Distinct Metabolomic Profiling of Serum Samples from High-Fat-Diet-Induced Insulin-Resistant Mice.

High-fat-diet (HFD)-induced obesity is associated with an elevated risk of insulin resistance (IR), which may precede the onset of type 2 diabetes mellitus and associated metabolic complications. Being a heterogeneous metabolic condition, it is pertinent to understand the metabolites and metabolic pathways that are altered during the development and progression of IR toward T2DM. Serum samples were collected from C57BL/6J mice fed with HFD or chow diet (CD) for 16 weeks. Collected samples were analyzed by gas chromatography-tandem mass spectrometry (GC-MS/MS). Data on the identified raw metabolites were evaluated using a combination of univariate and multivariate statistical methods. Mice fed with HFD had glucose and insulin intolerance associated with impairment of insulin signaling in key metabolic tissues. From the GC-MS/MS analysis of serum samples, a total of 75 common annotated metabolites were identified between HFD- and CD-fed mice. In the t-test, 22 significantly altered metabolites were identified. Out of these, 16 metabolites were up-accumulated, whereas 6 metabolites were down-accumulated. Pathway analysis identified 4 significantly altered metabolic pathways. In particular, primary bile acid biosynthesis and linoleic acid metabolism were upregulated, whereas the TCA cycle and pentose and glucuronate interconversion were downregulated in HFD-fed mice in comparison to CD-fed mice. These results show the distinct metabolic profiles associated with the onset of IR that could provide promising metabolic biomarkers for diagnostic and clinical applications.

Assessment of the dual role of Lyonia ovalifolia (Wall.) Drude in inhibiting AGEs and enhancing GLUT4 translocation through LC-ESI-QTOF-MS/MS determination and in silico studies.

Introduction: Diabetes mellitus (DM) is a metabolic disorder that results in glucose accumulation in the blood, accompanied by the production of advanced glycation end products (AGEs) through glycation of cellular proteins. These AGEs interfere with insulin signaling and prevent GLUT4 membrane translocation, thereby promoting the accumulation of more glucose in the blood and causing post-diabetic complications. Methods: In this study, we examine the anti-diabetic potential of Lyonia ovalifolia (Wall.) Drude, a well-known ethnomedicinal plant of the Indian Himalayas. Considering its various medicinal properties, we analyzed its ethanolic extract and various solvent fractions for in vitro antiglycation activity and antidiabetic potential, i.e., stimulation of GLUT4 translocation. Result and Discussions: The results showed that the extract and fractions exhibited increased antiglycation activity and an increased level of GLUT4 translocation. Analysis of a further 12 bioactive compounds of ethanolic extract, identified through LC-ESI-QTOF-MS/MS, revealed the presence of three new compounds: leucothol B, rhodoterpenoids A, and leucothol A. Moreover, we performed molecular docking of identified compounds against key proteins of diabetes mellitus: the sirtuin family of NAD (+)-dependent protein deacetylases 6 (SIRT6), aldose reductase (AR), and tyrosine kinase (TK). The results showed that flavonoid luteolin showed the best binding affinity ((-12.3 kcal/mol), followed by eriodictyol, astilbin, and syringaresinol. An ADMET study showed that luteolin, eriodictyol, astilbin, and syringaresinol may be promising drug candidates belonging to the flavonoid class of compounds, with no harmful effects and complying with all the drug-likeness guidelines. Furthermore, molecular dynamics (MD) simulations on a 50 ns timescale revealed that AR protein was most stable with luteolin throughout the simulation period. Therefore, this study reveals for the first time that L. ovalifolia plays an important role in insulin homeostasis, as shown in in vitro and in silico studies.

Furostanol saponins from Asparagus racemosus as potential hypoglycemic agents.

