| Background:Metabolic syndrome(metabolic syndrome,MS) is a group of diseases associated with insulin resistance.In 1988 Reaven used "X syndrome" to describe a variety of adult metabolic diseases status.In 1989 Kaplan used "Quartet of death" to describe central obesity,IGT,hypertension and high triglycerides.Since then scholars have referred it as "Insulin Resistance Syndrome","Many Metabolic Syndrome" and so on.In 1998 WHO recommend using "Metabolic Syndrome" to rename these adult metabolic diseases status.In 2003 the international medical experts incorporated the MS into International Classification of Diseases-9(ICD-9) Clinical Amended Version(No. 277.7).This showed that MS had the formal diagnosis.In April 2004,Diabetes Association branch of Chinese Medical Association also recommended using MS to rename the assembly of these diseases.Epidemiological and clinical studies showed that each composition of MS was etiological factor of the occurrence of cardiovascular diseases and with the composition of MS increasing the risks of cardiovascular diseases occurrence increase too.These seriously affect people's health and quality.It will become a social heavy burden.Insulin resistance(IR) may be the main pathogenesis of MS,other factors such as central obesity involved in the formation and development of MS by influencing insulin sensitivity.MS has many causes.Main causes are genetic susceptibility and environmental factors.Unhealthy life style(high-calorie,high fat diet,less physical activity,etc.) is one of main environmental factors.With the socio-economy and lifestyle changing,MS have increased year by year.In 2000 the United States census data showed that prevalence rate of MS had been extended to 24%of adults(20y-70y) and the prevalence rate of MS was over 10%in China.MS has been seriously affecting the physical and mental health of people.It had become a worldwide public health problem.The prevention and treatment of MS should be comprehensively control cardiovascular diseases risk factors,which based on improving the IR Primary prevention is actively changing life style,but in reality because of social environment and personal factors,it often can not be sustained.Secondary prevention is individualized drug therapy based on changing life style.In Theory the drugs for treating MS have two kinds and they are thiazolidinediones and biguanides.Therefore, looking for new preventing and treating drugs for MS has great significance and practical necessity.Diabetes mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either a deficiency of insulin secretion or to a combination of insulin resistance and inadequate insulin secretion to compensate.In recent years, with the improvement of living standard and changing of diet structure,the incidence of global diabetes increases rapidly.Diabetes mellitus has already become the third largest chronic disease threatenning the human health seriously following tumour and cardiovascular disease.Now countries all over the world have to face the public health problems including high lethality rate,high disability rate and high cost caused by diabetes.The number of diabetics in the world was from 135 million in 1997 to 155 million in 2000.It was up to 177 million in 2001.Without strong intervention, the global diabetics can be up to 300 million in 2025 and the situation of prevention and cure of diabetes mellitus is heavy.With the increasing of aged population and urban population and changing of the life style,China has already become the second largest country of diabetes mellitus in the world.The number of diabetics in our country has already been up to 2.4 million in 2003 and it will be up to 4.3 million in 2030.In recent years,the teenagers who suffered from type 2 diabetes mellitus have increased remarkably and the ages of most diabetics are in the age of active section. With the progress of the course of diabetes,the incidence of different chronic complications increases progressively too.The complication is the main reason of death and mutilation in diabetics.Cardiovascular and cerebrovascular complications have already become the main reason of death.The prevention and cure of diabetes mellitus and its complications will be a serious public health problem in China.Looking for a better treatment of diabetes mellitus has been hot in medical science research.The treatments are varied,including oral medication,insulin and its analog treatment,stem cell and islet cell transplantation,gene therapy,etc.In recent years,studies on the diabetic chronic complications have found that the main reason of high glucose-mediated tissue damage is too much of hyperoxidies in mitochondria electron transport respiratory chain.The state of oxidative stress should be "the common soil" of diabetic chronic complications.Oxidative stress means high bioactive molecule such as reactive oxygen species(ROS) and reactive nitrogen species(RNS) which produce too much or eliminate too less and thus cause tissue damage.In the condition of hyperglycosemia,free radical can cause organ and tissue damage by several different pathways,including increased level of advanced glycation end products(AGEs),heightened pathways of polyhydric alcohol and hexosamine activity and activated protein kinase C(PKC).This state is not only ROS elevation but also an unbalance between oxidation and anti-oxidation.Anti-oxidant system is playing an important role while diabetes and its complication happen. Inhibiting oxidative stress state could be an effective measure of prevention and cure of chronic diabetes complications.So antioxidant is an important component of medication therapies.Alpha-lipoic acid(ALA) is an eight-carbon fatty acid that is synthesized in trace quantities in organisms ranging from bacteria to humans.It is the strongest active antioxidant in nature.It is known as "omnipotent anti-oxidant".ALA has been prescribed in Germany for more than 30 years for the treatment of diabetes-induced neuropathy.Several studies have shown that ALA can inhibit AGEs production, remove active oxygen free radical,reduce oxidative stress,improve insulin