Effect Of Docetaxel On Glucose Tolerance And Islet Function In Wistar Rats And Diabetes Rats

Objective:Along with the aging of the population increasing,people lifestyle changing,the prevalence of diabetes mellitus has been increasing.At the same time,the morbility of cancer is rising sharply and the cure rate is low.Cancer is becoming a serious threat to human health.Due to the limitations of surgery and radiation therapy,chemotherapy has gradually become a kind of common clinical means for tumor treatment.The side effects of chemotherapy drugs,such as bone marrow suppression,gastrointestinal tract reaction,liver and kidney function damage,allergic reaction have been gradually revealed.It is reported that chemothery drugs has an influence on glucose metabolism,including islet function,even lead to diabetes mellitus.Taxane(paclitaxel and docetaxel)has been widely used in the treatment of ovarian cancer,breast cancer,lung cancer and other cancers.While reducing the mortality of patients with cancer,taxane affects the glycometabolism.The mechanism has not been fully elucidated.We studied the effect of docetaxel(TXT)on glucose tolerance and islet function in Wistar rats and diabetes rats.Methods:Female Wistar rats,six-weeks of age,were divided randomly into 2 groups:Normal control group(NC)and high-fat group(HF).After eight-weeks,when the rats in HF group appeared insulin resistance,STZ was injected intraperitoneally at 30mg/kg.After 72 hours,diabetes mellitus was confirmed by testing random glucose level when it was over 16.7mmol/L.The diabetes group(DM)and the normal group(NC)were divided randomly into 3groups,respectively,administered with normal saline(NC and DM group),dexamethasone(NCD and DMD group),TXT(NCT and DMT group)1or 4 cycles.Water intake,food intake,calorie intake and body weight were recorded.The oral glucose tolerance test(OGTT)was performed before or after STZ injection.Blood was taken to test blood glucose,insulin,C-pepide,triglyceride(TG),total cholesterol(TC),alanine transaminase(ALT),aspertate aminotransferase(AST).At the end of the experiment,all the rats were killed,pancreas,liver were taken for histopathological examiniation.Retrograde perfusion method was used to separated of the pancreas in normal Wistar rats.Pancreatic islets were isolated by collagenase digestion,purified by Ficoll-400.Islets were cultured in RPMI1640 containing different concentrations of TXT medium(containing 10% fetal bovine serum)for different periods.The insulin secrection was tested after these islets were stimulated by 5.6mmol/L or 16.7mmol/L glucose for 1h.ELISA method was used for determination of insulin concentration.Centrifugalization was used to get out DNA.SPSS21.0 software was used for all statistical analysis,all data are expressed as(?).Results:1 Comparison between NC and HF group1.1 Comparison of water intake,food intake,calorie intake There was no significant difference in food intake,water intake between NC and HF group after eight-weeks feeding,the calorie intake in HF group was higher than NC group(P<0.01).1.2 Comparison of body weight There was no significant difference in body weight between NC and HF group at the beginning of the experiment.After 8 weeks,the weight of rats in HF group was higher than that in NC group(P<0.01).1.3 Comparison of the results of OGTT,C-P andHOMA-IR,ISI,?I/?G The fasting glucose level and postload 30 min,60min,120 min glucose levels of HF group were higher than that of NC group,the peak of glucose delayed in the HF group(P<0.01).The postload 60 min,120min insulin and C-peptide levels of HF group were higher than that of NC group.HOMA-IR of HF group was higher than that of NC group(P<0.01),ISI and ?I/?G of HF group were lower than that of NC group(P<0.01).2 Comparison between NC and DM groupThe food intake,water intake and calorie intake in DM group were higher than that in NC group(P<0.01).The food intake,water intake and calorie intake in NCD1 group,NCT1 group,DMD group and DMT group were lower than that before in the same group(P<0.01).And the food intake,water intake and calorie intake in NCD4 group and NCT4 group