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Biochemical and Molecular Actions of Nutrients

Five Cysteine-Containing Compounds Delay Diabetic Deterioration in Balb/cA Mice¹

Department of Nutritional Science, Chungshan Medical University, Taichung City, Taiwan

²To whom correspondence should be addressed. E-mail: mcyin{at}csmu.edu.tw.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The effects of n-acetyl cysteine (NAC), s-allyl cysteine (SAC), s-ethyl cysteine, s-methyl cysteine and s-propyl cysteine (SPC) activity on Balb/cA mice against diabetic complications were examined. These complications included hyperglycemia, hyperlipidemia, oxidation stress, blood coagulation, and cytokine imbalance. To induce diabetes, mice were treated with streptozotocin i.p. for 5 consecutive days. Five cysteine-containing compounds at 1 g/L were added to the drinking water. After intake of the 5 cysteine-containing agents for 4 wk, body weight loss, plasma concentrations of glucose and insulin, and fibronectin levels were improved (P < 0.05) in diabetic mice. The administration of these agents restored the glutathione level (P < 0.05), reduced the loss of catalase and glutathione peroxidase activities in kidney and liver (P < 0.05), and decreased glucose-induced lipid oxidation, as assessed by malondialdehyde formation (P < 0.05). In all diabetic mice, the intake of these agents reduced triglyceride levels in plasma and liver (P < 0.05); however, only NAC, SAC and SPC treatments reduced cholesterol level in liver (P < 0.05). These cysteine-containing agents elevated the activity of 2 fibrinolytic factors, protein C and antithrombin III (P < 0.05). The overexpression of interleukin-6 and tumor necrosis factor- in diabetic mice was suppressed by the intake of the 5 cysteine-containing agents (P < 0.05). Via their antioxidant activities, the 5 compounds effectively improved glycemic control, delayed oxidation damage, downregulated inflammatory cytokines, and enhanced anticoagulant activity in diabetic mice. These data support the multiple roles of these agents as potential protective agents for delaying diabetic deterioration.

KEY WORDS: • diabetes • cysteine-containing agents • coagulation • oxidation • interleukin-6

Diabetic complications such as neuropathy, retinopathy, nephropathy, and atherosclerosis contribute to the severity of the disease and the mortality of diabetic patients; the clinical characteristics of these complications include hyperglycemia, hyperlipidemia, oxidation stress, cytokine imbalance, and coagulation predomination (1–4). It was shown that oxidation stress, inflammation, and blood coagulation are strongly associated with diabetes (4–6), and all are involved in the development of diabetic complications. Thus, it is very important to control these risk factors to delay diabetic deterioration.

n-Acetyl cysteine (NAC),³ s-allyl cysteine (SAC), s-ethyl cysteine (SEC), s-methyl cysteine (SMC), and s-propyl cysteine (SPC) are 5 hydrophilic cysteine-containing compounds naturally formed in Allium plants such as garlic and onion (7,8). In a study of normal mice, we found that these compounds exhibited marked enzymatic antioxidant protection and reduced fibronectin, triglyceride and cholesterol levels (9). However, it is unclear whether these agents could protect diabetic individuals against oxidative damage and improve diabetic complications such as hyperglycemia and hyperlipidemia.

Several studies indicated that the balance of Th1 type cytokines such as tumor necrosis factor (TNF)- and Th2-type cytokines such as interleukin (IL)-6 are disturbed, and both are involved in diabetic progression (10–12). Overexpression of these cytokines could worsen the severity of diabetes. On the other hand, the upregulation of blood coagulation factors such as fibrinogen and downregulation of anticoagulation factors such as antithrombin III (AT-III) in diabetic individuals was observed (13,14), and these factors may be responsible for the development of vascular diseases such as atherosclerosis. Thus, to improve diabetic complications, both cytokine and hemostatic balance warrant attention. Although our earlier study reported that the cysteine-containing compounds noted above could reduce oxidative damage in normal mice (9), it is not known whether these agents could improve the hemostatic and cytokine balance in diabetic individuals.

