cyanidin-3-o-beta-glucopyranoside and Hyperglycemia

Myrica faya Aiton (fire tree, faya) is an underused species with a diverse flavonoid composition (anthocyanins, flavonols, ellagitannins) which can promote positive effects on human health. M. faya has been reported to possess high antioxidant activities, but its potential in the prevention of type II diabetes has not been evaluated so far. In the present study, eight M. faya samples from different areas of Madeira and Azores archipelagos (Portugal) were collected to determine their phytochemical profile and then tested for their in vitro anti-diabetic and antioxidant activities. The analyzed extracts showed strong inhibitory activities towards α -glucosidase, aldose reductase and glycation of bovine serum albumin (BSA) and moderate effects towards α-amylase and lipase (by comparison with reference compounds). Cyanidin-3-O-glucoside and ellagitannins were the main bioactive agents involved in the anti-diabetic effects of M. faya. Such results may provide important scientific evidence for further utilization of M. faya as dietary or nutraceutical products for the prevention and/or control of hyperglycaemia-associated complications.

Topics: Aldehyde Reductase; alpha-Amylases; alpha-Glucosidases; Anthocyanins; Anti-Obesity Agents; Antioxidants; Azores; Diabetes Complications; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Flavonoids; Glucosides; Glycation End Products, Advanced; Humans; Hyperglycemia; Hypoglycemic Agents; Lipase; Myrica; Obesity; Phytochemicals; Plant Extracts; Polyphenols; Portugal; Serum Albumin, Bovine

A high glucose (Glu) milieu promotes generation of reactive oxygen species, which may not only cause cellular damage, but also modulate phase II enzymes that are responsible for the metabolism of flavonoids. Thus, we examined the effect of a high Glu milieu on quercetin (Q) metabolism in HepG2 cells. HepG2 cells were grown for 3 days in Glu ranging from 5.5 to 50 mmol/L and/or cyanidin-3-glucoside (C3G) ranging from 0 to 25 μmol/L. Subsequently, the capacity of HepG2 cells to metabolize Q was assessed for up to 16 h. Q metabolites were analyzed by high-performance liquid chromatography. Four major Q metabolites were observed in the culture medium and inside the HepG2 cells. Three of these metabolites appear to be sulfated forms of Q or methylated Q, and one was a methylated Q. These metabolites and Q itself were reduced or tended to be reduced in cells grown in a high Glu compared to a normal Glu medium. Addition of C3G or superoxide dismutase plus catalase did not prevent or enhance reduction of Q metabolites. In vitro, a hyperglycemic milieu decreases the production of the principal Q metabolites in HepG2 cells, mediated through mechanisms independent of oxidative stress.

Topics: Anthocyanins; Antioxidants; Catalase; Chromatography, High Pressure Liquid; Glucosides; Hep G2 Cells; Humans; Hyperglycemia; Oxidative Stress; Quercetin; Reactive Oxygen Species; Superoxide Dismutase

Procyanidins are the oligomeric or polymeric forms of epicatechin and catechin. In this study, we isolated and purified dimer to tetramer procyanidins from black soybean seed coat and investigated the anti-hyperglycemic effects by focusing on glucose transporter 4 (GLUT4) translocation and the underlying molecular mechanism in skeletal muscle of mice. The anti-hyperglycemic effects of procyanidins were also compared with those of monomer (-)-epicatechin (EC) and major anthocyanin, cyanidin-3-O-β-glucoside (C3G). To investigate GLUT4 translocation and its related signaling pathways, ICR mice were orally given procyanidins, EC and C3G in water at 10 μg/kg body weight. The mice were sacrificed 60 min after the dose of polyphenols, and soleus muscle was extracted from the hind legs. The results showed that trimeric and tetrameric procyanidins activated both insulin- and AMPK-signaling pathways to induce GLUT4 translocation in muscle of ICR mice. We confirmed that procyanidins suppressed acute hyperglycemia with an oral glucose tolerance test in a dose-dependent manner. Of these beneficial effects, cinnamtannin A2, one of the tetramers, was the most effective. In conclusion, procyanidins, especially cinnamtannin A2, significantly ameliorate postprandial hyperglycemia at least in part by promoting GLUT4 translocation to the plasma membrane by activating both insulin- and AMPK-signaling pathways.

