Design, synthesis and evaluation of tetrahydrocarbazole derivatives as potential hypoglycemic agents.

Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.

Discovery of tetrahydrocarbazoles with potent hypoglycemic and hypolipemic activities.

A series of tetrahydrocarbazole derivatives was designed and synthesized on the basis of the AMP-activated protein kinase activator GY3. All the synthesized compounds were screened in HepG2 cell lines for glucose consumption activity and several of them showed potent glucose decreasing activity. In vivo evaluation of the hypoglycemic and hypolipemic effects indicated that 7a exhibited comparable activity with pioglitazone, but with a weaker body-weight increasing effect. The pharmacokinetic profiles of 7a were also investigated.

Terpenoids from Curcuma wenyujin increased glucose consumption on HepG2 cells.

Thirty four terpenoids, including two new cadinane-type sesquiterpenoids containing conjugated aromatic-ketone moieties, curcujinone A (1) and curcujinone B (2), were isolated from 95% ethanol extract of the root tubers of Curcuma wenyujin. Their structures were determined by spectroscopic methods, especially 2D NMR and HRMS techniques. The relative and absolute configurations of 1 and 2 were identified by quantum chemical DFT and TDDFT calculations of the 13C NMR chemical shifts, ECD spectra, and specific optical rotations. All compounds and extracts were evaluated for their anti-diabetic activities with a glucose consumption model on HepG2 Cells. The petroleum fraction CWP (10µg/mL) and compounds curcumenol (4), 7α,11α-epoxy-5ß-hydroxy-9-guaiaen-8-one (5), curdione (17), (1S, 4S, 5S 10S)-germacrone (18), zederone (20), a mixture of curcumanolide A (25) and curcumanolide B (26), gajutsulactone B (27), and wenyujinin C (30) showed promising activities with over 45% increasing of glucose consumption at 10µM.

Oleanolic acid derivative DKS26 exerts antidiabetic and hepatoprotective effects in diabetic mice and promotes glucagon-like peptide-1 secretion and expression in intestinal cells.

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) is an important target for diabetes therapy based on its key role in maintaining glucose and lipid homeostasis. This study was designed to investigate antidiabetic and hepatoprotective effects of a novel oleanolic acid derivative DKS26 in diabetic mice and elucidate its underlying GLP-1 related antidiabetic mechanisms in vitro and in vivo. EXPERIMENTAL APPROACH: The therapeutic effects of DKS26 were investigated in streptozotocin (STZ)-induced and db/db diabetic mouse models. Levels of plasma glucose, glycosylated serum protein (GSP), lipid profiles, insulin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), oral glucose tolerance (OGT), pancreatic islets and hepatic histopathological morphology, liver lipid levels and expression of pro-inflammatory cytokines were assessed. Intestinal NCI-H716 cells and diabetic models were used to further validate its potential GLP-1-related antidiabetic mechanisms. KEY RESULTS: DKS26 treatment (100 mg·kg-1 ·day-1 ) decreased plasma levels of glucose, GSP, ALT and AST; ameliorated OGT and plasma lipid profiles; augmented plasma insulin levels; alleviated islets and hepatic pathological morphology; and reduced liver lipid accumulation, inflammation and necrosis in vivo. Furthermore, DKS26 enhanced GLP-1 release and expression, accompanied by elevated levels of cAMP and phosphorylated PKA in vitro and in vivo. CONCLUSION AND IMPLICATIONS: DKS26 exerted hypoglycaemic, hypolipidaemic and islets protective effects, which were associated with an enhanced release and expression of GLP-1 mediated by the activation of the cAMP/PKA signalling pathway, and alleviated hepatic damage by reducing liver lipid levels and inflammation. These findings firmly identified DKS26 as a new viable therapeutic option for diabetes control.