The major purpose of this study was to evaluate the in vivo protection from 5 cysteine-containing compounds in diabetic mice. The effects of these agents on the plasma levels of glucose, insulin, triglycerides, and cholesterol, and the activity of antioxidant enzymes, coagulation and anticoagulation factors, and plasma cytokine levels were determined.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Animals and diets. Male Balb/cA mice, 3–4 wk old, were obtained from National Laboratory Animal Center (National Science Council). Mice were housed on a 12-h light:dark schedule; water and rat and mouse standard diet were consumed ad libitum. The diet contained by weight (g/100 g): 64 starch, 23 protein, 3.5 fat, 5 fiber, 1 vitamin mixture, and 3 salt mixture (PMI Nutrition International). The use of the mice was reviewed and approved by the Chungshan Medical University animal care committee. To induce diabetes, mice with body weights of 22.3 ± 0.7 g were treated with streptozotocin (STZ, 40 mg/kg body weight in 0.1 mol/L citrate buffer, pH 4.5) i.p. for 5 consecutive days. The blood glucose level was monitored on d 2, 5, and 10 from the tail vein using a one-touch blood glucose meter (Lifescan). Food-deprived mice with blood glucose levels > 16.8 mmol/L were defined as diabetic mice and used for this study.

    Organosulfur compound treatment. NAC (99.5%), SMC (99%), and SEC (99.5%) were purchased from Sigma Chemical. SAC (99%) and SPC (99%) were supplied by Wakunaga Pharmaceutical. Each agent (1 g/L) was added to the drinking water of mice.

    Experimental design. Diabetic mice were divided into 6 groups (n = 16) on the basis of their intake of water or each of the 5 cysteine-containing compounds. Nondiabetic mice treated with water were used for comparison. All mice had free access to food and water at all times. The water volume consumed daily was recorded, and body weight was measured weekly. Plasma glucose levels were measured every week. After 4 wk, the mice were killed with carbon dioxide. Liver and kidney from each mouse were collected and weighted. Blood was also collected, and plasma was separated from erythrocytes immediately. Each organ (0.2 g) was homogenized on ice in 2 mL PBS (pH 7.2) and the filtrate was collected. The protein concentrations of plasma, kidney filtrate, and liver filtrate were determined by the method of Lowry et al. (15) using bovine serine albumin as a standard. In all experiments, the sample was diluted to a final concentration of 1 g protein/L using PBS, pH 7.2.

    Plasma glucose, insulin and fibronectin. The plasma glucose level (mmol/L) was measured by a glucose HK kit (Sigma Chemical). The fibronectin (g/L) level was determined by a rabbit anti-rat fibronectin polyclonal antibody (Gibco-BRL) and quantified by solid phase immunoenzymatic ELISA (16). Plasma insulin (nmol/L) was measured by RIA using a rat insulin RIA kit (SRI-13K; Linco Research).

    Tissue glutathione (GSH). The GSH concentrations (nmol/mg protein) in kidney and liver were determined by a colorimetric GSH kit (Oxis Research).

    Tissue catalase and glutathione peroxidase (GPX). Catalase and GPX activities (U/mg protein) in kidney and liver were determined by the respective assay kits (Calbiochem, EMD Biosciences).

    Lipid oxidation. Glucose at 50 mmol/L was used to initiate lipid oxidation in the filtrate from liver or kidney. After 7 d of incubation at 37°C, lipid oxidation was determined by measuring the level of malondialdehyde (MDA, µmol/L) using HPLC (17).

    Plasma triglyceride (TG) and cholesterol. TG and total cholesterol levels (mmol/L) in plasma were determined by triglycerides/GB kit and cholesterol/HP kit (Boehringer Mannheim), respectively. Total lipids were extracted from liver, and TG concentration (µmol/g wet tissue) was quantified by a colorimetric assay (18). Total liver cholesterol (µmol/g wet tissue) was measured using o-phthalaldehyde (19).

