Effect of thiazolidinediones and metformin on LDL oxidation and aortic endothelium relaxation in diabetic GK rats

Kaoruko Tada Iida1, Yasushi Kawakami2, Masatsune Suzuki1, Hitoshi Shimano1, Hideo Toyoshima1, Hirohito Sone1, Kazunori Shimada3, Yoshitaka Iwama3, Yoshiro Watanabe3, Hiroshi Mokuno3, Katsuo Kamata4, and Nobuhiro Yamada1

1 Division of Endocrinology and Metabolism, Department of Internal Medicine, and 2 Department of Clinical Pathology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575; 3 Department of Cardiology, Juntendo University, Tokyo 113-8421; and 4 Departments of Physiology and Morphology, Institute of Medical Chemistry, Hoshi University, Tokyo 142-8501, Japan


    ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In this study, using GK diabetic rats, we compared the effects of three insulin sensitizers on lipid oxidation and the aortic relaxation response. Eight-week-old rats were treated for 4 wk with either troglitazone or pioglitazone, both of which are thiazolidinediones, or with metformin. Despite the fact that only troglitazone has a similarity in structure to alpha -tocopherol, a potent antioxidant, the level of thiobarbituric acid-reactive substance was lower, and the lag time of the conjugated dienes was longer, in the blood samples from the rats in both troglitazone- and pioglitazone-treated groups. In contrast, another insulin sensitizer, metformin, failed to inhibit the oxidation of blood samples. The aortic vasorelaxation response was increased in both troglitazone- and metformin-treated groups compared with the untreated group. These findings suggest that thiazolidinediones have a beneficial effect on lipid oxidation irrespective of the drug's structural similarity to alpha -tocopherol. It is also suggested that the thiazolidinediones and metformin improve vascular function in diabetes. These effects may play a role in the prevention of atherosclerosis in diabetic patients.

diabetes mellitus; low-density lipoprotein; endothelium; Goto-Kakizaki rats


    INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

DIABETES MELLITUS IS A STRONG RISK FACTOR for all manifestations of atherosclerotic vascular diseases. Although the pathophysiological mechanism of the development of atherosclerosis in diabetic patients has not yet been fully elucidated, it is thought that hyperlipidemia, increased oxidation of low-density lipoproteins (LDL), and impaired vascular function promote atherogenesis in diabetic patients. In addition, several cohort studies on diabetic and nondiabetic patients have shown an association between insulin resistance and atherosclerotic disorders such as cardiovascular disease (11, 19), which is one of the major causes of death in such patients. In particular, the insulin-resistant state is often accompanied by other risk factors, including hyperinsulinemia, hypertension, glucose intolerance, and hypertriglyceridemia, which increase the risk for cardiovascular disease, presumably by promoting atherosclerosis (20, 30).

Thiazolidinediones are a new class of oral antidiabetic agents that reduce the blood glucose level by improving insulin resistance in diabetic patients. This class of agents works by binding to peroxisome proliferator-activated receptor-gamma (PPARgamma ), thereby promoting the synthesis of glucose transporters and affecting lipid metabolism (13, 21). In contrast, metformin hydrochloride, a biguanide, improves the insulin-resistant state by unknown mechanisms, reducing gluconeogenesis and enhancing peripheral glucose uptake. As a result, metformin hydrochloride promotes reduction of the plasma glucose level (3, 26). Despite their actions through different mechanisms, these two insulin sensitizers have been reported to prevent the development of atherosclerosis (5, 14, 17, 28). However, the precise mechanisms by which these drugs prevent the development of atherosclerotic disorders have not yet been fully elucidated.

It has been suggested that oxidation of LDL is a key initial event in the progression of atherosclerotic lesion formation, which is followed by the uptake of oxidized LDL by macrophages via their scavenger receptors (25). Moreover, it has been reported that an increase in modified LDL impairs vascular functions such as endothelium-dependent vasodilatation (12). One kind of thiazolidinedione, troglitazone, has been reported to act as an antioxidant and inhibit the oxidation of LDL (6, 16); therefore, this drug has been considered to play a beneficial role in preventing the development of atherosclerosis. In this study, to elucidate the mechanisms through which insulin sensitizers prevent atherosclerotic disorders in diabetic patients, we compared the effects of three different insulin sensitizers, troglitazone, pioglitazone, and metformin, on lipid metabolism and the oxidized state of blood lipids in Goto-Kakizaki (GK) rats, a model of type 2 diabetes. We also examined the relaxation response in strips of the aorta to investigate the effect of these drugs on vascular function.


