Evaluation of the Hypoglycemic Effects of Flavonoids and Extracts from Jatropha gossypifolia L

ABSTARCT: Jatropha gossypifolia L. (Euphorbiaceae) is a plant widely used in the treatment of type 2 diabetes mellitus (T2DM), but there are few scientific reports validating its activity in this area. In this work and through a bioguided assay, a crude extract stimulated glucose uptake in C2C12 myotubes up to 30%, thereby reducing insulin resistance induced by fatty acids compared to the basal control. A chromatographic fraction applied intraperitoneally (IP) in mice reduced glucose by 42% in a mouse model of T2DM, after administration of 10 doses during 20 days. A flavanone was purified from this active fraction and its structure was assigned by 1H- and 13C-NMR (1D and 2D) and MS. This compound retains the previously reported activity, stimulating in vitro the glucose uptake in a concentration-dependent manner. This study indicates that Jatropha gossypifolia L. extracts enhance glucose uptake in cultured myotubes and adipocytes and also improving glucose tolerance in an in vivo model. Keywords: Jatropha gossypifolia L, Flavanone, Flavone, Glucose regulation, Myotubes, Mic

AMP-Activated Protein Kinase Plays an Important Evolutionary Conserved Role in the Regulation of Glucose Metabolism in Fish Skeletal Muscle Cells

AMPK, a master metabolic switch, mediates the observed increase of glucose uptake in locomotory muscle of mammals during exercise. AMPK is activated by changes in the intracellular AMP∶ATP ratio when ATP consumption is stimulated by contractile activity but also by AICAR and metformin, compounds that increase glucose transport in mammalian muscle cells. However, the possible role of AMPK in the regulation of glucose metabolism in skeletal muscle has not been investigated in other vertebrates, including fish. In this study, we investigated the effects of AMPK activators on glucose uptake, AMPK activity, cell surface levels of trout GLUT4 and expression of GLUT1 and GLUT4 as well as the expression of enzymes regulating glucose disposal and PGC1α in trout myotubes derived from a primary muscle cell culture. We show that AICAR and metformin significantly stimulated glucose uptake (1.6 and 1.3 fold, respectively) and that Compound C completely abrogated the stimulatory effects of the AMPK activators on glucose uptake. The combination of insulin and AMPK activators did not result in additive nor synergistic effects on glucose uptake. Moreover, exposure of trout myotubes to AICAR and metformin resulted in an increase in AMPK activity (3.8 and 3 fold, respectively). We also provide evidence suggesting that stimulation of glucose uptake by AMPK activators in trout myotubes may take place, at least in part, by increasing the cell surface and mRNA levels of trout GLUT4. Finally, AICAR increased the mRNA levels of genes involved in glucose disposal (hexokinase, 6-phosphofructokinase, pyruvate kinase and citrate synthase) and mitochondrial biogenesis (PGC-1α) and did not affect glycogen content or glycogen synthase mRNA levels in trout myotubes. Therefore, we provide evidence, for the first time in non-mammalian vertebrates, suggesting a potentially important role of AMPK in stimulating glucose uptake and utilization in the skeletal muscle of fish

Antidiabetes and Anti-obesity Activity of Lagerstroemia speciosa

The leaves of Lagerstroemia speciosa (Lythraceae), a Southeast Asian tree more commonly known as banaba, have been traditionally consumed in various forms by Philippinos for treatment of diabetes and kidney related diseases. In the 1990s, the popularity of this herbal medicine began to attract the attention of scientists worldwide. Since then, researchers have conducted numerous in vitro and in vivo studies that consistently confirmed the antidiabetic activity of banaba. Scientists have identified different components of banaba to be responsible for its activity. Using tumor cells as a cell model, corosolic acid was isolated from the methanol extract of banaba and shown to be an active compound. More recently, a different cell model and the focus on the water soluble fraction of the extract led to the discovery of other compounds. The ellagitannin Lagerstroemin was identified as an effective component of the banaba extract responsible for the activity. In a different approach, using 3T3-L1 adipocytes as a cell model and a glucose uptake assay as the functional screening method, Chen et al. showed that the banaba water extract exhibited an insulin-like glucose transport inducing activity. Coupling HPLC fractionation with a glucose uptake assay, gallotannins were identified in the banaba extract as components responsible for the activity, not corosolic acid. Penta-O-galloyl-glucopyranose (PGG) was identified as the most potent gallotannin. A comparison of published data with results obtained for PGG indicates that PGG has a significantly higher glucose transport stimulatory activity than Lagerstroemin. Chen et al. have also shown that PGG exhibits anti-adipogenic properties in addition to stimulating the glucose uptake in adipocytes. The combination of glucose uptake and anti-adipogenesis activity is not found in the current insulin mimetic drugs and may indicate a great therapeutic potential of PGG

Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation

AMPK (AMP-activated protein kinase) is a key regulator of cellular and whole-body energy balance. AMPK phosphorylates and regulates many proteins concerned with nutrient metabolism, largely acting to suppress anabolic ATP-consuming pathways while stimulating catabolic ATP-generating pathways. This has led to considerable interest in AMPK as a therapeutic target for the metabolic dysfunction observed in obesity and insulin resistance. The role of AMPK in skeletal muscle and the liver has been extensively studied, such that AMPK has been demonstrated to inhibit synthesis of fatty acids, cholesterol and isoprenoids, hepatic gluconeogenesis and translation while increasing fatty acid oxidation, muscle glucose transport, mitochondrial biogenesis and caloric intake. The role of AMPK in the other principal metabolic and insulin-sensitive tissue, adipose, remains poorly characterized in comparison, yet increasing evidence supports an important role for AMPK in adipose tissue function. Obesity is characterized by hypertrophy of adipocytes and the development of a chronic sub-clinical pro-inflammatory environment in adipose tissue, leading to increased infiltration of immune cells. This combination of dysfunctional hypertrophic adipocytes and a pro-inflammatory environment contributes to insulin resistance and the development of Type 2 diabetes. Exciting recent studies indicate that AMPK may not only influence metabolism in adipocytes, but also act to suppress this pro-inflammatory environment, such that targeting AMPK in adipose tissue may be desirable to normalize adipose dysfunction and inflammation. In the present review, we discuss the role of AMPK in adipose tissue, focussing on the regulation of carbohydrate and lipid metabolism, adipogenesis and pro-inflammatory pathways in physiological and pathophysiological conditions