Bioactivity guided phytochemical investigation led to isolation of six undescribed furostanol saponins, furoasparoside A-F along with five known compounds, gallic acid, methyl gallate, quercetin-3-O-ß-glucopyranoside, liquiritigenin 4׳-O-ß-apiofuranosyl-(1 â†’ 2)-ß-glucopyranoside and ß-glucogallin for the first time from the roots of Asparagus racemosus. Isolated saponins were screened for their antidiabetic potential in L6-GLUT4myc myotubes in vitro followed by an in vivo evaluation in streptozocin-induced diabetic rats and db/db mice. Furoasparoside E produced a notable decrease in the postprandial blood glucose profile, in leptin receptor-deficient db/db mice, type 2 diabetes model. The effect of furoasparoside E on GLUT4 translocation was found to be mediated by the AMPK-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, it emerged as a stable plant metabolite with higher bioavailability and efficacy in in vivo pharmacokinetic studies. Therefore, these studies indicated that furoasparoside E may serve as a propitious lead for the management of type 2 diabetes and its secondary complications from natural source.

ß-Sitosterol-D-Glucopyranoside Mimics Estrogenic Properties and Stimulates Glucose Utilization in Skeletal Muscle Cells.

Estrogenic molecules have been reported to regulate glucose homeostasis and may be beneficial for diabetes management. Here, we investigated the estrogenic effect of ß-sitosterol-3-O-D-glucopyranoside (BSD), isolated from the fruits of Cupressus sempervirens and monitored its ability to regulate glucose utilization in skeletal muscle cells. BSD stimulated ERE-mediated luciferase activity in both ERα and ERß-ERE luc expression system with greater response through ERß in HEK-293T cells, and induced the expression of estrogen-regulated genes in estrogen responsive MCF-7 cells. In silico docking and molecular interaction studies revealed the affinity and interaction of BSD with ERß through hydrophobic interaction and hydrogen bond pairing. Furthermore, prolonged exposure of L6-GLUT4myc myotubes to BSD raised the glucose uptake under basal conditions without affecting the insulin-stimulated glucose uptake, the effect associated with enhanced translocation of GLUT4 to the cell periphery. The BSD-mediated biological response to increase GLUT4 translocation was obliterated by PI-3-K inhibitor wortmannin, and BSD significantly increased the phosphorylation of AKT (Ser-473). Moreover, BSD-induced GLUT4 translocation was prevented in the presence of fulvestrant. Our findings reveal the estrogenic activity of BSD to stimulate glucose utilization in skeletal muscle cells via PI-3K/AKT-dependent mechanism.

Chitosan encapsulated nanocurcumin induces GLUT-4 translocation and exhibits enhanced anti-hyperglycemic function.

AIM: The present study was undertaken to develop a Curcumin nanoparticle system with chitosan as a hydrophilic carrier. In addition, the anti-diabetic potential of curcumin loaded chitosan nanoparticles were assessed in comparison to those of free curcumin by examining the anti-hyperglycemic efficacy using in vitro assays. METHODS: Curcumin loaded chitosan nanoparticles were prepared and characterized for particle size by transmission electron microscopy, FT-IR, differential scanning calorimetry and therapeutic effects of curcumin loaded chitosan nanoparticles were evaluated by measuring the level of GLUT-4 present at the plasma membrane in L6myc myotubes followed by western blotting. Additionally, anti-inflammatory potential of curcumin loaded chitosan nanoparticles were assessed by enzyme immunoassay using appropriate ELISA kits. KEY FINDINGS: Transmission electron microscopy revealed an average nanocurcumin particle size of 74 nm. Under in vitro conditions, treatment with chitosan-nanocurcumin (CS-NC) caused a substantial increase in the GLUT-4 translocation to the cell surface in L6 skeletal muscle cells and the effect was associated with increased phosphorylation of AKT (Ser-473) and its downstream target GSK-3ß (Ser-9). SIGNIFICANCE: The therapeutic potential of nanocurcumin is prominent than that of curcumin alone. Nanocurcumin could improve the solubility of curcumin and may prolong its retention in the systemic circulation.

Multiple machine learning based descriptive and predictive workflow for the identification of potential PTP1B inhibitors.

