experimental evidence have suggested the strong association between hyperglycemia, oxidative stress and diabetic complications. Therefore, the antidiabetic drugs with antioxidant potential would have a higher therapeutic value. To check its antidiabetic and antioxidant properties in vivo, experiments were done wherein mice were fed with Syndrex^® in different schedules and/or made diabetic by intraperitoneal injection of streptozotocin. Animals fed with Syndrex^® prior to the induction of diabetes by streptozotocin injection showed resistance to an increase in blood glucose levels. This treatment increased the activities of antioxidant enzymes namely, catalase, glutathione reductase and superoxide dismutase and reduced serum triglyceride and cholesterol levels as compared to those found in uncontrolled diabetic mice. Among the three different schedules used for Syndrex^® treatment, the best effect was seen in the case of mice pretreated with Syndrex^® prior to STZ injection. In our opinion, Syndrex^® given along with insulin may reduce the amount of insulin dose required and because of its strong antioxidant activity would certainly help to reduce the development of diabetic complications.     

Beneficial effect of Embelia ribes ethanolic extract on blood pressure and glycosylated hemoglobin in streptozotocin-induced diabetes in rats

Embelia ribes (common name, Vidanga) is extensively used in traditional system of medicine for treatment of various disorders. It is described in Ayurveda, as a powerful anthelmintic, antifertility and antihyperlipidemic agent. The present study was undertaken to investigate modulatory effect of 6 weeks' chronic oral administration of E. ribes ethanolic extract on diabetes mellitus induced by a diabetogen, streptozotocin (STZ) with special reference to changes in glucose levels, glycated haemoglobin status and cardiac toxicity. STZ treatment (40 mg/kg iv) resulted in significant increase in blood glucose levels, glycated haemoglobin levels, heart rate (HR) and systolic blood pressure (SBP). Oral administration of E. ribes ethanolic extract in dose of 100 mg/kg and 200 mg/kg significantly reduced the levels of blood glucose, glycated haemoglobin, heart rate (HR) and systolic blood pressure (SBP) in animals when compared with diabetic rats.     

Anti-diabetic effects of emodin involved in the activation of PPARγ on high-fat diet-fed and low dose of streptozotocin-induced diabetic mice

Rheum palmatum Linn has been widely applied in the clinical treatment of diabetes mellitus. It has been found that emodin as the major bioactive component of R. palmatum L exhibits the competency to activate peroxisomal proliferator-activated receptor-γ (PPARγ) in vitro. So the aim of this study was to evaluate the anti-diabetic effects of emodin through the activation of PPARγ on high-fat diet-fed and low dose of streptozotocin (STZ)-induced diabetic mice. The diabetic mice were intraperitoneally injected with emodin for three weeks. No changes of food consumption and the body weight in emodin-treated mice were monitored daily during the entire experiment. At the end of experiment, the levels of blood glucose, triglyceride and total cholesterol in serum were significantly decreased after emodin treatment. However, serum high-density lipoprotein cholesterol (HDLc) concentration was significantly elevated. The glucose tolerance and insulin sensitivity in emodin-treated group were significantly improved. Furthermore, the results of quantitative RT-PCR analysis showed that emodin significantly elevated the mRNA expression level of PPARγ and regulated the mRNA expressions of LPL, FAT/CD36, resistin and FABPs (ap2) in liver and adipocyte tissues. No effects on the mRNA expressions of PPARα and PPARα-target genes were observed. Taken together, the results suggested that the activation of PPARγ and the modulation of metabolism-related genes were likely involved in the anti-diabetic effects of emodin.     

4-Hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis and act through AMPK and Akt dependent pathway

4-Hydroxyisoleucine (4-HIL) is an unusual amino acid isolated from fenugreek seeds (Trigonella foenum graecum L). Various studies have shown that it acts as an antidiabetic agent yet its mechanism of action is not clear. We therefore investigated the effect 4-HIL on the high fructose diet fed streptozotocin induced diabetic rats and L6 myotubes. 4-HIL (50 mg/kg) has improved blood lipid profile, glucose tolerance and insulin sensitivity in a diabetic rat model. It has increased the glucose uptake in L6 myotubes in AMPK-dependent manner and upregulated the expression of genes (PGC-1α, PGC-1β, CPT 1 and CPT 2), which have role in mitochondrial biogenesis and energy metabolism in the liver, skeletal muscles as well as in L6 myotubes. Interestingly, it also increased the AMPK and Akt expression along with their phosphorylated forms in the liver and muscle tissues of treated animals. Altogether we concluded that 4-HIL acts to improve insulin resistance by promoting mitochondrial biogenesis in high fructose diet fed STZ induced diabetic rats.     

