Oxidative stress, insulin signaling, and diabetes.

Flavonoids are polyphenolic compounds that are abundant in fruits and vegetables, and increasing evidence demonstrates a positive relationship between consumption of flavonoid-rich foods and disease prevention. Epidemiological, in vitro and animal studies support the beneficial effects of dietary flavonoids on glucose and lipid homeostasis. It is encouraging that the beneficial effects of some flavonoids are at physiological concentrations and comparable to clinicallyused anti-diabetic drugs; however, clinical research in this field and studies on the anti-diabetic effects of flavonoid metabolites are limited. Flavonoids act on various molecular targets and regulate different signaling pathways in pancreatic β-cells, hepatocytes, adipocytes and skeletal myofibers. Flavonoids may exert beneficial effects in diabetes by (i) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic β-cells; (ii) improving hyperglycemia through regulation of glucose metabolism in hepatocytes; (iii) reducing insulin resistance, inflammation and oxidative stress in muscle and fat and (iv) increasing glucose uptake in skeletal muscle and white adipose tissue. This review highlights recent findings on the anti-diabetic effects of dietary flavonoids, including flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones and isoflavones, with particular emphasis on the studies that investigated the cellular and molecular mechanisms involved in the beneficial effects of the compounds.

REVIEWS: CURRENT TOPICS Recent advances in understanding the anti-diabetic actions of dietary flavonoids

Flavonoids are polyphenolic compounds that are abundant in fruits and vegetables, and increasing evidence demonstrates a positive relationship between consumption of flavonoid-rich foods and disease prevention. Epidemiological, in vitro and animal studies support the beneficial effects of dietary flavonoids on glucose and lipid homeostasis. It is encouraging that the beneficial effects of some flavonoids are at physiological concentrations and comparable to clinically-used anti-diabetic drugs; however, clinical research in this field and studies on the anti-diabetic effects of flavonoid metabolites are limited. Flavonoids act on various molecular targets and regulate different signaling pathways in pancreatic β-cells, hepatocytes, adipocytes and skeletal myofibers. Flavonoids may exert beneficial effects in diabetes by (i) enhancing insulin secretion and reducing apoptosis and promoting proliferation of pancreatic β-cells; (ii) improving hyperglycemia through regulation of glucose metabolism in hepatocytes; (iii) reducing insulin resistance, inflammation and oxidative stress in muscle and fat and (iv) increasing glucose uptake in skeletal muscle and white adipose tissue. This review highlights recent findings on the anti-diabetic effects of dietary flavonoids, including flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones and isoflavones, with particular emphasis on the studies that investigated the cellular and molecular mechanisms involved in the beneficial effects of the compounds.

Recent advances in understanding the anti-diabetic actions of dietary flavonoids

Natural food products have been used for combating human diseases for thousands of years. Naturally occurring flavonoids including flavones, flavonols, flavanones, flavonols, isoflavones and anthocyanidins have been proposed as effective supplements for management and prevention of diabetes and its long-term complications based on in vitro and animal models. To summarize the roles of dietary flavonoids in diabetes management and their molecular mechanisms. Tremendous studies have found that flavonoids originated from foods could improve glucose metabolism, lipid profile, regulating the hormones and enzymes in human body, further protecting human being from diseases like obesity, diabetes and their complications. In the current review, we summarize recent progress in understanding the biological action, mechanism and therapeutic potential of the dietary flavonoids and its subsequent clinical outcomes in the field of drug discovery in management of diabetes mellitus.

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Antidiabetic properties of dietary flavonoids: a cellular mechanism review

Berries contain vitamin C and are also a rich source of phytochemicals, especially anthocyanins which occur along with other classes of phenolic compounds, including ellagitannins, flavan-3-ols, procyanidins, flavonols and hydroxybenzoate derivatives. This review examines studies with both human subjects and animals on the absorption of these compounds, and their glucuronide, sulphate and methylated metabolites, into the circulatory system from the gastrointestinal tract and the evidence for their localisation within the body in organs such as the brain and eyes. The involvement of the colonic microflora in catabolising dietary flavonoids that pass from the small to the large intestine is discussed along with the potential fate and role of the resultant phenolic acids that can be produced in substantial quantities. The in vitro and in vivo bioactivities of these polyphenol metabolites and catabolites are assessed, and the current evidence for their involvement in the protective effects of dietary polyphenols, within the gastrointestinal tract and other parts of the body to which they are transported by the circulatory system, is reviewed.

