Original articleIn vitro and in vivo antioxidant properties of gliclazide
Introduction
Diabetes is a state of increased oxidant stress and there is accumulating evidence that oxidative damage may play a role in the development of diabetic micro- and macrovascular disease. Atherosclerosis is a major cause of morbidity in diabetic patients, and cardiovascular disease accounts for up to 80% of diabetic deaths (Donahue & Orchard, 1992). Increased circulating levels of lipid peroxides have been found in diabetic patients, especially in those with vascular complications, and antibodies to oxidized low-density lipoprotein (LDL) are present in high levels in the plasma of diabetic patients Collier et al., 1990, O'Brien & Timmins, 1994. Diabetes can increase oxidative stress by several mechanisms. Glucose can catalyze lipid peroxidation in vitro (Hicks et al., 1988) and there is recent evidence that an acute glucose load can decrease antioxidant defenses in humans (Ceriello et al., 1998). Advanced glycation end products (AGE), which progressively accumulate in diabetes, can generate free radicals (Mullarkey et al., 1990), and antioxidants including glutathione, vitamin E, vitamin C and carotenoids have been found to be reduced in diabetic patients Karpen et al., 1985, Yue et al., 1990, Ford et al., 1999.
Gliclazide, a second-generation sulfonylurea that possesses a unique azabicyclo-octyl ring, has been found to act as a general free radical scavenger in vitro (Scott et al., 1991). We and others have previously reported that gliclazide can inhibit LDL oxidation in vitro Desfaits et al., 1997, O'Brien & Luo, 1997, and a study by Jennings et al. (1992) suggested that diabetic patients treated with the sulfonylurea gliclazide had lower plasma levels of lipid peroxides than patients receiving glibenclamide (Jennings et al., 1992).
The purpose of this study was twofold. Firstly, in an in vitro study, we have investigated the effects of gliclazide and other sulfonylureas on total plasma antioxidant capacity (TPAC), and on the oxidizability of LDL. Secondly, we have examined the in vivo antioxidant effects of gliclazide in a 10-month study in type 2 diabetic patients.
Section snippets
In vitro studies
Blood samples were collected from five patients with type 2 diabetes and five control subjects. Ten milliliters of fasting blood was drawn into an EDTA tube and immediately centrifuged at 3500 rpm for 10 min to obtain plasma. The procedure for LDL isolation has been described previously (O'Brien & Luo, 1997). Because only gliclazide and tolbutamide are water-soluble, all test solutions were prepared by initially dissolving the drug in 2 ml of pure ethanol, which was diluted to 100 ml using
In vitro studies
When added to LDL, gliclazide significantly inhibited copper-based oxidation. The results of experiments with LDL from diabetic and control subjects were identical and, therefore, pooled data are shown for both LDL oxidation and TPAC studies. Gliclazide (1 μM) increased the lag time (corresponding to the resistance of LDL to oxidation) from 53.6±2.6 to 113.6±5.1 min (p<0.001). None of the other sulfonylureas (glibenclamide, glimepiride, glipizide, and tolbutamide) had any effect on lag time
Discussion
These studies clearly show that gliclazide has antioxidant properties. We have found that gliclazide protects LDL from copper-induced oxidation, and this effect was demonstrated at the lower end of its therapeutic range. The normal therapeutic dose of gliclazide is 40–120 mg/day, which gives a plasma concentration between 0.77 and 24.7 μM (Palmer & Brogden, 1993), and gliclazide significantly inhibited LDL oxidation at a concentration of 1 μM. This effect was not shared by other sulfonylureas,
Acknowledgements
The authors are indebted to the following investigators who assisted with the management of the clinical study: Dr. K. Narayan, Box Hill Hospital, Box Hill; Dr. G. Jerums, Austin and Repatriation Medical Centre, Heidelberg; Dr. D. Cameron, Princess Alexandra Hospital, Woolloongabba; Dr. J. Karrasch, Peninsula Medical Centre, Kippa Ring; Dr. A. Roberts, Ashford Specialist Centre, Ashford, Australia.
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