Effects Of Curcumin On LPS-induced Type 2 Diabetic Rats And Its Mechanism

Background:Type 2 diabetes mellitus is a metabolic disease characterized by insulin resistance and low-grade chronic inflammation.With the change of people's life style,there is an upward trend in the incidence of diabetes,which seriously harms people's health and life.Diabetes is now one of the three main diseases which cause serious damage to the human health in addition to cardiovascular and cerebrovascular diseases and cancer.In recent years a large number of studies have shown that type 2 diabetes is the pathological basis of low-grade chronic inflammation.However,the reason why patients with type 2 diabetes appear low-grade chronic inflammation in vivo is unknown.A new study suggests that the bacteria-derived lipopolysaccharide(LPS)may be the initial factor of long-term low-grade inflammatory state in patients with diabetes.Curcumin is an active polyphenol ingredient extracted from the rhizome of turmeric(zingiberaceae),which has a long medication history in China with wide effects including anti-inflammatory,anti-oxidation,anti-tumor,immune regulation,and anti-cardiovascular disease,etc.It is also widely used as pigment,food additives and spices for its small side effects.It is shown in a lot of domestic and foreign animal tests that curcumin can remarkably reduce blood glucose of diabetes model animals and relieve insulin resistance;the latest clinical test in Thailand also shows that curcumin can control pre-diabetes patients' risk of developing into diabetes patients.However,its accurate mechanism is not clear yet.Objective:1.To investigate whether subcutaneous injection of small dose of LPS can activate inflammatory factor,cause elevated blood glucose of rats;and set up a type 2 diabetic rat model.2.To explore the effects of curcumin on glucolipid metabolism,intestinal flora and ?-arrestin2,PI-3K,AKT and IRS-1 in liver and muscle tissues of LPS-induced type 2 diabetes rats,so as to preliminarily discuss its mechanism of reducing blood glucose.Methods:The male Wistar rats(n=30)were randomly divided control group(n=10)and model group(n=20).Model group with LPS(300?g·kg·-1day·-1)subcutane-ous injection of eight weeks,rats in control group received isometric stroke-physiological saline solution injection in the same way.The changes in appearance,weight and fasting blood glucose(FBG)of rats were observed every week.At the end of the 8th week,thelevels of tumor necrosis factor a(TNF-?),interleukin-1(IL-1),interleukin-6(IL-6),monocyte chemotactic protein-1(MCP-1),fasting insulin(FINS).Oral glucose tolerance test(OGTT)was also performed.The successful rat model was determined by the standards that FBG was?11.1 mmol/L.After successful modeling,become the model of 20 rats were randomly divided into 2 groups,namely curcumin treatment group(n=10)and T2DM model group(n=10).Gavage with curcumin 200mg/(kg·-1day·-1)was given to the curcumin treatment group.Gavage with saline solution of the same dosage was conducted to rats in the normal control group(n=10)and the T2DM model group(n=10).It was continued for 8 weeks in total.The rats were recorded for general conditions,FBG,FINS,total cholesterol(TC),triglyceride(TG),TNF-?,IL-1,IL-6,MCP-1,low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C)and HbAlc.16S rRNA gene amplification sub-sequencing was used to compare rat intestinal flora between groups.Then the rats were sacrificed and their liver and muscle specimens were taken for western blot analysis(?-arrestin2,PI-3K,AKT,and IRS-1).Results:1?FBG,TNF-?,IL-1,IL-6,MCP-1 and FINS of rats in LPS-induced type 2 diabetes group were significantly higher than normal control group(p<0.05).Curcumin could significantly reduce blood glucose of rats in LPS-induced type 2 diabetes group,TG,TC,LDL-C,GHbAlc,and FINS in LPS-induced type 2 diabetes rats(p<0.05),while increase HDL-C level(p<0.05).2.Compared with normal control group,LPS-Ab and SIgA in rectum contents of LPS-induced type 2 diabetic rats were increased(P<0.05);Melainabactera and enterobater in rectum contents of LPS-induced type 2 diabetic rats were significantly increased(P<0.05);while lactobacillus,prevotellaceae and bifidobacterium were decreased significantly(p<0.05).In LPS-induced type 2 diabetes rats,rats treated by curcumin gavage had lower Melainabactera and Enterobater in intestinal tract(p<0.05),and increased contents of Lactobacillus,Prevotellaceae and Bifidobacterium at the same time(p<0.05).3.For liver and muscular tissues of rats in LPS-induced type 2 diabetes group,the expression of ?-arrestin2,PI-3K and IRS-1 and the increase of AktSer473 phosphorylation after insulin stimulation were lower in comparison with the normal control group(p<0.05);curcumin could increase the expression of ?-arrestin2,PI-3K and IRS-1 and the AktSer473 phosphorylation after insulin stimulation in liver and muscular tissues of rats in LPS-induced type 2 diabetes group(p<0.05).Conclusion:1.LPS is the promoter in insulin-resistance type 2 diabetes.A type 2 diabetic rat model can be set up through subcutaneous LPS injection.2.Curcumin has the effects to reduce blood glucose and blood lipid in LPS-induced type 2 diabetic rats.The mechanisms may be related to reducing inflammation,adjusting intestinal microecology,and activating PI-3K/AKT signaling pathways.