Effects and molecular mechanisms of the antidiabetic fraction of Acorus calamus L. on GLP-1 expression and secretion in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: The radix of Acorus calamus L. (AC) is widely used in diabetes therapies in traditional folk medicine from America and Indonesia, and we have previously reported that the ethyl acetate fraction of AC (ACE) acts as an antidiabetic through insulin sensitizing, insulin releasing and alpha-glucosidase inhibitory activities. The present study is designed to investigate the effects and molecular mechanisms of ACE on glucagon-like peptide-1 (GLP-1) expression and secretion related to its hypoglycemic effects. MATERIALS AND METHODS: The hypoglycemic effect of ACE (100mg/kg, i.g.) was confirmed by testing blood glucose levels or via oral glucose tolerance test (OGTT) in streptozotocin (STZ) induced hyperglycemic mice, db/db diabetic mice and diet-induced obese (DIO) mice. Plasma insulin, GLP-1 levels and intestinal GLP-1 related gene expression were determined in STZ-induced and db/db diabetic mice. The in vitro effects of ACE (12.5µg/ml) on the expression and secretion of GLP-1 were detected in NCI-H716 intestinal L-cells, and the correlation between ACE and molecules in the Wnt signaling pathway was further explored. RESULTS: ACE (100mg/kg) significantly lowered fasting blood glucose in STZ-induced and db/db diabetic mice and improved the OGTT in DIO mice. Insulin releasing and islet protective effects, along with the increased secretion of GLP-1, were observed. The expression of proglucagon gene (gcg) and post-translational processing gene prohormone convertase 3 (pc3) and the GLP-1 content in the culture medium of L-cells notably increased after the ACE treatment (12.5µg/ml). At the same time, ß-catenin nuclear translocation occurred, and its downstream protein cyclin D1 was activated, showing the involvement of Wnt signaling. CONCLUSIONS: ACE might activate Wnt signaling to increase the gene expression of gcg and pc3 and exert incretin effects, including insulinotropic and islet protection, to lower blood glucose levels via elevated GLP-1 secretion either directly or indirectly.

[Studies on anti-hyperglycemic effect and its mechanism of Dendrobium candidum].

OBJECTIVE: To study the anti-hyperglycemic effect and its mechanism of Dendrobium candidum (DC). METHOD: Normal mice, adrenaline-induced hyperglycemic mice, streptozotocin-induced diabetic (STZ-DM) rats were used. The mechanisms of the anti-hyperglycemic action were studied with radio-immunoassay, immunohistochemical HRP-SPA stain, etc. RESULT: DC could not obviously decrease the serum glucose concentrations and insulin levels in normal mice. It could increase serum insulin levels and decrease serum glucagons concentrations in STZ-DM rats. The results of immunohistochemical stain demonstrated that the number of islet beta cells was increased and that of islet a cells was decreased in STZ-DM rats. It could also decrease the serum glucose concentrations and increase liver glucogen contents in adrenaline-induced hyperglycemic mice. CONCLUSION: DC has obvious anti-hyperglycemic effects in adrenaline-induced hyperglycemic mice and STZ-DM rats. Its mechanisms are stimulating the secretion of insulin from beta cells and inhibiting the secretion of glucagons from a cells, and it can probably decrease the decomposition of liver glucogen and increase the synthesis of liver glucogen.

Insulin releasing and alpha-glucosidase inhibitory activity of ethyl acetate fraction of Acorus calamus in vitro and in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: The radix of Acorus calamus L. (AC) is widely used in the therapy of diabetes in traditional folk medicine of America and Indonesia, and we previously reported the insulin sensitizing activity of the ethyl acetate fraction of AC (ACE). AIM OF THE STUDY: To investigate the insulin releasing and alpha-glucosidase inhibitory activity of ACE in vitro and in vivo. MATERIALS AND METHODS: Insulin releasing and alpha-glucosidase inhibitory effects of different fractions from AC were detected in vitro using HIT-T15 cell line and alpha-glucosidase enzyme. Furthermore, effects of ACE orally on serum glucose were detected in fasted and glucose/amylum challenged normal mice. RESULTS: AC and ACE increased insulin secretion in HIT-T15 cells as gliclazide did. As in vivo results, ACE (400 and 800 mg/kg) significantly decreased fasting serum glucose, and suppressed the increase of blood glucose levels after 2g/kg glucose loading in normal mice. In addition, ACE as a mixed-type inhibitor inhibited alpha-glucosidase activity in vitro with an IC(50) of 0.41 microg/ml, and 100mg/kg of it clearly reduced the increase of blood glucose levels after 5 g/kg amylum loading in normal mice. CONCLUSIONS: Apart from its insulin sensitizing effect, ACE may have hypoglycemic effects via mechanisms of insulin releasing and alpha-glucosidase inhibition, and thus improves postprandial hyperglycemia and cardiovascular complications.

Insulin sensitizing activity of ethyl acetate fraction of Acorus calamus L. in vitro and in vivo.