    Blood coagulation and anticoagulation factors. Blood samples were anticoagulated using sodium citrate according to the protocols provided by the manufacturers of the kits used. Plasma fibrinogen level (g/L) was measured using a commercial kit (Iatroset Fbg, Iatron Laboratory) based on the principle of salting out. Plasminogen activator inhibitor-1 (PAI-1) activity (kU/L) was assayed by a commercial kit (Trinity Biotech). The activity (%) of AT-III and protein C in plasma was determined by chromogenic assays according to the manufacturer’s instruction using commercial AT-III and protein C kits (Sigma Chemical), and was shown as a ratio of those in normal human plasma.

    Plasma cytokines. Plasma levels of IL-6 and TNF- were measured by ELISA using Cytoscreen Immunoassay Kits (BioSource International Camarillo). Samples were assayed in duplicates according to manufacturer’s instructions. The sensitivity of the assay, i.e., the lower limit of detection, was 5 nmol/L for IL-6 and 10 nmol/L for TNF-.

    Statistical analysis. The effect of each treatment was analyzed in 16 mice (n = 16). Data were subjected to 1-way ANOVA using the SAS General Linear Model (GLM) procedure (20). Differences with P-values < 0.05 were considered to be significant.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Compared with water-treated nondiabetic mice and diabetic mice, treatment of diabetic mice with cysteine-containing compounds did not significantly affect liver (0.68–0.73 g) or kidney weight (0.27–0.30 g). The body weight of water-treated diabetic mice decreased and their plasma glucose level increased during the experiment (P < 0.05); however, the body weight and plasma glucose concentration of diabetic mice treated with cysteine-containing compounds did not change (Table 1). From wk 2, all diabetic mice treated with cysteine-containing compounds had higher body weights and lower plasma glucose concentrations than water-treated diabetic mice (P < 0.05, Table 1). All diabetic mice had greater daily food and water intake than water-treated nondiabetic mice (P < 0.05, Table 2). Administration of the cysteine-containing agents did not affect daily food intake, but tended to decrease (P = 0.08) daily water intake. All diabetic mice had higher levels of fibronectin and lower insulin levels than nondiabetic mice (P < 0.05, Table 2); administration of the cysteine-containing agents decreased plasma fibronectin levels (P < 0.05). Mice treated with agents other than SMC had higher insulin levels than water-treated diabetic mice (P < 0.05). Kidney and liver glutathione levels and catalase and GPX activities were lower in water-treated diabetic mice than in nondiabetic mice (P < 0.05, Table 3). However, the diabetic mice treated with the cysteine-containing compounds had higher glutathione concentrations and catalase and GPX activities than the water-treated diabetic mice (P < 0.05).

View this table: [in this window] [in a new window]   TABLE 6 Coagulation factors, fibrinogen level, PAI-1 activity, activity of coagulation factors, protein C and AT-III, and levels of cytokines, IL-6 and TNF-, in plasma of nondiabetic mice treated with water (Non-DM) and diabetic mice treated with water (DM) or 1 of 5 cysteine-containing agents (NAC, SAC, SEC, SMC, SPC)1

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

In agreement with others (21–23), both enhanced oxidative stress and reduced antioxidant enzyme activities were present in the diabetic mice used in this study. The oxidative stress may result from glucose toxicity, leading to the loss of antioxidant enzyme activity. Our previous animal study indicated that these cysteine-containing compounds could elevate GSH and enhance catalase and GPX activities in normal mice (9). In the present study, supplementing these agents also effectively restored GSH in diabetic mice, thus enhancing GPX and catalase activities and contributing to the antioxidant protection of these mice against the progression of oxidation. Fibronectin is one of the extracellular matrix (ECM) proteins. A high-glucose condition markedly elevates reactive oxygen species (ROS) and protein kinase C activity, causing increased expression of fibronectin and other extracellular proteins (16,24). Consequently, they produced excessive fibronectin and other ECM proteins that accumulate in the glomerular mesangium and tubulointerstium, eventually causing glomerulosclerosis and tubulointerstitial fibrosis (6). Our current work found that these cysteine-containing agents could suppress fibronectin biosynthesis in diabetic mice. The antifibronectin effect of these agents might be due in part to their antioxidant activities, which reduce the ROS available for stimulating fibronectin biosynthesis. The influence of these agents on the activity of protein kinase C also warrants further study.