Topics: AMP-Activated Protein Kinases; Animals; Anthocyanins; Biflavonoids; Catechin; Disease Models, Animal; Glucose; Glucose Transporter Type 4; Glucosides; Humans; Hyperglycemia; Insulin; Mice; Muscle, Skeletal; Proanthocyanidins; Signal Transduction

Enhanced oxidative stress due to high glucose contributes to pathological changes in diabetes-related liver complications. Reducing oxidative stress may alleviate these pathogenic processes. Anthocyanin, a natural antioxidant, has been reported to reduce intracellular reactive oxygen species (ROS) levels but the mechanism of this reduction is not fully understood. The glutathione (GSH) antioxidant system is critical for counteracting oxidative stress-induced intracellular injury. In this study, we evaluated the mechanism of the anthocyanin-mediated regulation of GSH synthesis and reduction in intracellular ROS levels. We observed that treatment of human HepG2 cells with the anthocyanin C3G significantly reduced ROS levels induced by high glucose. C3G incubation increased glutamate-cysteine ligase expression, which in turn mediated the reduction in ROS levels. However, the upregulation of glutamate-cysteine ligase catalytic subunit (Gclc) expression by C3G occurred independent of the Nrf1/2 transcription factors. Notably, the cAMP-response element binding protein (CREB) was identified as the target transcription factor involved in the C3G-mediated upregulation of Gclc expression. C3G increased phosphorylation of CREB through protein kinase A (PKA) activation, which induced a CREB-mediated upregulation of Gclc transcription. In vivo, treatment with C3G increased the GSH synthesis in the liver of diabetic db/db mice through PKA-CREB-dependent induction of Gclc expression. Finally, oxidative stress determined by lipid peroxidation, neutrophil infiltration, and hepatic steatosis was attenuated in C3G-treated db/db mice. Our results demonstrate that the anthocyanin C3G has an effect of activating GSH synthesis through a novel antioxidant defense mechanism against excessive ROS production, contributing to the prevention of hyperglycemia-induced hepatic oxidative damage.

Topics: Animals; Anthocyanins; Antioxidants; Apoptosis; Cell Survival; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Cytoprotection; Enzyme Activation; fas Receptor; Fatty Liver; Gene Expression; Glucosides; Glutamate-Cysteine Ligase; Glutathione; Hep G2 Cells; Hepatocytes; Humans; Hyperglycemia; Liver; Male; MAP Kinase Kinase 4; Mice; Mice, Obese; Oxidative Stress; Protein Binding; Reactive Oxygen Species; Signal Transduction; Thiobarbituric Acid Reactive Substances; Up-Regulation

Chinese bayberry fruit is a rich source of anthocyanins, especially cyanidin-3-glucoside (C3G). The present study investigated the protective effects of C3G-rich bayberry fruit extract (CRBFE) against pancreatic β cells against oxidative stress-induced injury as well as its hypoglycemic effect in diabetic mice. Bayberry extract from "Biqi" was used for both in vitro and in vivo testing because of its high C3G content and high antioxidant capacity. Pretreatment of β cells with CRBFE (containing 0.5 μmol/L C3G) prevented cell death, increased cellular viability, and decreased mitochondrial reactive oxygen species production and cell necrosis induced by 800 or 1,200 μmol/L H₂O₂. CRBFE dose-dependently up-regulated pancreatic duodenal homeobox 1 gene expression, contributing to increased insulin-like growth factor II gene transcript levels and insulin protein in INS-1 cells. In addition, administration of CRBFE (150 μg of C3G/10 g of body weight twice per day) significantly reduced blood glucose in streptozotocin-induced diabetic ICR mice and increased the glucose tolerance in an oral glucose tolerance test (P<.05). Such results indicated that CRBFE might be useful in prevention and control of diabetes mellitus and diabetes-associated complications.

Topics: Animals; Anthocyanins; Antioxidants; Cell Line; Cell Survival; China; Diabetes Mellitus, Experimental; Fruit; Gene Expression Regulation; Glucosides; Homeodomain Proteins; Hyperglycemia; Hypoglycemic Agents; Insulin-Like Growth Factor II; Insulin-Secreting Cells; Male; Mice; Mice, Inbred ICR; Myrica; Plant Extracts; Random Allocation; Rats; Reactive Oxygen Species; RNA, Messenger; Trans-Activators