Hypoglicemic effect of Leandra lacunosa in normal and alloxan-induced diabetic rats

Leandra lacunosa, popularly known as "erva-do-jabuti", is used in Brazilian folkloric medicine for the treatment of diabetes mellitus. Based on this traditional indication, the aim of this work was to evaluate the hypoglycemic activity of the hydroalcoholic extract of L. lacunosa aerial parts (LLH) in normal and alloxan-induced diabetic rats. Chromatographic fractionation of LLH was also carried out by several techniques, affording isolation of the following major compounds: ursolic acid (1), kaempferol (2), luteolin (3), and quercetin (4). The oral administration of LLH (500 mg/kg) in normal rats caused a significant reduction of 24.7% (P<0.05) in the blood glucose levels after 2 h of treatment, while the administration of chlorpropamide (20 mg/kg, p.o.) led to a reduction of 40.2% (P<0.01). After oral administration of glucose (10 g/kg, p.o.), LLH (500 mg/kg, p.o.) significantly inhibited the increase in blood glucose levels compared with the negative control group. The oral treatment with LLH (500 mg/kg) in alloxan-induced diabetic rats significantly reduced the blood glucose levels in 47.8% after 4 h of treatment, while chlorpropamide resulted in a significant reduction of 71.7% in the 4th hour. Our results showed that LLH, displays hypoglycemic activity, which may be related to the effect of the major compounds identified in the crude extract. This study seems to provide biological evidence for the folkloric use of L. lacunosa in the treatment of diabetes mellitus.     

Compound K,a final intestinal metabolite of ginsenosides,enhances insulin secretion in MIN6 pancreatic β-cells by upregulation of GLUT2

Compound K (CK) is a final intestinal metabolite of protopanaxadiol-type ginsenosides from Panax ginseng and shows various bioactivities. Although it has also been found to have the property of anti-diabetes, the long-term effect of CK on insulin secretion in β-cells is still unclear. In this study, CK was prepared from ginsenoside Rd by snailase hydrolysis and its effect on the insulin secretion activity in MIN6 pancreatic β-cell lines in vitro was assessed. The expression of glucose transporter isoform-2 (GLUT2) and the cellular ATP content were also examined by western blot and HPLC analysis, respectively. The results showed that CK significantly enhanced insulin secretion, increased cellular ATP content, and upregulated the expression of GLUT2. These findings indicate that CK exerts prominent stimulatory effects on insulin secretion in the MIN6 cells partly via upregulating the expression of GLUT2.     

Hypoglycemic and antidiabetic activities on the stem bark aqueous and ethanol extracts of Musanga cecropioides in normal and alloxan-induced diabetic rats

Daily oral administration of the aqueous and ethanolic extracts of Musanga cecropioides stem bark in normal and diabetic rats at doses of 250, 500 and 1000 mg/kg/day, for 14 days significantly lowered the fasting plasma glucose levels in normal and alloxan-induced diabetic rats in dose-dependent fashion. The ethanol extract induced more significant antidiabetic effect than the aqueous extract.     

Antiobesity and lipid lowering effects of Murraya koenigii (L.) Spreng leaves extracts and mahanimbine on high fat diet induced obese rats

The dichloromethane (MKD) and ethyl acetate (MKE) extracts of Murraya koenigii leaves significantly reduced the body weight gain, plasma total cholesterol (TC) and triglyceride (TG) levels significantly when given orally at a dose of 300 mg/kg/day to the high fat diet (HFD) induced obese rats for 2 weeks. The observed antiobesity and antihyperlipidemic activities of these extract are correlated with the carbazole alkaloids present in them. Mahanimbine (1) when given orally (30 mg/kg/day) also significantly lowered the body weight gain as well as plasma TC and TG levels. These findings demonstrate the excellent pharmacological potential of mahanimbine to prevent obesity.     

Antidiabetic potential of Butea monosperma in rats

The antihyperglycemic activity of the ethanolic extract of Butea monosperma (BMEE) was studied in glucose-loaded and alloxan-induced diabetic rats. Single dose treatment of BMEE (200 mg/kg, p.o.) significantly improved glucose tolerance and caused reduction in blood glucose level in alloxan-induced diabetic rats. Repeated oral treatment with BMEE (200 mg/kg/day) for 2 weeks significantly reduced blood glucose, serum cholesterol and improved HDL-cholesterol and albumin as compared to diabetic control group.     

