**5.1. Quercetin**

Quercetin (3,3΄,4΄,5-7-penta- hydroxyflavone), belongs to the class flavonol, a member of the flavonoid family and is widely distributed in plants. Quercetin and rutin are the flavonoids most abundantly consumed in foods [64]. Sources of quercetin include brassica green vegeta‐ bles, carrots, berries, onions, apple, legumes, green tea, citrus fruits, red wines etc [65]. Quercetin has been shown to prevent oxidative stress [66] by different mechanisms, including scavenging free radicals [67], inhibiting xanthine oxidase [68], lipid peroxidation, and chelating metal ions [69]. Quercetin is a powerful antioxidant, proven by *in vitro* [70] and *in vivo* studies [71]. Quercetin ameliorated the damage caused by oxidative stress in pancreatic tissues in rats, by directly quenching lipid peroxides and indirectly enhancing the production of endogenous antioxidants [72].

**Figure 1.** The chemical structure of quercetin.

improve glycemic index and/or oxidative stress will be beneficial in the treatment of diabetes

Majority of the drugs currently used in the treatment of diabetes mellitus have antioxidant activities in addition to their primary pharmacological activity. For example, aminoguanidine has been shown to exhibit free radical scavenging properties and inhibit lipid peroxidation [39-43] although clinical trials were discontinued in Europe and in the United States due to its long term toxicity. Troglitazone lowered hydroperoxides and decreased SOD activity in type 2 diabetic rats [44]. Glibenclamide, a sulphonylureas in addition to its glucose lowering effect possesses antioxidant properties due to its ability to restore liver catalase and superoxide dismutase in diabetic rats [45]. Also, repaglinide used in the treatment of type 2 diabetes mellitus exhibited antioxidant properties and inhibited protein peroxidation by upregulating glutathione reductase and glutathione levels in diabetic rabbits in addition to its insulin

Several *in vivo* studies have been carried out to ascertain the effects of antioxidants on exper‐ imental diabetic models [47-53]. Most of these studies reported the beneficial role of antioxi‐ dants against specific biomarkers of oxidative stress and provided the foundation for clinical trials embarked on later [54-60]. Majority of the studies were not designed specifically to assess the effects of antioxidant use in diabetic patients and none has been carried out yet on antioxidant-rich plant products despite the large evidence supporting its use. Medicinal plants and antioxidant-rich plant products definitely hold promise in this area in the near future.

The presence of polyphenolic compounds such as flavonoids, phenols, flavonols, and proan‐ thocyanidins in plants is associated with the antioxidant and antidiabetic potentials [61]. A number of studies have reported on the beneficial effect of flavonoids in diabetes mellitus [62-63]. Examples of flavonoids include quercetin, rutin, diosmin, luteolin, lycopene, catechins

Quercetin (3,3΄,4΄,5-7-penta- hydroxyflavone), belongs to the class flavonol, a member of the flavonoid family and is widely distributed in plants. Quercetin and rutin are the flavonoids most abundantly consumed in foods [64]. Sources of quercetin include brassica green vegeta‐ bles, carrots, berries, onions, apple, legumes, green tea, citrus fruits, red wines etc [65]. Quercetin has been shown to prevent oxidative stress [66] by different mechanisms, including scavenging free radicals [67], inhibiting xanthine oxidase [68], lipid peroxidation, and chelating metal ions [69]. Quercetin is a powerful antioxidant, proven by *in vitro* [70] and *in vivo* studies [71]. Quercetin ameliorated the damage caused by oxidative stress in pancreatic tissues in rats, by directly quenching lipid peroxides and indirectly enhancing the production of endogenous

mellitus and its complications.

320 Antioxidant-Antidiabetic Agents and Human Health

releasing effects [46].

and cinnamic acids.

**5.1. Quercetin**

antioxidants [72].

**5. Role of flavonoids in diabetes mellitus**

Quercetin reduces intestinal glucose absorption by inhibiting GLUT 2 in CaCo-2 intestinal cells [73-74]. Quercetin has been extensively investigated in diabetic rat models in recent times. It decreases the fasting blood glucose and improves glucose tolerance [75]; protects against oxidative damage and preserves pancreatic beta cell integrity [76]. Kobori *et al.* [77] reported that quercetin alleviated diabetic symptoms and liver injury in diabetic patients. Quercetin blocks tyrosine kinase thereby interfering with insulin signaling and the propagation of the biological actions of the hormone [78-79]. Quercetin elevated insulin secretion in insulinsecreting cell line induced by glucose and glibenclamide [80] by mediating ERK1/2 pathway [81]. Insulin resistance was improved in genetically obese Zucker rats upon administration of quercetin [82]. Quercetin also reduced maltose-induced postprandial hyperglycemia in type 2 diabetic patients by inhibiting intestinal alpha glucosidase activity [83]. Several mechanisms of action of quercetin in diabetes have been postulated and those included: decreases lipid peroxidation, increases antioxidant enzymes activity like superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase [76]. Other mechanisms are inhibition of insulindependent activation of phosphoinositol-3 kinase (PI-3K) [84], increase adiponectin levels [85], and decrease the intestinal maltose activity [27].

**Figure 2.** Proposed mechanisms for anti-diabetic effects of Quercetin. Reproduced from Portillo *et al.,* (2011).
