Antidiabetic effects of quercetin in streptozocin-induced diabetic rats

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Abstract

Effects of the intraperitoneal injection of quercetin in streptozocin-induced diabetic and normal rats were investigated and compared. Although quercetin had no effect on plasma glucose level of normal animals, it significantly and dose-dependently decreased the plasma glucose level of streptozocin-induced diabetic rats. Glucose tolerance tests of the diabetic animals approached those of normal rats, their plasma cholesterol and triglycerides were reduced significantly, while their hepatic glucokinase activity was significantly increased upon quercetin treatment. In normal rats, quercetin did not affect the glucose tolerance test, but resulted in an increase of plasma cholesterol and triglycerides and a decrease in hepatic glucokinase activity. No significant pathologic changes were noted in hepatocytes or kidney tubules and glomeruli, while the number of pancreatic islets significantly increased in both treated normal and diabetic groups. It is concluded that quercetin, a flavonoid with antioxidant properties brings about the regeneration of the pancreatic islets and probably increases insulin release in streptozocin-induced diabetic rats; thus exerting its beneficial antidiabetic effects. However, it may be of little value in normoglycemic animals.

Introduction

The most common substances inducing diabetes in the rat are alloxan and streptozocin (streptozotocin, STZ). STZ is taken up by pancreatic β-cells via glucose transporter GLUT2. The main cause of STZ-induced β-cell death is alkylation of DNA by the nitrosourea moiety of this compound. However, production of NOo and reactive oxygen species may also be involved in DNA fragmentation and other deleterious effects of STZ. The toxic action of alloxan on pancreatic β-cells involves several processes such as oxidation of essential SH groups, inhibition of β-cell glucokinase, generation of free radicals and disturbances in intracellular calcium homeostasis. Calcium does not play a significant role in necrosis of β-cells by STZ since calcium channel antagonists do not protect β-cells against this drug (Szkudelski, 2001). Interestingly, STZ is not equally effective in all vertebrates and mechanisms of action may differ between groups (Wright et al., 1999).

β-Cells are affected by many immunological and chemical agents leading to local inflammations producing IL-6 and glucocorticoids. IL-6/glucocorticoid stimulation produces an active transcriptional complex for Reg, a β-cell regenerating factor gene, in which poly (ADP-ribose) synthetase/polymerase (PARP) is involved. In the presence of PARP inhibitors such as nicotinamide when PARP is not itself poly (ADP-ribosyl)-ated, the transcriptional complex is stabilized and Reg gene transcription and subsequent Reg protein formation occurs in β-cells. This protein acts as a growth factor on β-cells via Reg receptor. DNA replication in β-cells takes place and β-cell regeneration is accomplished. DNA damaging substances such as superoxide (Oo2) and nitric oxide (NOo) are produced in inflammatory processes by cytotoxic agents such as STZ. When DNA is damaged, PARP senses the nicks and autopoly (ADP-ribosyl)-ates itself for DNA repair. Autopoly (ADP-ribosylation) of PARP inhibits the formation of Reg gene transcriptional complex and transcription of this gene stops (Akiyama et al., 2001).

Chemicals with antioxidant properties and free radical scavengers in particular prevent autopoly (ADP-ribosyl)-ation of PARP and by stabilizing Reg gene transcriptional complex, result in the regeneration of β-cells and protect pancreatic islets against cytotoxic effects of STZ or alloxan (Szkudelski, 2001).

Recently, there has been renewed interest in the use of plant compounds as antidiabetic compounds (Pari and Saravanan, 2002). Flavonoids are naturally occurring phenolic compounds that are widely distributed in plants. Due to the presence of aromatic hydroxyl groups, flavonoids have strong antioxidant properties. They are scavengers of reactive oxygen and nitrogen species and, therefore, inhibit peroxidation reactions. They also protect macrophages from oxidative stress by keeping glutathione in its reduced form (du Thie and Crozier, 2000, Fuhrman and Aviram, 2001).

Flavonoids have the capacity to inhibit enzymes such as cyclooxygenases and protein kinases involved in cell proliferation and apoptosis (Formica and Regelson, 1995). It was reported that a flavonoid, (−)-epicatechin, protects normal rat islets from alloxan, normalizes blood glucose levels and promotes β-cell regeneration in islets of alloxan—treated rats (Chakravarthy et al., 1981, Chakravarthy et al., 1982a, Chakravarthy et al., 1982b). Tritiated thymidine incorporation into islet cell DNA was also enhanced by this flavonoid in an in vitro study (Hii and Howell, 1984). However, the beneficial effects of (−)-epicatechin in STZ—diabetic animals could not be demonstrated (Bone et al., 1985). A different flavonoid, quercetin, used in doses of 10–50 mg/kg body mass was capable of normalizing blood glucose level, augmenting liver glycogen content and significantly reducing serum cholesterol and LDL concentration in alloxan–diabetic rats (Nuraliev and Avezov, 1992).

Hii and Howell (1985) showed that exposure of isolated rat islets to certain flavonoids such as (−)-epicatechin or quercetin enhances insulin release by 44–70%. They argue that such flavonoids may act on islet function, at least in part, via alteration in Ca2+ fluxes and in cyclic nucleotide metabolism.

Due to differences in the mechanism of action of streptozocin and alloxan and the presence of controversial reports on the antidiabetic effects of different flavonoids in alloxan-treated and STZ-induced diabetes, we decided to re-evaluate the effects of two different doses of quercetin in STZ-induced diabetic rats and compare the results with the effects of this flavonoid on normoglycemic animals.

This study compares the action of quercetin on blood glucose concentration, glucose tolerance test, pancreatic islet regeneration, activity of an insulin-induced enzyme (hepatic glucokinase), and the levels of plasma cholesterol and triglycerides (TG) in normoglycemic and diabetic rats.

Section snippets

Reagents

Glucose and fatty acid free bovine serum albumin were purchased from Roche chemical company (Germany). Leuconostoc mesenteroides glucose 6-phosphate dehydrogenase (G6PD), Na2.ATP, quercetin, HEPES buffer and dithiothreitol were obtained from Sigma Chemical Company (St. Louis, MO, USA). Na2.NAD was from Fluka chemical company (Switzerland), and streptozocin vials containing 1 g streptozocin and 220 mg citric acid was obtained from Upjohn Co. (Kalamazoo, MI, USA). Streptozocin was reconstituted

Results

Quercetin had no effect on plasma glucose concentration of normoglycemic animals, but significantly reduced blood glucose level of diabetic rats in 8–10 days at the two doses used. The blood glucose level of the diabetic animals treated with quercetin reached normal values at the end of this period (Fig. 1).

Quercetin exerted no effect on the glucose tolerance curve of the normoglycemic animals, but at the two doses used, normalized the glucose tolerance curves of the streptozocin diabetic rats (

Discussion

The plasma glucose lowering effects of quercetin in streptozocin-induced diabetic rats and its lack of effects on plasma glucose level of normoglycemic animals (Fig. 1) is in agreement with the results of Chakravarthy et al., 1981, Chakravarthy et al., 1982a, Chakravarthy et al., 1982b on similar effects of (−)-epicatechin, in alloxan diabetic rats and also in accord with the data of Nuraliev and Avezov (1992) on hypoglycemic effects of quercetin in alloxan diabetic animals. However, the latter

Acknowledgements

This investigation was supported by Grant No. 79–1038 from the office of Vice Chancellor for Research, Shiraz University of Medical Sciences.

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