Hypoglycemic effect of Mucuna pruriens seed extract on normal and streptozotocin-diabetic rats

The hypoglycemic effect of the aqueous extract of the seeds of Mucuna pruriens was investigated in normal, glucose load conditions and streptozotocin (STZ)-induced diabetic rats. In normal rats, the aqueous extract of the seeds of Mucuna pririens (100 and 200 mg/kg body weight) significantly (P<0.001) reduced the blood glucose levels after an oral glucose load from 127.5+/-3.2 to 75.6+/-4.8 mg% 2 h after oral administration of seed extract. It also significantly lowered the blood glucose in STZ diabetic rats from 240.5+/-7.2 to 90.6+/-5.6 mg% after 21 days of daily oral administration of the extract (P<0.001). Thus, this study shows that M. pruriens has an anti-hyperglycemic action and it could be a source of hypoglycemic compounds.     

竹膳食纤维粉的减肥降脂作用研究

通过建立肥胖大鼠模型,对肥胖大鼠灌胃一定量的竹膳食纤维粉,研究竹膳食纤维对大鼠的减肥和降脂作用。结果表明：竹膳食纤维粉能够很好地控制大鼠的体重,随着竹膳食纤维粉在饲料中所占的比例增加,大鼠体重控制的效果也明显增加,当竹膳食纤维粉所占比例达30%时,减肥效果最好,再加大竹膳食纤维粉的比例时减肥效果下降;竹膳食纤维粉能显著降低大鼠血清中总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL-C）的含量水平,提高高密度脂蛋白（HDL-C）的含量水平,并能降低大鼠器官及其周围脂肪的质量,以饲料中添加30%的竹膳食纤维粉效果最好。     

Antihyperglycemic activity of Euphrasia officinale leaves.

The effects of the aqueous extract of the leaf of Euphrasia officinale on blood glucose levels in normal and alloxan-diabetic rats were investigated. The treatment of alloxan-induced diabetic rats brought down the raised glucose levels, while the extract was devoid of hypoglycemic effect in normal rats.     

杨树皮不饱和脂肪酸乙酯化学组成及其药效

杨树(PopulussimoniiCarr.)皮提取物经皂化、萃取、分离和精制,能够得到30%～36%的不饱和脂肪酸乙酯产品。该产品经气相色谱分析,共分离出22个色谱峰,鉴定出21个化合物,其中主要的不饱和脂肪酸乙酯成分为亚油酸乙酯,含量高达94.04%。已鉴定的组分占产品总量的99.19%,其中不饱和脂肪酸酯占95.94%,饱和脂肪酸酯占3.14%。药效试验证明,杨树皮不饱和脂肪酸乙酯产品能显著降低试验性高脂血症大鼠的血清总胆固醇(TC)、甘油三脂(TG)和低密度脂蛋白的胆固醇(LDL-C)水平(P<0.001),而对血清中高密度脂蛋白的胆固醇(HDL-C)含量有升高作用。     

Anti-hyperglycemic action of apigenin-6-C-β-fucopyranoside from Averrhoa carambola

A stimulatory effect of apigenin-6-C-β-fucopyranoside (1) on glucose uptake was observed when rat soleus muscle was incubated with 1, 10 and 100μM of this flavonoid glycoside. The presence of specific insulin signaling inhibitors, such as wortmannin, an inhibitor of phosphoinositide 3-kinase (PI3K), RO318220, an inhibitor of protein kinase C (PKC), PD98059, an inhibitor of mitogen-activated protein kinase (MEK), and HNMPA(AM)(3), an insulin receptor tyrosine kinase activity inhibitor showed that apigenin-6-C-β-fucopyranoside triggers different metabolic pathways in skeletal muscle. The oral administration of crude extract, fractions and isolated flavonoids (apigenin-6-C-β-fucopyranoside (1) and apigenin-6-C-(2″-O-α-rhamnopyranosyl)-β-fucopyranoside (2)) from Averrhoa carambola leaves exhibited a potential hypoglycemic activity in hyperglycemic normal rats. Additionally, both flavonoids significantly increased the muscle and liver glycogen content after an acute treatment. The results indicate that A. carambola can be regarded as a potent antihyperglycemic agent with insulin secretagogue and insulin mimetic properties.