Diabetes is a thrombosis-prone condition because hyperglycemia-induced ROS cause platelet dysfunction and insulin deficiency reduces the release of thrombolytic enzymes such as tissue plasminogen activator (25,26). Thus, we expected that the cysteine-containing agents would alleviate thrombotic stress through their antioxidant activities and insulin-elevating effect. Fibrinogen is a precursor in fibrin formation and a cofactor in platelet aggregation; PAI-1 is the primary physiologic inhibitor of fibrinolysis (27). Thus, the elevated plasma fibrinogen level and PAI-1 activity in diabetic mice contributed to the progression of thrombosis and cardiovascular diseases. The current study was in agreement with previous studies because both fibrinogen level and PAI-1 activity increased in diabetic mice. However, these cysteine-containing agents only tended to reduce the fibrinogen level and PAI-1 activity. On the other hand, activated AT-III and protein C are important anticoagulation factors because AT-III can inhibit the activity of a number of proteases in the coagulation cascade (13), and protein C can inactivate coagulation factors such as factors Va and VIIIa (28). The reduction in activity of both AT-III and protein C in these diabetic mice suggests that their anticoagulation system was impaired. We found that these cysteine-containing agents could effectively elevate AT-III and protein C activities; therefore, these agents should be able to improve the hemostatic balance by enhancing the activity of fibrinolytic factors such as AT-III and protein C.

Both IL-6 and TNF- are macrophage-associated proinflammatory cytokines. Several studies indicated that the excessive production of IL-6 and TNF- in type I diabetes contributed to diabetic deterioration because IL-6 increased platelet sensitivity to thrombin activation, TNF- impaired ß-cell function, and both IL-6 and TNF- increased intracellular ROS generation (10,29,30). The results of the current study agreed with previous studies because both IL-6 and TNF- levels were markedly elevated in these diabetic mice. Furthermore, supplementation with the cysteine-containing agents downregulates IL-6 and TNF-, thereby diminishing the inflammatory response, inflammation-oriented coagulation, and oxidative deterioration. The synergistic interaction of ROS and cytokines accelerates the destruction of pancreatic ß-cells (30,31). Although the mode of action of these agents on cytokines remains unclear, the reduced oxidation stress due to the antioxidant activity of these agents could contribute to the alleviation of inflammatory responses.

In conclusion, the intake of cysteine-containing agents resulted in greater insulin and glutathione levels, thereby improving glycemic control, enhancing antioxidant protection, and lowering TG concentrations in diabetic mice. These agents reduced oxidation stress by their antioxidant activities, which further alleviated other diabetic complications such as the overproduction of inflammatory cytokines and coagulation predomination. These data suggest that the compounds potentially have a number of protective roles in delaying diabetic deterioration.

	ACKNOWLEDGMENTS

 
The authors thank Wakunaga Pharmaceutical (Hiroshima, Japan) for kindly supplying s-allyl cysteine and s-propyl cysteine.

	FOOTNOTES

 
¹ Supported by grants from National Science Council, Taiwan, ROC (NSC 93–2320-B-040–033).

³ Abbreviations used: AT-III, antithrombin III; ECM, extracellular matrix; GPX, glutathione peroxidase; GSH, glutathione; IL, interleukin; MDA, malondialdehyde; NAC, n-acetyl cysteine; PAI-1, plasminogen activator inhibitor-1; ROS, reactive oxygen species; SAC, s-allyl cysteine; SEC, s-ethyl cysteine; SMC, s-methyl cysteine; SPC, s-propyl cysteine; STZ, streptozotocin; TG, triglyceride; TNF-, tumor necrosis factor-.

Manuscript received 17 August 2004. Initial review completed 8 September 2004. Revision accepted 23 September 2004.

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TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hsu, C.-c. Articles by Hsieh, C.-h. Search for Related Content PubMed PubMed Citation Articles by Hsu, C.-c. Articles by Hsieh, C.-h.