    MATERIALS AND METHODS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Materials and experimental protocols. Troglitazone, pioglitazone, and metformin were obtained from Sankyo Pharmaceuticals (Tokyo, Japan), Takeda Pharmaceuticals (Tokyo, Japan), and Sigma (St. Louis, MO), respectively. Twenty-four male GK rats bred in a closed colony were obtained from Charles River Laboratories (Wilmington, MA). They were fed standard powdered rodent chow (Oriental Yeast, Tokyo, Japan) and maintained in an environmentally controlled room under a 12:12-h light-dark cycle. Before drug administration, a blood sample was taken from the tail vein, and fasting plasma glucose was measured in each sample. Age-matched, male, nondiabetic Wistar rats (obtained from Charles River Laboratories) were used as the controls for measurement of plasma glucose to confirm that the diabetic state was completely established in the GK rats. The GK rats were divided into four groups (n = 6 in each group). There were no significant differences in diabetic parameters among the four groups: the untreated control group, the Troglitazone group [which had the powdered chow containing 0.2% (wt/wt) troglitazone], the Pioglitazone group [which had the powdered chow containing 0.02% (wt/wt) pioglitazone], and the Metformin group [which had the powdered chow containing 0.5% (wt/wt) metformin]. Administration of the drug was started at 8 wk of age, when the diabetic state was already established, and was continued for 4 wk. The weight of the residual chow was measured every day for 1 wk after drug administration commenced, and the average food intake of each animal was estimated by dividing the amount of consumed chow by the number of animals per cage (3 animals/cage). After drug administration, the animals were kept off chow for >= 12 h and were then killed. Blood samples were collected from the abdominal aorta with an anticoagulant agent to measure various metabolic markers.

Assay methods. The plasma concentrations of glucose, cholesterol, and triglycerides were measured by the enzymatic colorimetric method using a commercially available kit (Wako Chemicals, Tokyo, Japan) and the Hitachi Auto Analyzer (type 7170; Hitachi Electronics, Hitachi, Japan). The free fatty acid (FFA) level was measured by the enzymatic colorimetric method using a commercial kit (NEFA-SSAK, Eiken Chemicals, Tokyo, Japan). The plasma insulin level was measured with a radioimmunoassay kit (Linco Research, St. Charles, MO). The percentage of glycosylated hemoglobin A1C (Hb A1C) was calculated using a commercial kit (Unimate HbA1c; Roche Diagnostics, Basel, Switzerland) according to the manufacturer's protocol. All parameters in the plasma samples were assayed in duplicate.

Isolation of LDL. LDL was isolated by sequential density ultracentrifugation of the collected plasma from blood samples containing EDTA (at a 2 mM final concentration). Briefly, the plasma samples were overlaid with normal saline (d = 1.006 g/ml) and then centrifuged in a Beckman TLA 100.4 rotor (Beckman Coulter, Fullerton, CA) at 100,000 rpm at 15°C for >3 h to float the very low-density lipoproteins (VLDL). After the VLDL layer was removed, the salt density of the sample was adjusted to 1.063 g/ml by adding NaBr. The samples were then recentrifuged at 100,000 rpm at 15°C for >3 h. The layer of isolated LDL (d = 1.006-1.063 g/ml) was collected and dialyzed three times against phosphate-buffered saline containing 1 mM EDTA and sterilized using a 22-µm filter. The protein content was measured with a modified procedure of the Lowry assay as an estimate of the level of total LDL in each isolated sample.

Biochemical markers of lipid peroxidation. The levels of thiobarbituric acid-reactive substance (TBARS) formation in the plasma and in the LDL samples were assayed as described by Yagi (29). The concentration of TBARS was calculated as the malondialdehyde (MDA) equivalent (nmol/ml plasma or nmol/100 µg protein) by use of the standard curve of MDA generated by the hydrolysis of 1,1,3,3-tetraethoxypropane. The lag time of the formation of conjugated dienes was determined as follows. The protein concentration was adjusted to 20 µg/ml in each isolated LDL sample. Aliquots of LDL sample were then mixed with CuSO4 (at a 5 µM final concentration) and incubated at 37°C. The absorbance level at 234 nm was continuously measured at 5-min intervals until the absorbance reached the plateau level. The lag time was defined as the interval of time up to the time at which the absorbance started to increase.