Elevated concentrations of circulating free fatty acids (FFAs) have been demonstrated to potentially link obesity, insulin resistance and type 2 diabetes. Inhibition of lipolysis reduces FFAs availability and improves insulin sensitivity. Anthocyanins from different plant foods were shown to improve hyperlipidemia and insulin resistance in vivo. In this study, cyanidin-3-O-β-glucoside (C3G), a typical anthocyanin was selected to examine its in vitro effects on high-glucose-induced lipolysis in cultured 3T3-L1 adipocytes. Incubation with C3G efficiently inhibited FFAs and glycerol release from the adipocytes during hyperglycemia in a dose- and time-dependent manner. C3G treatment also increased the activity of AMP-activated protein kinase, decreased the activity of glutamine:fructose 6-phosphate aminotransferase, reduced cellular UDP-N-acetylglucosamine production, thereby suppressing the hexosamine biosynthetic pathway. In addition, C3G attenuated high-glucose-promoted O-glycosylation of transcription factor FoxO1, resulting in decreased expression of adipose triglyceride lipase (ATGL). Our findings reveal a novel mechanism by which anthocyanin regulates FoxO1-mediated transcription of ATGL and thus inhibits adipocyte lipolysis, suggesting its potential therapeutic application in diabetes-associated hyperlipidemia.

Topics: 3T3-L1 Cells; Acylation; Adenylate Kinase; Adipocytes; Animals; Anthocyanins; Base Sequence; DNA Primers; Enzyme Activation; Forkhead Box Protein O1; Forkhead Transcription Factors; Glucose; Glucosides; Hyperglycemia; Lipase; Lipolysis; Mice; Polymerase Chain Reaction; Transcription, Genetic

Adipocyte dysfunction is strongly associated with the development of obesity and insulin resistance. It is accepted that the regulation of adipocytokine expression is one of the most important targets for the prevention of obesity and improvement of insulin sensitivity. In this study, we have demonstrated that anthocyanin (cyanidin 3-glucoside; C3G) which is a pigment widespread in the plant kingdom, ameliorates hyperglycemia and insulin sensitivity due to the reduction of retinol binding protein 4 (RBP4) expression in type 2 diabetic mice. KK-A(y) mice were fed control or control +0.2% of a C3G diet for 5 weeks. Dietary C3G significantly reduced blood glucose concentration and enhanced insulin sensitivity. The adiponectin and its receptors expression were not responsible for this amelioration. C3G significantly upregulated the glucose transporter 4 (Glut4) and downregulated RBP4 in the white adipose tissue, which is accompanied by downregulation of the inflammatory adipocytokines (monocyte chemoattractant protein-1 and tumor necrosis factor-alpha) in the white adipose tissue of the C3G group. These findings indicate that C3G has significant potency in an anti-diabetic effect through the regulation of Glut4-RBP4 system and the related inflammatory adipocytokines.

Topics: Adipokines; Adiponectin; Adipose Tissue, White; Animals; Anthocyanins; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Down-Regulation; Glucose Tolerance Test; Glucose Transporter Type 4; Glucose-6-Phosphatase; Glucosides; Hyperglycemia; Inflammation Mediators; Insulin Resistance; Liver; Male; Mice; Mice, Inbred Strains; Molecular Structure; Receptors, Adiponectin; Retinol-Binding Proteins, Plasma; Reverse Transcriptase Polymerase Chain Reaction

Anthocyanins, which are used as a food coloring, are widely distributed in human diets, suggesting that we ingest large amounts of anthocyanins from plant-based foods. Mice were fed control, cyanidin 3-glucoside-rich purple corn color (PCC), high fat (HF) or HF + PCC diet for 12 wk. Dietary PCC significantly suppressed the HF diet-induced increase in body weight gain, and white and brown adipose tissue weights. Feeding the HF diet markedly induced hypertrophy of the adipocytes in the epididymal white adipose tissue compared with the control group. In contrast, the induction did not occur in the HF + PCC group. The HF diet induced hyperglycemia, hyperinsulinemia and hyperleptinemia. These perturbations were completely normalized in rats fed HF + PCC. An increase in the tumor necrosis factor (TNF)-alpha mRNA level occurred in the HF group and was normalized by dietary PCC. These results suggest that dietary PCC may ameliorate HF diet-induced insulin resistance in mice. PCC suppressed the mRNA levels of enzymes involved in fatty acid and triacylglycerol synthesis and lowered the sterol regulatory element binding protein-1 mRNA level in white adipose tissue. These down-regulations may contribute to triacylglycerol accumulation in white adipose tissue. Our findings provide a biochemical and nutritional basis for the use of PCC or anthocyanins as a functional food factor that may have benefits for the prevention of obesity and diabetes.

Topics: Adipose Tissue; Animals; Anthocyanins; Base Sequence; Body Weight; CCAAT-Enhancer-Binding Proteins; Diet; DNA Primers; DNA-Binding Proteins; Energy Intake; Glucosides; Hyperglycemia; Insulin Resistance; Lipids; Liver; Male; Mice; Mice, Inbred BALB C; Obesity; Organ Size; Sterol Regulatory Element Binding Protein 1; Transcription Factors