In insulin and leptin signaling pathway, Protein-Tyrosine Phosphatase 1B (PTP1B) plays a crucial controlling role as a negative regulator, which makes it an attractive therapeutic target for both Type-2 Diabetes (T2D) and obesity. In this work, we have generated classification models by using the inhibition data set of known PTP1B inhibitors to identify new inhibitors of PTP1B utilizing multiple machine learning techniques like naïve Bayesian, random forest, support vector machine and k-nearest neighbors, along with structural fingerprints and selected molecular descriptors. Several models from each algorithm have been constructed and optimized, with the different combination of molecular descriptors and structural fingerprints. For the training and test sets, most of the predictive models showed more than 90% of overall prediction accuracies. The best model was obtained with support vector machine approach and has Matthews Correlation Coefficient of 0.82 for the external test set, which was further employed for the virtual screening of Maybridge small compound database. Five compounds were subsequently selected for experimental assay. Out of these two compounds were found to inhibit PTP1B with significant inhibitory activity in in-vitro inhibition assay. The structural fragments which are important for PTP1B inhibition were identified by naïve Bayesian method and can be further exploited to design new molecules around the identified scaffolds. The descriptive and predictive modeling strategy applied in this study is capable of identifying PTP1B inhibitors from the large compound libraries.

Deoxyandrographolide promotes glucose uptake through glucose transporter-4 translocation to plasma membrane in L6 myotubes and exerts antihyperglycemic effect in vivo.

Skeletal muscle is the principal site for postprandial glucose utilization and augmenting the rate of glucose utilization in this tissue may help to control hyperglycemia associated with diabetes mellitus. Here, we explored the effect of Deoxyandrographolide (DeoAn) isolated from the Andrographis paniculata Nees on glucose utilization in skeletal muscle and investigated its antihyperglycemic effect in vivo in streptozotocin-induced diabetic rats and genetically diabetic db/db mice. In L6 myotubes, DeoAn dose-dependently stimulated glucose uptake by enhancing the translocation of glucose transporter 4 (GLUT4) to cell surface, without affecting the total cellular GLUT4 and GLUT1 content. These effects of DeoAn were additive to insulin. Further analysis revealed that DeoAn activated PI-3-K- and AMPK-dependent signaling pathways, account for the augmented glucose transport in L6 myotubes. Furthermore, DeoAn lowered postprandial blood glucose levels in streptozotocin-induced diabetic rats and also suppressed the rises in the fasting blood glucose, serum insulin, triglycerides and LDL-Cholesterol levels of db/db mice. These findings suggest the therapeutic efficacy of the DeoAn for type 2 diabetes mellitus and can be potential phytochemical for its management.

Fructose induces mitochondrial dysfunction and triggers apoptosis in skeletal muscle cells by provoking oxidative stress.

Mitochondrial dysfunction in skeletal muscle has been implicated in the development of insulin resistance, a major characteristic of type 2 diabetes. There is evidence that oxidative stress results from the increased production of reactive oxygen species and reactive nitrogen species leads to mitochondrial dysfunction, tissue damage, insulin resistance, and other complications observed in type 2 diabetes. It has been suggested that intake of high fructose contributes to insulin resistance and other metabolic disturbances. However, there is limited information about the direct effect of fructose on the mitochondrial function of skeletal muscle, the major metabolic determinant of whole body insulin activity. Here, we assessed the effect of fructose exposure on mitochondria-mediated mechanisms in skeletal muscle cells. Exposure of L6 myotubes to high fructose stimulated the production of mitochondrial reactive oxygen species and nitric oxide (NO), and the expression of inducible NO synthase. Fructose-induced oxidative stress was associated with increased translocation of nuclear factor erythroid 2-related factor-2 to the nucleus, decreases in mitochondrial DNA content and mitochondrial dysfunctions, as evidenced by decreased activities of citrate synthase and mitochondrial dehydrogenases, loss of mitochondrial membrane potential, decreased activity of the mitochondrial respiratory complexes, and impaired mitochondrial energy metabolism. Furthermore, positive Annexin-propidium iodide staining and altered expression of Bcl-2 family members and caspases in L6 myotubes indicated that the cells progressively became apoptotic upon fructose exposure. Taken together, these findings suggest that exposure of skeletal muscle cells to fructose induced oxidative stress that decreased mitochondrial DNA content and triggered mitochondrial dysfunction, which caused apoptosis.