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Berry flavonoids and phenolics: bioavailability and evidence of protective effects

Effect of nonenzymatic glycation on functional and structural properties of hemoglobin.

Objectives Glycyrrhizin is the main water-soluble constituent of the root of liquorice (Glycyrrhiza glabra). The study investigates the effect of glycyrrhizin on streptozotocin (STZ)-induced diabetic changes and associated oxidative stress, including haemoglobin-induced free iron-mediated oxidative reactions.



Methods  Male Wistar rats were grouped as normal control, STZ-induced diabetic control, normal treated with glycyrrhizin, diabetic treated with glycyrrhizin and diabetic treated with a standard anti-hyperglycaemic drug, glibenclamide. Different parameters were studied in blood and tissue samples of the rats.



Key findings  Glycyrrhizin treatment improved significantly the diabetogenic effects of STZ, namely enhanced blood glucose level, glucose intolerant behaviour, decreased serum insulin level including pancreatic islet cell numbers, increased glycohaemoglobin level and enhanced levels of cholesterol and triglyceride. The treatment significantly reduced diabetes-induced abnormalities of pancreas and kidney tissues. Oxidative stress parameters, namely, serum superoxide dismutase, catalase, malondialdehyde and fructosamine in diabetic rats were reverted to respective normal values after glycyrrhizin administration. Free iron in haemoglobin, iron-mediated free radical reactions and carbonyl formation in haemoglobin were pronounced in diabetes, and were counteracted by glycyrrhizin. Effects of glycyrrhizin and glibenclamide treatments appeared comparable.



Conclusion  Glycyrrhizin is quite effective against hyperglycaemia, hyperlipidaemia and associated oxidative stress, and may be a potential therapeutic agent for diabetes treatment.

Ameliorative effects of glycyrrhizin on streptozotocin-induced diabetes in rats.

Action of pelargonidin on hyperglycemia and oxidative damage in diabetic rats: implication for glycation-induced hemoglobin modification.

Heme proteins––hemoglobin and myoglobin possess esterase activities. Studies with purified hemoglobin from normal individuals and diabetic patients revealed that the esterase activity as measured from hydrolysis of p-nitrophenyl acetate (p-NPA) was higher in diabetic condition and increased progressively with extent of the disease. HbA1c, the major glycated hemoglobin, which increases proportionately with blood glucose level in diabetes mellitus, exhibited more esterase activity than the non-glycated hemoglobin fraction, HbA0, as demonstrated spectrophotometrically as well as by activity staining. Glycation influenced esterase activity of hemoglobin by increasing the affinity for the substrate and the rate of the reaction. Both HbA0 and HbA1c-mediated catalysis of p-NPA hydrolysis was pH-dependent. Esterase activity of in vitro-glycated myoglobin (GMb) was also higher than that of its non-glycated analog (Mb). The amplified esterase activities of hemoglobin and myoglobin might be associated with glycation-induced structural modifications of the proteins.

Effect of non-enzymatic glycation on esterase activities of hemoglobin and myoglobin.

Metmyoglobin (Mb) was glycated by glucose in a nonenzymatic in vitro reaction. Amount of iron release from the heme pocket of myoglobin was found to be directly related with the extent of glycation. After in vitro glycation, the unchanged Mb and glycated myoglobin (GMb) were separated by ion exchange (BioRex 70) chromatography, which eliminated free iron from the protein fractions. Separated fractions of Mb and GMb were converted to their oxy forms -MbO2 and GMbO2, respectively. H2O2-induced iron release was significantly higher from GMbO2 than that from MbO2. This free iron, acting as a Fenton reagent, might produce free radicals and degrade different cell constituents. To verify this possibility, degradation of different cell constituents catalyzed by these fractions in the presence of H2O2 was studied. GMbO2 degraded arachidonic acid, deoxyribose and plasmid DNA more efficiently than MbO2. Arachidonic acid peroxidation and deoxyribose degradation were significantly inhibited by desferrioxamine (DFO), m...

Subhrojit Sen

Papers

Effect of nonenzymatic glycation on functional and structural properties of hemoglobin.

Ameliorative effects of glycyrrhizin on streptozotocin-induced diabetes in rats.

Action of pelargonidin on hyperglycemia and oxidative damage in diabetic rats: implication for glycation-induced hemoglobin modification.

Effect of non-enzymatic glycation on esterase activities of hemoglobin and myoglobin.

In vitro nonenzymatic glycation enhances the role of myoglobin as a source of oxidative stress.