ginsenoside-m1 and Diabetes-Mellitus--Type-2

Imeglimin (PXL008, EMD-387008, Twymeeg

Topics: Biological Transport; Diabetes Mellitus, Type 2; Humans; Pharmacology, Clinical

The prevalence of pre-diabetes and of type 2 diabetes mellitus is increasing. Preventing disease progression is important to improve outcomes. Natural products are becoming popular alternatives to pharmaceutical products for preventative health and treatment of disease; however, the evidence to support the use of natural alternatives for pre-diabetes and type 2 diabetes is lacking. Two such natural medicines include alpha-cyclodextrin (marketed as FBCx), a fibre derived from corn starch that has been found to bind triglycerides in the intestines to prevent its absorption, aiding weight maintenance and lipid control, and hydrolysed ginseng extract (marketed as GINST15), a formula containing high amounts of Compound K, a metabolite of ginsenosides thought to be an active ingredient contributing to the anti-hyperglycaemic effects of ginseng. This paper describes the rationale and design of a 12-month randomized controlled trial to investigate the metabolic effects of these two products in people with pre-diabetes and overweight or obesity. A total of 400 participants will be randomized to one of four groups (FBCx + GINST15, FBCx + placebo, placebo + GINST15, placebo + placebo) for 6 months, followed by 6 months of follow-up. Participants will also receive lifestyle advice for healthy eating and weight loss. Data collected during the trial will include weight, waist circumference, body composition and blood pressure. Blood samples will also be collected to measure lipid profile and glycaemia. If the products are found to improve lipid and glucose levels, it will provide evidence for their use in people with pre-diabetes to help reduce the risk of progression to type 2 diabetes.

Topics: Adult; alpha-Cyclodextrins; Blood Glucose; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Female; Ginsenosides; Humans; Male; Middle Aged; Obesity; Overweight; Prediabetic State; Triglycerides

Topics: Diabetes Mellitus, Type 2; Dynamins; Fatty Acids; Humans; Insulin Resistance; Mitophagy; Muscle, Skeletal; Protein Kinases

Many natural products can be bio-converted by the gut microbiota to influence pertinent efficiency. Ginsenoside compound K (GCK) is a potential anti-type 2 diabetes (T2D) saponin, which is mainly bio-transformed into protopanaxadiol (PPD) by the gut microbiota. Studies have shown that the gut microbiota between diabetic patients and healthy subjects are significantly different. Herein, we aimed to characterize the biotransformation of GCK mediated by the gut microbiota from diabetic patients and healthy subjects. Based on 16S rRNA gene sequencing, the results indicated the bacterial profiles were considerably different between the two groups, especially Alistipes and Parabacteroides that increased in healthy subjects. The quantitative analysis of GCK and PPD showed that gut microbiota from the diabetic patients metabolized GCK slower than healthy subjects through liquid chromatography tandem mass spectrometry (LC-MS/MS). The selected strain A. finegoldii and P. merdae exhibited a different metabolic capability of GCK. In conclusion, the different biotransformation capacity for GCK may impact its anti-diabetic potency.

Topics: Biotransformation; Chromatography, Liquid; Diabetes Mellitus, Type 2; Feces; Gastrointestinal Microbiome; Healthy Volunteers; Humans; RNA, Ribosomal, 16S; Tandem Mass Spectrometry

Incretin impairment refers to L-cell-derived glucagon-like peptide-1 (GLP-1) deficiency, commonly observed in patients with type 2 diabetes mellitus (T2DM). Promoting the enteroendocrine L-cell population to elevate GLP-1 secretory capacity represents a potential therapeutic strategy for T2DM. It has been established that ginsenoside compound K (CK) could stimulate GLP-1 secretion; however, the underlying mechanisms remain elusive.. CK was intragastrically administered to male db/db mice for 4 weeks that subsequently underwent oral glucose tolerance testing. Serum samples were collected to measure the GLP-1 secretion, insulin level, inflammatory factors, and bile acid (BA) profiles. Ileum epithelial injury was detected by Hematoxylin and Eosin (H&E) and Masson staining. Gene markers associated with L-cell differentiation were evaluated by RT-PCR, and L-cells were labeled by Gcg via immunofluorescence assays. TGR5 and YAP expression was analyzed by immunoblotting and immunofluorescence assays.. Compound K attenuated hyperglycemia and inflammation in db/db mice and upregulated TGR5 expression by increasing lithocholic acid (LCA) and deoxycholic acid (DCA) levels in response to ileum epithelium injury. Meanwhile, fibrosis was alleviated, and the crypt architecture was restored, with increased L-cell abundance and serum GLP-1 levels. The upregulation in genes associated with L-cell differentiation promoted transformation into L-cells. Further mechanistic analyses showed that the effects of CK on the L-cell population required YAP activation, which triggered actin cytoskeleton dynamics.. Our results indicate that TGR5 could modulate the abundance of L-cells to enhance GLP-1 release through YAP-driven intestinal regeneration in db/db mice. Accordingly, CK has huge prospects for application to alleviate incretin impairment in T2DM.