Glycolipids: isolated from Oplismenus burmannii induce glucose uptake in L6-GLUT4myc myotube cells.

Bioactivity guided separation of combined n-hexane and chloroform extracts of Oplismenus burmannii resulted in the isolation and characterization of five new glycoglycerolipids, (2S)-1,2,6'-tri- O-hexadecanoyl-3-O-ß-D-galactopyranosyl glycerol (1a), (2S)-1,2,6'-tri-O-[(9Z,12Z)-octadeca-9,12- dienoyl]-3-O-ß-D-galactopyranosyl glycerol (1b), (2S)-1,6'-di-O-[(9Z,12Z)-octadeca-9,12-dienoyl]-3- O-ß-D-galactopyranosyl glycerol (2b), (2S)-1,6'-di-O-[(9Z,12Z,15Z)-octadeca-9,12,15-trienoyl]-3-O-ß-D-galactopyranosyl glycerol (2c), and (2S)-1,2-di-O-[(9Z,12Z)-octadeca-9,12-dienoyl]-3-O-(6- sulpho-α-D)-quinovopyranosyl glycerol (3b) along with five known glycoglycerolipids (1c, 2a, 3a, 3c and 4), a cerebroside (5), three monoacylglycerols (6a-c) and α-linoleic acid (7). The isolated compounds, 1-5 were in-vitro tested for their antihyperglycemic potential in terms of increase in 2-deoxyglucose uptake in L6-GLUT4myc myotube cells. The results showed that compounds, 1-5 were showing 1.52 (P<0.05), 1.50 (P<0.05), 1.28, 1.49 (P<0.05) and 1.50 (P<0.05) fold increase in the glucose uptake at concentration of 10 µg/mL and 1.71 (P<0.001), 1.74 (P<0.001), 1.50 (P<0.05), 1.76 (P<0.001) and 1.74 (P<0.001) fold increase in the glucose uptake at concentration of 25 µg/mL respectively. However, standard drug Rosiglitazone increases the glucose uptake by 1.59 fold at the concentration of 10µM. Further work on optimization of the anti-diabetic lead is under progress.

Free fatty acid induced impairment of insulin signaling is prevented by the diastereomeric mixture of calophyllic acid and isocalophyllic acid in skeletal muscle cells.

Elevated fatty acid levels play a pathogenic role in the development of insulin resistance, associated with type 2 diabetes. Interventions with ability to ameliorate fatty acid-induced insulin resistance might be useful for the management of diabetes. Here, we explored the effect of the diastereomeric mixture of calophyllic acid and isocalophyllic acid (F015) on palmitate-induced insulin resistance in skeletal muscle cells. An incubation of L6 myotubes with palmitate inhibited insulin-stimulated glucose uptake and translocation of GLUT4 to cell surface. Addition of F015 strongly prevented these inhibitions. Furthermore, F015 effectively inhibited the ability of palmitate to reduce insulin-stimulated phosphorylation of IRS-1, AKT and GSK-3ß in L6 myotubes. F015 presented a strong inhibition on palmitate-induced production of reactive oxygen species and associated inflammation, as the activation JNK, ERK1/2 and p38 MAPK were greatly reduced. F015 also inhibited inflammation-stimulated IRS-1 serine phosphorylation and restored insulin-stimulated IRS-1 tyrosine phosphorylation in presence of palmitate, resulted in enhanced insulin sensitivity. Results suggest that F015 inhibits palmitate-induced, reactive oxygen species-associated MAPK kinase activation and restored insulin sensitivity through regulating IRS-1 function. All these indicate F015 to be a potentially therapeutic candidate for insulin resistance and type 2 diabetes.