UNLABELLED: Acorus calamus L. (AC), family Araceae, have been used in the Indian and Chinese systems of medicine for hundreds of years. The radix of AC is widely used in the therapy of diabetes in traditional folk medicine of America and Indonesia. AIM OF THE STUDY: To investigate the insulin sensitizing activity and antidiabetic effects of the ethyl acetate fraction of AC (ACE). MATERIALS AND METHODS: Glucose consumption mediated by insulin was detected in L6 rat skeletal muscle cells. Diabetes and its complications related indexes were monitored after orally administrating to genetically obese diabetic C57BL/Ks db/db mice daily for 3 weeks. RESULTS: ACE (12.5 and 25 microg/ml) increased glucose consumption mediated by insulin in L6 cells (p<0.05 and p<0.01). In db/db mice, ACE (100 mg/kg) significantly reduced serum glucose, triglyceride, reinforce the decrease of total cholesterol caused by rosiglitazone (at least p<0.05), and markedly reduced free fatty acid (FFA) levels and increased adiponectin levels (p<0.01 and p<0.05) as rosiglitazone did (p<0.05 and p<0.001). Serum insulin was decreased but not significantly. In addition, ACE decreased the intake of food and water, and did not increase body weight gain whereas rosiglitazone did. CONCLUSIONS: Owing to the ability of insulin sensitizing, ACE has the potential to be useful for the treatment of diabetes and cardiovascular complications without body weight gain.

A fraction of Acorus calamus L. extract devoid of beta-asarone enhances adipocyte differentiation in 3T3-L1 cells.

The effects of fractions partitioned from the ethanol extract of Acorus calamus L. (AC) on adipocyte differentiation were investigated using cultured mouse 3T3-L1 preadipocytes. The degree of differentiation was evaluated by measuring the cellular triglycerides and protein expression of the glucose transporter GLUT4 in 3T3-L1 cells. The ethyl acetate fraction of the AC extract (ACE) was found to enhance adipocyte differentiation as did rosiglitazone. The results of further fractionation of ACE indicated that the active fraction does not consist of beta-asarone, which is a toxic component of this plant. This finding suggests that ACE has potential insulin-sensitizing activity like rosiglitazone, and may improve type 2 diabetes.

Insulin-sensitizing effects of a novel alpha-methyl- alpha -phenoxylpropionate derivative in vitro.

AIM: To examine the insulin sensitizing effects of a novel alpha-methyl-alpha- phenoxylpropionate derivative YY20 in insulin-sensitive cell lines. METHODS: The peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist bioactivities of YY20 were detected by a preadipocyte differentiation assay. RT-PCR and Western blotting analysis were used to detect the expression of the target gene or protein. The effects of YY20 on insulin-mediated glucose consumption were determined in the HepG2 human hepatocellular carcinoma line. RESULTS: YY20 could enhance the differentiation of preadipocytes to adipocytes and upregulate the gene expression of PPAR gamma 2, as well as the protein expression of insulin receptor substrate- 1 (IRS-1), glucose transporter-4 (GLUT4), and adiponectin (ACRP30). The effects on GLUT4 and ACRP30 could be reversed by the PPAR gamma inhibitor SR-202. Furthermore, YY20 efficiently reduced glucose consumptions in HepG2 cells after 24 h culture, and the effects were related to insulin and YY20 concentrations. CONCLUSION: YY20, a potential insulin-sensitizing agent like rosiglitazone, could enhance glucose consumption in HepG2 cells in a concentration- and insulindependent manner. It may improve the insulin resistance associated with type 2 diabetes.

The potential insulin sensitizing and glucose lowering effects of a novel indole derivative in vitro and in vivo.

Thiazolidinediones (TZDs) such as rosiglitazone are antidiabetic peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma agents improve diabetes by increasing insulin sensitivity and enhancing the differentiation of preadipocytes into adipocytes. The present study aimed to identify if 1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-3-indoleacetitic acid (GY3), a newly synthesized indole compound, could enhance adipocytes differentiation and insulin sensitivity. The results showed that both GY3 and rosiglitazone significantly increased the lipid accumulating of 3T3-L1 adipocytes induced by isobutylmethylxanthine, dexamethasone and insulin mixture, but GY3 (not rosiglitazone) failed to increase the lipid accumulation when induced by insulin alone. In addition, GY3- or rosiglitaozne-induced protein expression of GLUT4 and adiponectin was determined by Western blot analysis. GY3 activated PPARalpha weakly but did not affect PPARgamma, while rosiglitazone activated PPARgamma significantly, suggesting different mechanisms between GY3 and rosiglitazone on adipocyte differentiation. Furthermore, both GY3 and rosiglitazone enhanced the adiponectin and insulin pathway proteins expression and adiponectin secretion in mature adipocytes, but only GY3 not rosiglitazone elevated gene expression of leptin and resistin. Both GY3 and rosiglitazone enhanced glucose consumption in HepG2 cells especially in the presence of insulin. In the in vivo study, GY3 decreased serum glucose and insulin in db/db mice, indicating the insulin sensitizing effect might contribute to its antidiabetic mechanism. Altogether, these results suggest that GY3 could improve insulin resistance and lower glucose level, GY3 and its derivatives might be developed as a substitution therapy for diseases with insulin resistance.