sensitivity in skeletal muscle cell,adipocyte and type 2 diabetic animal model,and promote glycometabolism.It is an important measure in prevention and treatment of diabetes. Investigators have reported that intravenous infusion of ALA substantially increases insulin-mediated glucose disposal(30～50%),whereas oral administration of ALA has only marginal effects(＜20%).Perhaps this limitation of orally administered ALA might be a function of its short-term duration in plasma(in comparison with intravenously administered ALA),resulting from extensive first-pass metabolism (＞50%) and short plasma half-life(＜0.5 hour).In order to provide a lasting raised level of ALA in plasma,commercially available oral dosage forms have to be administered at least six times a day.The development of a sustained release(SR) delivery system for ALA should therefore minimize the frequency of dosing,lengthen half-life,increase stability and improve the compliance.Now there are several kinds of formulations of ALA in our country such as injection,capsule,soft capsule,tablet, but we can't find any studies and reports about sustained release ALA tablet.So it is necessary to explore a novel formulation for ALA—sustained release ALA tablet, which will have enormous market prospects and good economic benefits.Objectives:Through the method of prescriptions optimized screen,our laboratory has prepared sustained-release tablet ofα-lipoic acid and made quality standards already.On this basis,the topic will explore the influence of sustained-release tablet ofα-lipoic acid on blood lipids,blood glucose and serum insulin concentration of New Zealand rabbit with high blood cholesterol,thereby,verify the Pharmacodynamics of sustained-release tablet ofα-lipoic acid on the treatment and prevention of MS and diabetes,and provide a theoretical basis for further clinical application of sustained-release tablets.Method:1.High-fat diet:1%cholesterol(cholesterol 20071206,Guangzhou Jia Wei Technology Co.,Ltd.),8%lard(self-made),10%egg yolk powder(egg yolk powder 20071118,Nantong Kant's Biological Products Co.,Ltd.),81%basic feed, made by medical experiments Center of Guangdong Province.2.Animal grouping:24 New Zealand white rabbits after adapted feeding were randomized into three groups,including normal feed group,high-fat diet group and high-fat diet+SRLA(300mg/tablet) group.3.Feeding methods:Normal diet group was given ordinary feed 150g/d fours weeks. High-fat diet group was given ordinary feed 75g/d and the high-fat feed 75g/d fours weeks.High-fat diet+SRLA group was given ordinary feed 75g/d,high-fat feed 75g/d and SRLA 300mg/d fours weeks.4.SRLA Delivery Methods:New Zealand white rabbits were fixed by rabbit half-bucket-fixation,exposed to the head,squeezed tightly in their cheeks and put the cheek-distender into mouth.And then cheek-distender was fixed.SRLA was fixed at the end of gastric canal,which was inserted suitable hard tube at another end.Then SRLA was pushed by the hard tube when the drug tube was inserted down the esophagus.Resistance disappearance reveled SRLA filling into stomach. Finally gastric canal was pulled out.5.Detection indexes:Whole blood was drew and centrifuged four weeks later,for detecting serum total cholesterol(TC),triglyceride(TG),high density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and blood glucose.In addition,serum insulin was determined using radioimmunoassay.And insulin sensitivity index(ISI) was calculated.6.Statistical Analysis:Any detections indexes of three groups were expressed by mean±standard deviation.The normality assumption of each distribution was investigated by using histograms.Non-normal variable was transformed into natural logarithm before comparison.If data with homogeneity of variance,we used one-way ANOVA and LSD for comparison.If not,we used F test using Welch method and Tambanes's T2 for comparison.The statistical analyses were performed with SPSS software version 13.0.Differences were considered statistically significant at P values＜0.05.Results:1.Indicators of animals in normal diet group after fed 4 weeks:glucose 5.612±0.893mmol/L,serum insulin 6.750±1.908μIU/ml,ISI 0.029±0.009,TC 1.175±0.353 mmol/L,TG 0.535±0.177 mmol/L,LDL-C 0.389±0.187 mmol/L, HDL-C 0.460±0.116 mmol/L.2.Indicators of animals in high-fat diet group after fed 4 weeks:glucose 5.700±0.823 mmol/L,serum insulin 11.00±1.309μIU/ml,ISI 0.017±0.003,TC 4.986±0.838 mmol/L,TG 0.742±0.106 mmol/L,LDL-C 2.935±1.004 mmol/L, HDL-C 0.914±0.136 mmol/L.3.Indicators of animals in high-fat and SRLA diet group after fed 4 weeks:glucose 5.400±0.995 mmol/L,serum insulin 6.500±1.604μIU/ml,ISI 0.032±0.015,TC 1.667±0.416 mmol/L,TG 0.587±0.172 mmol/L,LDL-C 0.620±0.253 mmol/L,HDL-C 1.067±0.220 mmol/L.4.The high fat diet group compared with normal diet group,serum insulin,TC,LDL-C(P＜0.01),TG and HDL-C(P＜0.05) were significantly higher,the ISI was significantly lower(P＜0.01),there was no statistical significance in the level of blood glucose(P＞0.05).5.There were no significant differences in glucose,serum insulin,ISI,TC,TG, LDL-C in high fat and SRLA diet group between normal diet group(P＞0.05) but HDL-C was significantly higher(P＜0.05).6.Compared with that in high fat died group,the blood sugar was lower in high fat and SRLA died group,but there is no statistical significance(P＞0.05);the serum insulin,TC,LDL-C(P＜0.01) and TG(P＜0.05) were significantly lower;ISI was significantly higher(P＜0.01);HDL-C was higher,but there was no statistical significance(P＞0.05).Conclusion:1.New Zealand rabbit with hyperlipidemia model is established successfully.This study confirms that high-fat feed can make New Zealand white rabbits being hyperlipidemia in experiment.2.The impact on New Zealand rabbit with high blood cholesterol by SRLA:SRLA reduce the level of blood glucose,improve the level of serum lipid and the sensitivity of plasma insulin concentration and insulin.3.SRLA may become a new agent for prevention and treatment for MS and diabetes. This study apply experimental basis and theoretical foundation for its clinical application... |
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