Antidiabetic property of Aerva lanata (L.) Juss. ex Schult. is mediated by inhibition of alpha glucosidase, protein glycation and stimulation of adipogenesis.

BACKGROUND: Diabetes is the leading cause of morbidity and mortality, with a number currently diagnosed as high as 371 million. Plant-based therapy could be an ideal choice because of fewer side-effects and wider acceptability. Hence, the antihyperglycemic potential of Aerva lanata, a herb prescribed for diabetes in Ayurveda was evaluated to elucidate its possible mechanism of action. METHODS: High performance liquid chromatography analysis was used for the characterization of 70% ethanolic (aqueous leaf extract [ALE]) and ethyl acetate (AEA) extracts. Further, they were evaluated for their antioxidant, inhibition of alpha glucosidase, protein glycation dipeptidyl peptidase IV (DPP IV), protein tyrosine phosphatase 1B (PTP1B) and stimulation of glucose uptake and glitazone like property (adipogenic potential) using in vitro models. The promising alpha glucosidase inhibitory potential of ALE was further evaluated in normal and streptozotocin (STZ) diabetic rats. RESULTS: ALE inhibited yeast (IC50 - 81.76 µg/mL) and rat intestinal alpha glucosidase (IC50 - 108.7 µg/mL), protein glycation, DPP IV enzyme (IC50 - 118.62 µg/mL) and PTP1B (IC50 - 94.66 µg/mL). ALE stimulated maximal adipogenesis at 50 µg/mL and enhanced insulin mediated glucose uptake (threefold of basal) at 100 µg/mL in L6 myotubes. ALE (500 mg/kg b.w.) showed a significant antihyperglycemic activity in sucrose loaded STZ normal (15.57%) and diabetic (18.44%) rats. HPLC analysis of ALE revealed the presence of bioactives like alpha amyrin, betulin and beta sitosterol. CONCLUSIONS: Alpha glucosidase inhibition, antiglycation, and adipogenic potential significantly contribute to the antidiabetic property of Aerva lanata. In addition, insulin sensitization and antioxidant potential also enhance its therapeutic potential.

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-1ß, 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.

4-Hydroxyisoleucine ameliorates fatty acid-induced insulin resistance and inflammatory response in skeletal muscle cells.

The 4-hydroxyisoleucine (4-HIL), an unusual amino acid isolated from the seeds of Trigonella foenum-graecum was investigated for its metabolic effects to ameliorate free fatty acid-induced insulin resistance in skeletal muscle cells. An incubation of L6 myotubes with palmitate inhibited insulin stimulated-glucose uptake and -translocation of glucose transporter 4 (GLUT4) to the cell surface. Addition of 4-HIL strongly prevented this inhibition. We then examined the insulin signaling pathway, where 4-HIL effectively inhibited the ability of palmitate to reduce insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1), protein kinase B (PKB/AKT), AKT substrate of 160 kD (AS160) and glycogen synthase kinase 3ß (GSK-3ß) in L6 myotubes. Moreover, 4-HIL presented strong inhibition on palmitate-induced production of reactive oxygen species (ROS) and associated inflammation, as the activation of NF-κB, JNK1/2, ERK1/2 and p38 MAPK was greatly reduced. 4-HIL also inhibited inflammation-stimulated IRS-1 serine phosphorylation and restored insulin-stimulated IRS-1 tyrosine phosphorylation in the presence of palmitate, leading to enhanced insulin sensitivity. These findings suggested that 4-HIL could inhibit palmitate-induced, ROS-associated inflammation and restored insulin sensitivity through regulating IRS-1 function.

PTP1B inhibitors for type 2 diabetes treatment: a patent review (2011 - 2014).

