| 1. Objectives and significanceWith development of society and improvement of people's life standard,life-style changes, and aging of population, diabetes prevalence increased steadily in the world, which has become another serious public health hazard Chronic non-communicable diseases secondary only to the heart and cerebrovascular diseases, tumors.Diabetes is a lifelong disease and cannot be cured, with the prolonged course prone to multiple organ complications, harmful to health of human body and mind of family and society; it also imposes heavy economic burden.It is known that 90% diabetic patients are of type 2 diabetes mellitus, whose pathogenesis is still not completely clear.In academic community T2DM is commonly recognized as a disease which is induced by heredity and multi-environment factors. That's to say, on the basis of genetic predisposition, the role of environmental factors causing obesity can lead to insulin resistance (IR) accompanied by P-cell function obstacle. Then the secretion of insulin is deficient and insulin response is low, leading to comprehensive metabolic disorder of carbohydrate, lipid, protein and salt and water. Its main clinical manifestations are fasting blood-glucose and postprandial blood sugar abnormalities, polydipsia, polyphagia, urorrhagia and body weight loss, accompanied hyperlipidemia, insulin resistance, obesity, and finally leading to chronic diseases in heart, brain, kidney, eyes, nerves and vessels.The indeterminateness of path mechanisms results in multitargets and blindness in the treatment of T2DM. Western medicine is efficacious in plasma glucose control and clinical symptom improvement. But takes for a long time may initiate to adverse effects such as the liver and kidney function damage, skin rash, anemia,diarrhea,as well as to medicine insensitive. Recently, research has found that Chinese medicine is far inferior to western medicine in decreasing blood sugar and acting time, however, blood glucose lowering effect of Chinese Medicine were mild and long-lasting with little side-effect and it is achieved through multiple paths, multiple factors,multiple targets. It has a certain role in promoting insulin secretion, but also reduces the IR and improves insulin utilization, showing a promising prospect and distinct advantages in regulating glucose and lipid metabolism and prevention of complications. Therapy by aditional Chinese medicine is becoming the research hotspot.T2DM belongs to the concept of Xiao Ke in TCM.<HuangDi Neijing> and <Suwen·Qijuelun>have given elaboration on its pathogeny, symptom, sort, complication and taboo. In traditional Chinese medicine, etiology and pathogenesis of diabetes have been understood well, and rich therapeutic experience has been accumulated through long-term clinical practice. Long-term, extensive and in-depth discussion has been carried out on its etiology, pathogenesis and treatment. It has complete theoretical system and unique advantages in clinical treatment.Mei lian xiao ke Capsule(MLXK-capsule) involves in Ebony, berberine, aconite, ginger, Asarum, ginseng,etc which has excellent blood glucose lowering effect in clinical application, We adopted High-fat diet combined with low dose streptozotocin (STZ)-induced experimental typeⅡdiabetic rats (T2DM) and alloxan-induced diabetic mice model to evaluate pharmacodynamics of Mei lian xiao ke Capsule, and its related blood glucose loweing mechanisms.2. Methods2.1 The effects of MLXK-capsule on glycometabolism on typeⅡdiabetes rats.Animal model of experimentalⅡdiabetes in Male Sprague-Dawley rats were induced by low-dose streptozotocin (STZ) (30 mg·kg-1) intraperitoneal injection after 5 weeks of high fat and sugar diet,it was tested for the oral glucose tolerance test (OGTT) after 72h. the inclusion criteria:FBG level greater than 7.0 and 11.1 mmol·L-1 at 0 h and 2 h.Rats with diabetes were randomly divided into five groups model control, positive control, the high, middle, and low dose of MLXK-capsule, together with normal control group. Corresponding drugs were administered orally by gavage once a day for 4 weeks. All animals were weighed every week; food and water consumption of all rats were daily recorded; At the end of experiment, the levels of fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were measured. After the last administration, all rats were fasted for food (water was allowed) for 12 h, then blood samples were collected through the abdominal aorta EDTA anticoagulated to measure the glycosylated hemoglobin (HbAlc)2.2 The effects of MLXK-capsule on lipid metabolism and insulin resistance improved on typeⅡdiabetes rats.Animal model of experimentalⅡdiabetes in Male Sprague-Dawley rats were induced by low-dose streptozotocin (STZ) (30 mg·kg-1) intraperitoneal injection after 5 weeks of high fat and sugar diet. Rats with diabetes were randomly divided into five groups model control, positive control, the high, middle, and low dose of MLXK-capsule, together with normal control group.Corresponding drugs were administered orally by gavage once a day for 4 weeks. At the end of the experiment, the total cholesterol(TC), triglycerides(TG), high-density lipoprotein(HDL-C) and low-density lipoprotein(LDL-C) and free fatty acids(FFA) in serum were tested by abdominal aortic blood, the concentration of serum insulin(FINS) was assayed by radioactive immune method. Insulin sensitive index(ISI) and insulin resistance index(HMOA-IR) were calculated.2.3 The effect of MLXK-Capsule on pancreas pathology on typeⅡdiabetes rats.At the end of the experiment,the pancreas were fixed in neutral formaldehyde after collection of the blood samples through the abdominal aorta. HE stained paraffin sections and histological observation were performed. 