Measurement of isometric force. The section of the aorta from between the aortic arch and the diaphragm was removed from the euthanized rats and placed in oxygenated, modified Krebs-Henseleit solution (KHS; in mM: 118 NaCl, 4.7 KCl, 25 NaHCO3, 1.8 CaCl2, 1.2 NaH2PO4, 1.2 MgSO4, 11 dextrose). The aorta was cut into helical strips 3 mm wide and 20 mm long and then placed in a well-oxygenated (95% O2-5% CO2) bath of 10-ml KHS with one end connected to a tissue holder and the other to a force displacement transducer (Nihon-Koden, TB-611T). The tissue was equilibrated for 60 min under a resting tension of 1.0 g. After equilibration, each strip was precontracted with norepinephrine (NE; 5 × 10-8-3 × 10-7 M) to develop a tension of ~95 mg/mg tissue. When the NE-induced contraction reached the plateau level, acetylcholine (ACh) or sodium nitroprusside (SNP) was added in a cumulative manner. The relaxation response was expressed as a percentage of the contraction induced by NA.

Statistical analysis. The results are expressed as means ± SD. Group means were compared using the one-way ANOVA. A P value of <0.05 was considered to be statistically significant.


    RESULTS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Diabetic statement. Before drug administration was started, the body weight and fasting plasma glucose (FPG) level of each animal were measured. The body weight was significantly lower, and the FPG levels were significantly higher, in the four groups of GK rats than in the age-matched, control Wistar rats (Table 1) at 8 wk of age, indicating that the diabetic state was already established in the GK rats at that time. There were no significant differences in body weight and FPG level among these four groups of GK rats. Several blood parameters of the diabetic state after the 4-wk drug administration are shown in Table 2. At 12 wk of age, although the GK rats in all four groups exhibited hyperglycemia that was more pronounced than at 8 wk of age, the FPG levels in the Troglitazone, Pioglitazone, and Metformin groups were significantly lower than in the untreated group. The Hb A1C levels in the three drug-treated groups were also significantly lower than the levels in the untreated group. In addition, all of the three antidiabetic drugs that we used significantly reduced the fasting insulin level, which was associated with the reduction in the FPG level, suggesting that these drugs improved the susceptibility to insulin in GK rats.

                              
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Table 1.   Diabetic parameters in 8-wk-old rats before drug administration


                              
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Table 2.   Diabetic parameters of 12-wk-old rats at end of 4 wk of drug administration

We also measured the food consumption of the animals in each group. Among the GK rats, the food consumption of the Metformin group (17.9 g · rat-1 · day-1) was lower than that of the three other groups (21.9 g · rat-1 · day-1 in the untreated group, 23.4 g · rat-1 · day-1 in the Troglitazone group, and 24.5 g · rat-1 · day-1 in the Pioglitazone group).

Blood lipid statement. To evaluate the effect of each antidiabetic drug on lipid metabolism, we measured the fasting levels of plasma cholesterol (total or HDL), triglyceride, and FFA in the GK rats 4 wk after treatment (Table 3). The two antidiabetic thiazolidinedione agents troglitazone and pioglitazone caused a significant reduction in the total cholesterol level. However, the HDL-cholesterol levels of the untreated GK rats and the thiazolidinedione-treated rats did not significantly differ, indicating that the non-HDL cholesterol level in the GK rats was decreased by the treatment with thiazolidinediones. In addition, in these two groups, the fasting triglyceride and FFA levels dramatically fell to <60% of the respective value in the untreated group (triglyceride: P < 0.05, P < 0.05; FFA: P < 0.01, P < 0.01). In contrast, the values of the lipid parameters in the Metformin group did not significantly differ from those in the untreated group.

                              
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Table 3.   Blood lipid parameters of 12-wk-old rats at end of 4 wk of drug administration

Lipid oxidation. To assess the effect of each drug on lipid oxidation, the TBARS level, which represents the plasma lipid peroxide content, was measured in the four groups of GK rats. As shown in Table 4, the two thiazolidinedione agents significantly reduced the TBARS level in the plasma samples of the GK rats after treatment for 4 wk. The TBARS levels in the LDL samples of the rats in the thiazolidinedione groups were also reduced but not significantly. We also measured the level of conjugated dienes in the LDL samples and analyzed the lag time to evaluate the effect of each drug on the susceptibility of the LDL samples to oxidation (Fig. 1). The lag times were significantly longer in the Troglitazone and Pioglitazone groups than in the untreated group. In contrast, there was no significant difference in lag time between the Metformin group and the untreated group. Therefore, the therapeutic use of thiazolidinediones appeared to reduce the susceptibility of LDL to oxidation.