INTRODUCTION: Protein tyrosine phosphatase 1B (PTP1B) plays an important role in the negative regulation of insulin signal transduction pathway and has emerged as novel therapeutic strategy for the treatment of type 2 diabetes. PTP1B inhibitors enhance the sensibility of insulin receptor (IR) and have favorable curing effect for insulin resistance-related diseases. A large number of PTP1B inhibitors, either synthetic or isolated as bioactive agents from natural products, have developed and investigated for their ability to stimulate insulin signaling. AREAS COVERED: This review includes an updated summary (2011 - 2014) of PTP1B inhibitors that have been published in patent applications, with an emphasis on their chemical structure, mode of action and therapeutic outcomes. The usefulness of PTP1B inhibitors as pharmaceutical agents for the treatment of type 2 diabetes is also discussed. EXPERT OPINION: PTP1B inhibitors show beneficial effects to enhance sensibility of IR by restricting the activity of enzyme and have favorable curing effects. However, structural homologies in the catalytic domain of PTP1B with other protein tyrosine phosphatases (PTPs) like leukocyte common antigen-related, CD45, SHP-2 and T-cell-PTP present a challenging task of achieving selectivity. Thus, for therapeutic application of PTP1B inhibitors, highly selective molecules exhibiting desired effects without side effects are expected to find clinical application.

Design and synthesis of lupeol analogues and their glucose uptake stimulatory effect in L6 skeletal muscle cells.

Structure modifications of lupeol at the isopropylene moiety have been described via allylic oxidation using selenium dioxide. The antidiabetic efficacy of lupeol analogues were evaluated in vitro as glucose uptake stimulatory effect in L6 skeletal muscle cells. From all tested compounds, 2, 3, 4b and 6b showed significant stimulation of glucose uptake with respective percent stimulation of 173.1 (p <0.001), 114.1 (p <0.001), 98.3 (p <0.001) and 107.3 (p <0.001) at 10µM concentration. Stimulation of glucose uptake by these compounds is associated with enhanced translocation of glucose transporter 4 (GLUT4) and activation of IRS-1/PI3-K/AKT-dependent signaling pathway in L6 cells. Structure-activity relationship analysis of these analogues demonstrated that the integrity of α,ß-unsaturated carbonyl and acetyl moieties were important in the retention of glucose uptake stimulatory effect. It is therefore proposed that naturally occurring lupeol and their analogues might reduce blood glucose, at least in part, through stimulating glucose utilization by skeletal muscles.

Antidiabetic activity of heart wood of Pterocarpus marsupium Roxb. and analysis of phytoconstituents.

The crude powder, ethanolic extract and aqueous, chloroform, hexane and n-butanol soluble fractions of ethanolic extract of heart wood of P. marsupium showed marked improvement on oral glucose tolerance post sucrose load in normal rats. All these fractions except aqueous fraction showed improvement on oral glucose tolerance post sucrose load on streptozotocin (STZ)-induced diabetic rats. The crude powder, ethanolic extract and hexane and n-butanol fractions showed marked decline in blood glucose level on STZ-induced diabetic rats. The ethanolic extract (100 mg/kg body weight) when given to STZ-induced diabetic rats for 10 consecutive days declined blood glucose, improved OGTT and increased their serum insulin levels. The ethanolic extract also showed marked improvement on oral glucose tolerance on high fat-low dosed STZ-induced diabetic rats and neonatally STZ treated rats. The ethanolic extract of P. marsupium also showed marked antidyslipidemic effects on high fat diet fed Syrian golden hamsters. Altered renal and hepatic function markers and serum insulin levels of high fat diet fed-low dosed STZ-treated diabetic rats were also found towards normalization when these animals were treated with ethanolic extract of P. marsupium for 28 consecutive days. The four out of five phenolic C-glycosides isolated from n-butanol fraction of ethanolic extract of P. marsupium enhanced glucose uptake by skeletal muscle cells (C2C12) in a dose dependent manner. It may primarily be concluded that phenolic-C-glycosides present in P. marsupium heart wood are the phytoconstituents responsible for the antihyperglycemic activity and validate the claim of antidiabetic activity of heart wood of P. marsupium.