2.4 The effect of MLXK-Capsule on diabetic mice induced by alloxan81 Kunming male mice which weigh 18-22g were received food and water ad libitum after a week of acclimation,11 of the mice weigh between 26 and 28g after a fast of 12h were selected as the normal group randomly,70 diabetic models of mice were established by intravenous injection of alloxan(55mg/kg) through the tail, and the mice of normal control group only receied an injection of same amount of saline. The fasting blood glucose of mice were measured by shearing tail to pick the blood after 72 hours.The FBG between 10 and 25 mmol·L-1 of diabetic mice were randomized into 5 groups:model group, metformin group, and MeilianXiaoke capsule groups of low, moderate and high doses. The mice in the normal control and model groups received intragastric administration of saline (10g/0.15ml), and those in the other 4 treatment groups were treated with correspondent medicine (10g/0.15ml) for 4 weeks. The amount of water drinking and food intake were measured every day, the body weight were monitored every week, FBG was measured after 4 weeks of administration.3 Results3.1 The effects of MLXK-capsule on glycometabolism on type II diabetes rats.In this experiment, compared with normal group, model control group have reduced weight(P<0.05), food and water consumption increased,the levels of FBG, HbAlc and area under the curve (AUC) of OGTT markedly increased (P<0.01) Compared with model group, for Metformin group, the levels of FBG, area under the curve (AUC) of OGTT and HbAlc obvious reduced (P<0.05,0.01),for MLXK-capsule high groups the levels of FBG, area under the curve (AUC) of OGTT ans HbAlc could markedly decresed(P<0.05,0.01),for MLXK-capsule middle groups the levels of FBG and HbAlc were significantly decreased (P<0.05), meanwhile, area under the curve (AUC) of OGTT could be decreased but statistically insignificant.3.2 The effects of MLXK-capsule on lipid metabolism and insulin resistance improved on type II diabetes rats.In this experiment,compared with the normal group model control group,the level of TC,TQ LDL-C,FINS and FFA were markedly increased (P<0.05,0.01).The level of HDL-C/TC decreased. Compared with model group, Metformin group show insignificant differences on lipid metabolism and insulin resistance,for MLXK-capsule groups the levels of TC,TG,HDL-C,LDL-C and HDL-C/CHO can be reduced,but it was all not statistically significant. MLXK-capsule high and middle groups the levels of FFA,FINS and HOMA-IR declined (P<0.05,0.01), ISI can improve but statistically insignificant.3.3 Effects of MLXK-capsule on pancreas and liver pathology on type II diabetes rats.In this experiment,Analysis on rank data of pancreas pathology (χ2=35.561, P=0.000) showed that there is statistical significance in each groups, revealing that pancreas can be protected by all the drugs, while further studies on mean rank pointed out that Metformin has the best protective effect, followed by middle dosage group,high dosage group and low dosage group in sequential order.3.4 Effects of MLXK-capsule on experimental diabete model induced by alloxanIn this study, model control group the FBG of was significantly increased (P<0.01), body weight was significantly decreased (P<0.01) compared with normal group.The increased intake of food and water demonstrated that the model is successful and steady. After 4 weeks administration, each group was compared with previous treatment, the fasting blood-glucose level decrease significantly in positive group (P<0.01) and MLXK-capsule high group (P<0.05),while no remarkable difference was obtained in middle and low dosage groups. In every MLXK-capsule group, experimental animals' activities and intake of food and water was improved.4 Conclusion4.1 Remarkable improvement of general clinical symptoms on experimental diabetic animalsOur results confirmed that MLXK-capsule has quite effective on improving glycometabolism on type II diabetes mellitus (T2DM) rats and experimental diabete model induced by alloxan, the clinical symptoms such as polydipsia, polyphagia, and weight loss were significantly improved on type II diabetes mellitus (T2DM) rats and experimental diabete model induced by alloxan.4.2 Improvement of glycometabolism on experimental diabetic animalsIt can regulate glycometabolism, significantly reduce the level of FBG,HbAlc and the area under the curve of oOGTT on type II diabetes mellitus (T2DM) rats. The level of FBG was significantly lower in diabetic rats induced with alloxan,4.3 Improvement of insulin resistance, increase of insulin sensitivityMLXK-capsule showed obvious activity improve the insulin resistance,it can be improve sensibility of liver and Peripheral Tissue to insulin utilization,increase and improvement of insulin sensitivity to target tissue.4.4 Regulate lipid metabolismMLXK-capsule has certain effect on lipids metabolism, compared with normal group MLXK-capsule high,middle and low group were significantly reduce the level of FFA, the level of Tc and TG were decreased but no statistically significant.4.5 Protective and reparative efficacy on islet cellsOur results confirmed that MLXK-capsule can protect pancreas through lowering blood glucose and lipid levels, which in turn reduce glucose toxicity and lipotoxicity to the body, protecting the pancreas... |
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