Examining the role of insulin in the regulation of cardiovascular health

A substantial body of evidence has reported that insulin has direct actions on the cardiovascular system independent of its systemic effects on plasma glucose or lipids. In particular, insulin regulates endothelial synthesis of the vasoactive mediators nitric oxide and endothelin-1, yet the importance of this in the maintenance of cardiovascular health remains poorly understood. Recent studies using animals with targeted downregulation of insulin signaling in vascular tissues are improving our understanding of the role of insulin in vascular health. This article focuses on the direct actions of insulin in cardiovascular tissues, with particular emphasis on the molecular mechanisms of insulin action on endothelial function. The potential contribution of impaired vascular insulin action to the cardiovascular complications of diabetes will also be discussed

Determination of Anti-Diabetic Activity of Gynura Procumbens Using Bioassay–Guided Fractionation

This study aims to investigate the antidiabetic and hypoglycaemic properties of Malaysian herb, Gynura procumbens (Sambung nyawa). Bioassay guided fractionation has been carried out to identify the bioactive crude fraction responsible for antidiabetic activity of Gynura procumbens. Both in vitro and in vivo model study were used to evaluate the antidiabetic properties of this plant. In vitro insulin secretion study, glucose uptake study and cytotoxicity were used as primary assay on crude methanolic extract, hexane, ethyl acetate and butanol fractions. Cytotoxicity studies demonstrated that crude methanolic extract have the lowest cytotoxicity when compared with crude fractions Gynura procumbens in BRIN BD11 cell lines. Cytotoxicity study with adipocytes and muscle cell lines showed that the crude methanolic extract of Gynura procumbens have the lowest toxicity when compared with the crude fractions of the plant. Determination of insulin secretion response was done by using BRIN BD11 cell lines and from the result, it showed that crude hexane and ethyl acetate crude fractions have good potential in stimulation of insulin release. Glucose uptake study with adipocytes cell lines (3T3 mouse adipocytes cell lines) indicated that this plant has the dose dependent manner and Gynura procumbens crude hexane fraction indicated the highest activity on stimulating glucose uptake. Effect of crude methanolic extract and crude fractions in the presence of insulin showed moderate glucose uptake activity when compared with Gynura procumbens crude extract/ fractions alone. Glucose uptake study with a mouse L6 muscle cell lines indicated that Gynura procumbens crude methanolic extract has highest reading from all of the crude extracts. When comparing the crude extract and fractions with insulin, all of the results showed moderate glucose uptake activity and thus expressed that this plant has dose dependent manner. Further study was done with Type 1 and Type 2 model diabetic rats. It shows that crude methanolic extract of Gynura procumbens have hypoglyceamic activity on both models. This result was further investigated with gut perfusion study using crude methanolic extract and ethyl acetate fraction of Gynura procumbens and showed positive result by delaying glucose absorption in the rat intestine.Further investigation was done with ethyl acetate fraction that showed potential activity from In vitro and In vivo study. Identification of compounds by using reverse phase HPLC showed some promising peaks of interesting compounds. Isolation and purification was carried on by using various chromatography techniques such as normal chromatography and gel filtration Sephadex LH-20. Two compounds from isolated from ethyl acetate fraction were mix of β-sitosterol and stigmasterol, and kaemferol-3-O- glucoside

Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells.

Glucagon is one of the main regulators of blood glucose levels and dysfunctional stimulus secretion coupling in pancreatic A-cells is believed to be an important factor during development of diabetes. However, regulation of glucagon secretion is poorly understood. Recently it has been shown that Na(+)/glucose co-transporter (SGLT) inhibitors used for the treatment of diabetes increase glucagon levels in man. Here, we show experimentally that the SGLT2 inhibitor dapagliflozin increases glucagon secretion at high glucose levels both in human and mouse islets, but has little effect at low glucose concentrations. Because glucagon secretion is regulated by electrical activity we developed a mathematical model of A-cell electrical activity based on published data from human A-cells. With operating SGLT2, simulated glucose application leads to cell depolarization and inactivation of the voltage-gated ion channels carrying the action potential, and hence to reduce action potential height. According to our model, inhibition of SGLT2 reduces glucose-induced depolarization via electrical mechanisms. We suggest that blocking SGLTs partly relieves glucose suppression of glucagon secretion by allowing full-scale action potentials to develop. Based on our simulations we propose that SGLT2 is a glucose sensor and actively contributes to regulation of glucagon levels in humans which has clinical implications

Why honey is effective as a medicine. 2. The scientific explanation of its effects

The effectiveness of honey as a therapeutic agent has been unequivocally demonstrated in the literature reviewed in Part 1 of this article published in 1999, but the biochemical explanation of these effects is more hypothetical. However, a rational explanation can be seen when one looks at the scientific literature outside that on honey. Some of the components of honey are substances known to have physiological actions that would explain many of its therapeutic effects. In addition, research on honey has shown directly that it has physiological actions that would give therapeutic effects