Diastereomeric mixture of calophyllic acid and isocalophyllic acid stimulates glucose uptake in skeletal muscle cells: involvement of PI-3-kinase- and ERK1/2-dependent pathways.

The diastereomeric mixture of calophyllic acid and isocalophyllic acid (F015) isolated from the leaves of Calophyllum inophyllum was investigated for the metabolic effect on glucose transport in skeletal muscle cells. In L6 myotubes, F015 dose-dependently stimulated glucose uptake by increasing translocation of glucose transporter4 (GLUT4) to plasma membrane without affecting their gene expression. The effects on glucose uptake were additive to insulin. Inhibitors analyses revealed that F015-induced glucose uptake was dependent on the activation of phosphatidylinositol-3-kinase (PI-3-K) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), while independent to the activation of 5'AMP-activated kinase (AMPK). F015 significantly increased the phosphorylation of AKT, AS160 and ERK1/2, account for the augmented glucose transport capacity in L6 myotubes. Furthermore, F015 improved glucose tolerance and enhanced insulin sensitivity in skeletal muscle of dexamethasone-induced insulin resistant mice. Our findings demonstrate that F015 activates glucose uptake in skeletal muscle cells through PI-3-K- and EKR1/2-dependent mechanisms and can be a potential lead for the management of diabetes and obesity.

Synthesis of novel imbricatolic acid analogues via insertion of N-substituted piperazine at C-15/C-19 positions, displaying glucose uptake stimulation in L6 skeletal muscle cells.

A new class of N-substituted piperazine analogues of imbricatolic acid have been designed and synthesized by using the appropriate synthetic routes in excellent yield. All synthesised compounds were screened for their in vitro glucose uptake stimulatory activity. Among them compounds 4b, 4e, 8b, and 8e triggered L6 skeletal muscle cells for glucose uptake at 54.73%, 40.79%, 40.90%, and 39.55% stimulation, respectively. Compound 4b has emerged as important lead compound showing potential antidiabetic activity. Illustration about their synthesis and in vitro glucose uptake activity is described.

Antidiabetic effect of Eclipta alba associated with the inhibition of alpha-glucosidase and aldose reductase.

The antidiabetic effect of the ethanolic extract of Eclipta alba (EEA) on hyperglycaemia and diabetic nephropathy was investigated in streptozotocin-induced diabetic rats. Single-dose treatment of EEA to streptozotocin-induced diabetic rats lowered the blood glucose level by 17.6% (p < 0.05) at 250 mg kg(-1) dose after 5 h post oral administration. Treatment of animals after 10 weeks of STZ-treatment with EEA (250 mg kg(-1)) for 21 days significantly reduced the elevated levels of blood glucose, %HbA1C, urea, uric acid and creatinine, and significantly increased the depressed serum insulin level. The extract exerted a significant inhibitory effect on alpha-glucosidase in a noncompetitive manner with an IC(50) value of around 54 µg mL(-1) and was found inhibitory to eye lens aldose reductase with an IC(50) value of around 4.5 µg mL(-1). The results suggest that EEA possesses antidiabetic effect associated with alpha-glucosidase and aldose reductase inhibition.

Chemical constituents of Kigelia pinnata twigs and their GLUT4 translocation modulatory effect in skeletal muscle cells.

Phytochemical investigation of the ethanolic extract of twigs of Kigelia pinnata DC. afforded one new iridoid 7-hydroxy eucommiol (1), and nine known compounds (2-10). The structure of compounds was elucidated by extensive spectroscopic methods, including 1D, 2D NMR experiments and MS analysis. All these compounds were evaluated for GLUT4 translocation modulatory effect in skeletal muscle cells. Four of the tested compounds 1, 5, 6 and 7 showed significant stimulation of GLUT4 translocation to cell surface in skeletal muscle cells without any adverse effect on cell viability. Effect of these four compounds was concentration-dependent and comparable to standard drug rosiglitazone. These findings indicate that constituents of K. pinnata may provide leads for the therapeutics for insulin resistance and diabetes.