                              
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Table 4.   Lipid peroxides in blood samples obtained from 12-wk-old rats at end of 4 wk of drug administration



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Fig. 1.   A: time course of the conjugated diene formation of LDL from blood samples obtained from Wistar rats (n = 6, ), Goto-Kakizaki (GK) rats (n = 6, ), or GK rats that had been treated with troglitazone (n = 6, ), pioglitazone (n = 6, open circle ) or metformin (n = 6, black-triangle) for 4 wk. Each data point represents the mean of 6 samples in each group. B: results are expressed as means ± SD of the lag time of 6 samples in each group. *P < 0.01 vs. untreated control.

Relaxation response to ACh in aorta. To assess the effect of thiazolidinediones and metformin on vascular function, the vasorelaxation response to ACh was examined in the following three groups: the Troglitazone group, the Metformin group, and the untreated group. The maximum relaxation responses were significantly increased in the aortic strips of the animals in the drug-treated groups compared with those in the untreated group (74.5 ± 3.6% in the Troglitazone group and 71.6 ± 3.2% in the Metformin group vs. 61.2 ± 7.8% in the untreated group, P < 0.01). The concentration of ACh achieving 50% relaxation (log EC50) was significantly lower in the drug-treated groups than in the untreated group [Troglitazone: -7.12 ± 0.08 and Metformin: -7.09 ± 0.05 vs. control: -6.84 ± 0.08 (-log M), P < 0.01; Fig. 2]. These results indicated that the treatments with troglitazone and metformin similarly improved the vasorelaxation response in the GK rats.


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Fig. 2.   Concentration-response curves for acetylcholine-induced relaxation of aortic strip obtained from untreated GK rats (n = 6, open circle ), or GK rats that had been treated with troglitazone (n = 6, ) or metformin (n = 6, black-triangle) for 4 wk. Relaxation of aorta was shown as a %contraction induced by an equieffective concentration of norepinephrine. Each data point represents the mean ± SD of 6 samples in each group.

We also assessed the effect of each drug in vasorelaxation response induced by nitric oxide donor. Although the relaxation responses of aortic strips induced by SNP were significantly increased in both drug-treated groups compared with the untreated group (91.3 ± 3.9% in the Troglitazone group, P < 0.05; 107.5 ± 0.8% in the Metformin group, P < 0.01, vs. 77.5 ± 14.5% in the untreated group), the relaxation responses were more intensified in the Metformin group than in the Troglitazone group (Metformin group vs. Troglitazone group, P < 0.05; Fig. 3). Taken together, these findings suggest that the treatment with metformin increases not only the endothelium-dependent but also the endothelium-independent relaxation in the aorta.


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Fig. 3.   Concentration-response curves for sodium nitroprusside (SNP)-induced relaxation of aortic strip obtained from untreated GK rats (n = 6, open circle ) or GK rats that had been treated with troglitazone (n = 6, ) or metformin (n = 6, black-triangle) for 4 wk. Relaxation of aorta was shown as a %contraction induced by an equieffective concentration of norepinephrine. Each data point represents the mean ± SD of 6 samples in each group.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

In this study, we attempted to compare the effects of three insulin sensitizers on lipid metabolism in GK rats, an animal model of spontaneous diabetes. GK rats exhibit moderate hyperglycemia that does not progress to a ketotic state, and they have a normal or slightly elevated plasma insulin level (18, 23). In addition, a euglycemic-clamp study showed that these animals have insulin resistance (4). Therefore, this animal model has been established as a model of type 2 diabetes possessing insulin resistance. In this study, we demonstrated that troglitazone, pioglitazone, and metformin improved the fasting plasma glucose and Hb A1C levels, which were associated with the reduction in the plasma insulin level in GK rats. These results indicate that these drugs improve insulin resistance in GK rats to a similar degree.

The clinical use of thiazolidinediones, including troglitazone and pioglitazone, has been known to reduce the plasma triglyceride level in diabetic patients and also in various genetically obese and diabetic rodent models (8, 9). Our data showed that troglitazone and pioglitazone reduced the plasma levels not only of triglyceride but also of cholesterol and FFA in GK rats. The mechanism through which thiazolidinediones affect these plasma lipids has not yet been elucidated; however, our data showed that not only troglitazone but also pioglitazone regulated the levels of plasma lipids in vivo to a similar extent, suggesting that PPARgamma is involved in the reduction of these plasma lipid levels. In contrast, the 4-wk metformin treatment did not reduce the plasma levels of cholesterol and triglyceride in the GK rats despite the improvement in glycemic control. In addition, in several previous clinical studies (2, 27), no significant improvement was observed in the blood lipid profiles in type 2 diabetes treated with metformin, suggesting that metformin was not as effective as thiazolidinediones in reducing hyperlipidemia.