Topics: Animals; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Incretins; L Cells; Male; Mice; Mice, Inbred Strains

Ginsenoside Rb1 has been shown to have antidiabetic and anti-inflammatory effects. Its major metabolite, compound K (CK), can stimulate the secretion of glucagon-like peptide-1 (GLP1), a gastrointestinal hormone that plays a vital role in regulating glucose metabolism. However, the mechanism underlying the regulation of GLP1 secretion by compound K has not been fully explored. This study was designed to investigate whether CK ameliorates incretin impairment by regulating the RhoA/ROCKs/YAP signaling pathway and cytoskeleton formation in NCI-H716 cells. Using NCI-H716 cells as a model cell line for GLP1 secretion, we analyzed the effect of CK on the expression of RhoA/ROCK/YAP pathway components. Our results suggest that the effect of CK on GLP1 secretion depends on the anti-inflammatory effect of CK. We also demonstrated that CK can affect the RhoA/ROCK/YAP pathway, which is downstream of transforming growth factor β1 (TGFβ1), by maintaining the capacity of intestinal differentiation. In addition, this effect was mediated by regulating F/G-actin dynamics. These results provide not only the mechanistic insight for the effect of CK on intestinal L cells but also the molecular basis for the further development of CK as a potential therapeutic agent to treat type 2 diabetes mellitus (T2D).

Topics: Cell Cycle Proteins; Cell Line; Cytoskeleton; Diabetes Mellitus, Type 2; Ginsenosides; Glucagon-Like Peptide 1; Humans; Molecular Targeted Therapy; Phytotherapy; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Transcription Factors; Transforming Growth Factor beta1

Non-alcoholic fatty liver disease is associated with insulin resistance. Compound K (CK) is the final metabolite of panaxadiol ginsenosides that have been shown to exert antidiabetic effects. However, the molecular mechanism of the antidiabetic effects in the liver have not been elucidated; further, whether CK has beneficial effects in hepatosteatosis remains unclear. Therefore, we evaluated the effect of CK on hepatosteatosis as well as its mechanism in high-fat diet (HFD)-fed type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats.. Twenty-four-week-old male OLETF rats were assigned to four groups: control (saline), CK 10 mg/kg, CK 25 mg/kg, or metformin 300 mg/kg (positive control); all treatments were administered orally for 12 weeks.. Fasting glucose levels of the CK25 group were significantly lower than those of the control group during the 12 weeks. The results of the oral glucose tolerance test showed that both the glucose concentration after glucose loading and the fasting insulin levels of the CK25 group were significantly lower than those of the control. Hepatosteatosis was significantly improved by CK25. CK25 and metformin significantly increased the phosphorylation of hepatic adenosine monophosphate-activated protein kinase (AMPK). CK25 significantly inhibited the expression of sterol regulatory element-binding protein-1c and fatty acid synthase, while upregulating that of peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1.. CK improved glucose intolerance and hepatosteatosis in HFD-fed OLETF rats through AMPK activation, which has dual mode of action that involves decreasing the synthesis of fatty acids and increasing fatty acid oxidation.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Ginsenosides; Glucose Intolerance; Japan; Liver; Male; Protein Kinases; Rats; Rats, Inbred OLETF; Republic of Korea; Seoul

Compound K (CK) is a final intestinal metabolite of protopanaxadiol-type ginsenoside. We have reported that CK presented anti-diabetic effect via diminishing the expressions of hepatic gluconeogenesis key enzyme. Here, we further explore the possible mechanism of CK on suppression hepatic gluconeogenesis via activation of adenosine-5'monophosphate kinase (AMPK) on type 2 diabetes mice in vivo and in HepG2 cells.. Type 2 diabetes mice model was developed by high fat diet combined with STZ injection. 30mg/kg/d CK was orally administrated for 4weeks, the fasting blood glucose level and 2h OGTT were conducted, and the protein expression of AMPK, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) were examined. The mechanism of Compound K on hepatic gluconeogenesis was further explored in HepG2 hepatocytes. Glucose production, the protein expression of AMPK, PEPCK, G6pase and PGC-1α, hepatic nuclear factor 4α (HNF-4α) and forkhead transcription factor O1 (FOXO1) were determined after Compound K treatment at the presence of AMPK inhibitor Compound C.. We observed that CK inhibited the expression of PEPCK and G6Pase in the liver and in HepG2 hepatocytes. Meanwhile, CK treatment remarkably increased the activation of AMPK, while decreasing the expressions of PGC-1α, HNF-4α and FOXO1. However, AMPK inhibitor Compound C could reverse these effects of CK on gluconeogenesis in part.. The results indicated that the effect of CK on suppression hepatic gluconeogenesis might be via the activation the AMPK activity.

Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Enzyme Activation; Ginsenosides; Gluconeogenesis; Glucose; Glucose-6-Phosphatase; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; Liver; Male; Mice; Panax; Peroxisome Proliferator-Activated Receptors

Compound K (CK) is a final metabolite of panaxadiol ginsenosides from Panax ginseng. Although anti-diabetic activity of CK has been reported in recent years, the molecular mechanism of CK in the treatment of diabetes mellitus remains unclear. In the present investigation, we established a rat model of type 2 diabetes mellitus (T2DM) with insulin resistance using high-fat diet (HFD) and streptozotocin (STZ), and attempted to verify more details and exact mechanisms in the treatment of T2DM. CK was administered orally at three doses [300, 100 and 30 mg/kg bodyweight (b.w.)] to the diabetic rats. Bodyweight, food-intake, fasting blood glucose (FBG), fasting serum insulin (FINS), insulin sensitivity (ISI), total glycerin (TG), total cholesterol (TC), as well as oral glucose tolerance test (OGTT) were evaluated in normal and diabetic rats. According to our results, CK could improve bodyweight and food-intake of diabetic rats. CK exhibited dose-dependent reduction of FBG, TG and TC of diabetic rats. CK treatment also enhanced FINS and ISI. Meanwhile, the glucose tolerance observed in the present study was improved significantly by CK. It is concluded from the results that CK may have improving effects on hyperglycemia and insulin resistance of diabetic rats. Furthermore, research showed that CK could promote the expression of InsR, IRS1, PI3Kp85, pAkt and Glut4 in skeletal muscle tissue of diabetic rats. These results indicate that the hypoglycemic activity of CK is mediated by improvement of insulin sensitivity, which is closely related to PI3K/Akt signaling pathway.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Ginsenosides; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Male; Molecular Structure; Panax; Plant Roots; Rats; Rats, Wistar; Signal Transduction; Streptozocin

Compound K (CK) is known to possess anti-diabetic activities but the mechanism for this action is unknown. The present study observed the protective effect of CK on islet cell apoptosis through the AMP-activated protein kinase (AMPK) mediated C-Jun N-terminal kinase (JNK) pathway.. Treatment effect of CK on type 2 diabetic (T2D) mice and palmitate-induced MIN6 β-cells injury was observed. Fasting plasma glucose, triacylglycerol, total cholesterol, insulin levels and glucose tolerance test were evaluated. The expression of AMPK and JNK was detected in islet and MIN6 cells.. CK treatment (30 mg/kg) decreased fasting plasma glucose, triacylglycerol, total cholesterol, elevated plasma insulin levels and improved glucose tolerance in T2D mice. CK treatment attenuated islet cell apoptosis and caspase-3 activity accompanied by a decrease in AMPK and JNK activation. Meanwhile, CK treatment attenuated the palmitate-induced reduction in MIN6 β-cell viability, apoptosis and caspase-3 activity and activation of AMPK and JNK. The AMPK activator AICAR attenuated the CK-mediated inhibition of palmitate-induced apoptosis.. These data suggest that CK treatment provides a beneficial anti-diabetic effect in mice with T2D and this protective effect may be mediated through prevention of β-cell apoptosis via inhibition of the AMPK-JNK pathway.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Blood Glucose; Blotting, Western; Caspase 3; Cells, Cultured; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Ginsenosides; Glucose Tolerance Test; Insulin; Insulin-Secreting Cells; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Inbred ICR; Palmitates; Phosphorylation

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 100mg/kg of STZ injected intraperitoneally. After 4 weeks, mice with fasting (12h) 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.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dietary Fats; Ginsenosides; Gluconeogenesis; Hypoglycemic Agents; Insulin; Liver; Mice; Molecular Structure

Compound K (CK) is a major intestinal metabolite of ginsenosides derived from ginseng radix. In our preliminary studies, CK has shown to exhibit anti-hyperglycemic effect through its insulin-secreting action, similar to that of insulin secretagogue sulfonylureas. Metformin, a biguanide, improves insulin resistance by reducing gluconeogenesis and enhancing peripheral glucose uptake, promoting reduction of the plasma glucose level. The aim of this study was to compare the anti-diabetic effects of CK and metformin due to differences in their mechanisms of action and also to investigate whether treatment of CK and metformin in combination show synergistic or additive effects compared to each drug alone. Seven week-old male db/db mice were treated for 8 weeks. CK was given at a dose of 10 mg/kg, metformin at 150 mg/kg and the same dosage of each drug was applied to CK plus metformin combination group. Significant improvements were observed in plasma glucose and insulin levels, homeostasis model assessment-insulin resistance (HOMA-IR) index and in hematoxylin and eosin-stained liver tissues in combination group. Although further studies to elucidate the benefits of co-administration of CK and metformin are needed, our findings may provide basis to the discovery of a new combination therapy on diabetes control in type 2 diabetics.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Ginsenosides; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Metformin; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Mutant Strains; Random Allocation; Time Factors