Not only an elevated LDL level but also the oxidative modifications of LDL have recently been considered to be an important factor in atherosclerotic diseases (25). Therefore, the effect of several antidiabetic drugs on the susceptibility of LDL to oxidation has been investigated, and troglitazone has been reported to inhibit the oxidation of LDL in vitro and in vivo (6, 16). It has been considered that the mechanism of the inhibitory effect of troglitazone on oxidation was based on its molecular similarity to alpha -tocopherol (Fig. 4), which is one of the potent antioxidant-scavenging ROS (10, 16). However, in the present study, another thiazolidinedione, pioglitazone, inhibited the oxidation of LDL to a degree similar to that of troglitazone despite the fact that its structure differs from the structure of alpha -tocopherol. In contrast, another insulin sensitizer, metformin, failed to inhibit the oxidation of LDL. These results point to a novel finding that one particular effect of thiazolidinediones may be to improve the susceptibility of LDL to oxidation irrespective of the drug's structural similarity to alpha -tocopherol.


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Fig. 4.   Structures of troglitazone, alpha -tocopherol, and pioglitazone.

An impairment of vascular function has been considered to be involved in diabetic vascular complications. In some previous reports, it was observed that the functions of the cells that construct the arterial walls were impaired in diabetic animal models (7, 22). It was also reported that oxidized LDL itself impaired vascular function, such as endothelium-dependent vasodilatation (12, 24). In the present study, we hypothesized that thiazolidinediones ameliorate vascular function by decreasing the native and oxidized LDL in diabetic animals. As was expected, the treatment with troglitazone significantly improved ACh-induced vasodilatation in GK rats. However, it was reported that troglitazone did not improve the impaired vasorelaxation in obese but nondiabetic Wistar rats, although it improved obesity-induced lipid-metabolic changes (15). In the present study, we also showed a novel finding that the treatment with metformin improved the endothelium-dependent vasorelaxation to a similar degree compared with thiazolidinediones despite the fact that metformin did not inhibit the oxidation of LDL. These results suggest this possible explanation: in diabetic rats, not only oxidized LDL but also high plasma glucose or glucose derivatives such as abnormal glycosylated proteins lead directly to vascular dysfunction, and treatment with troglitazone or metformin improves the diabetes-induced vascular dysfunction by decreasing the plasma glucose level. It is also possible that the improvement of insulin resistance with these drugs directly ameliorates vascular function, because it has been reported that insulin resistance itself causes impairment of endothelium function (1). In addition, we found that metformin increased endothelium-independent vasorelaxation to a similar or greater extent compared with troglitazone. The effects of metformin reported in the present study may play a role in preventive effects of this drug against the diabetic atherosclerosis, demonstrated in some previous clinical studies such as the UK Prospective Diabetes Study (28).

In conclusion, the present study demonstrated a novel finding that the thiazolidinediones troglitazone and pioglitazone reduce the plasma lipid peroxide levels and the susceptibility of LDL to oxidation in GK rats irrespective of the drug's structural similarity to alpha -tocopherol. In contrast, another insulin sensitizer, metformin, had a much smaller effect on lipid metabolism, even though this drug improved the impairment of glucose metabolism in GK rats to a similar extent to the two thiazolidinediones. However, metformin improved vascular function as well as troglitazone, as analyzed by measuring the relaxation response in strips of the aorta. Recently, evidence has been presented from epidemiological studies showing that thiazolidinediones and metformin reduce the risk of atherosclerotic diseases such as coronary artery disease in diabetic patients (5, 14, 17, 28). The protective effects of thiazolidinediones and metformin may be due to their beneficial effects on the metabolism of lipids and the oxidation of LDL, or on vascular functions in diabetic patients.


    ACKNOWLEDGEMENTS

This study was supported by the Japan Foundation for Aging and Health.


    FOOTNOTES

Address for reprint requests and other correspondence: N. Yamada, Div. of Endocrinology and Metabolism, Dept. of Internal Medicine, Inst. of Clinical Medicine, Univ. of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan (E-mail: ymdnbhr{at}md.tsukuba.ac.jp).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

First published February 4, 2003;10.1152/ajpendo.00430.2002

Received 4 October 2002; accepted in final form 28 January 2003.


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RESULTS
DISCUSSION
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Am J Physiol Endocrinol Metab 284(6):E1125-E1130
0193-1849/03 $5.00 Copyright © 2003 the American Physiological Society




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