were lower than that in NCD1 group and NCT1 group(P<0.01).2.1 Comparison of water intake,food intake,calorie intake2.2 Comparison of body weight The body weight of NCT4 group was lower than that of NC4 group and NCD4 group(P<0.01).The body weight of rats in DMD group and DMT group were lower than that in DM group(P<0.05).2.3 Comparison of the results of OGTT,C-P and HOMA-IR,ISI,?I/?G The fasting glucose level and postload 30 min,60min,120 min glucose levels of DM group were higher than that of NC group,the peak of glucose delayed in the DM group(P<0.01).The fasting insulin and fasting C-peptide levels and postload 30 min,60min,120 min insulin and C-peptide levels of DM group were lower than that of NC group(P<0.01).HOMA-IR of DM group was higher than that of NC group(P<0.01).ISI and ?I/?G of DM group were lower than that of NC group(P<0.01).The postload 60 min glucose level of NCT1 group were higher than that of NC1 group and NCD1 group(P<0.01).There was no significant difference in insulin,C-peptide,HOMA-IR,ISI and ?I/?G among NC1,NCD1 and NCT1 group.The fasting glucose level and postload 30 min,60min,120 min glucose levels of NCT4 group were higher than that of NC4 group and NCT1group(P<0.01),the peak of glucose delayed in the NCT4 group.The fasting insulin and fasting C-peptide levels and postload 30 min,60min,120 min insulin and C-peptide levels of NCT4 group were lower than that of NC4 group and NCD4 group(P<0.01).The postload 30 min insulin level of NCT4 group were lower than that of NCT1 group(P<0.01).The fasting C-peptide levels and postload 30 min,60min,120 min insulin and C-peptide levels of NCT4 group were lower than that of NCT1 group(P<0.01).HOMA-IR of NCT4 group was higher than that of NC4 group,NCD4 group and NCT1group(P<0.01).ISI and ?I/?G of NCT4 group were lower than that of NC group,NCD4 group and NCT1group(P<0.05).The fasting glucose level and postload 30 min,60min,120 min glucose levels of DMT group were higher than that of DM group,DMD group and NCT1group(P<0.01).The fasting C-peptide level and postload 30 min,60min,120 min C-peptide levels of DMT group were lower than that of DM group and NCT1 group(P<0.01).The postload 30 min C-peptide level of DMT group were lower than that of DMD group(P<0.01).2.4 Comparison of TG,TC,ALT and AST The level of TG and TC in NCT1 group were higher than that in NC1group(P<0.05).The level of TG,TC,ALT and AST in NCT4 group were higher than that in NC4,NCD4 and NCT1 group(P<0.01).The level of TG,TC,ALT and AST in DMT group were higher than that in DMD and DM group(P<0.05).3 Comparison of the pancreas and liver weight The weight of pancreas and liver in DMT group were lower than that in DM and DMD group.There was no significant difference in pancreas and liver weights among NC1,NCD1 and NCT1 group(P<0.01).The weight of pancreas and liver in NCT4 group were lower than that in NC4 and NCD4group(P<0.01).4 The result of pancreatic and liver tissue with HE-staining In NC group:the numbers of pancreatic islet cells were more,and pancreatic islet cells rank tight,cell nucleus stain royal large and round,and endochylema was abundant.In NCT4 group:the numbers of pancreatic islet cells were less than that in NC group.In DM group:pancreatic islet structure was not clear,the numbers of pancreatic islet decreased,and some islet becomed vacuole.In DMT group:the numbers of pancreatic islet cells decreased,and pancreatic islet cells rank disorder.In NC group:liver cell rank tight,cell nucleus were in the middle,and lobular rules.In NCT4 group:liver cell becomed vacuoles,and hepatic sinus congestion.In DM group:more liver cells becomed vacuoles,and lipid infiltrated.In DMT group:there were more lipid infiltrated,and hepatic sinus congestion abviously.5 Comparison of insulin secretion from pancreatic islets Stimulated by 5.6mmol/L glucose,the insulin secretion from islets cultured with TXT(0.01ug/ml)for 1h,3h,6h,12 h,24h were lower than those of other groups.The insulin secretion cultured for 6h,12 h,24h were lower than those for 1h.Stimulated by 16.7mmol/L glucose,the insulin secretion from islets cultured TXT(0.005ug/ml)for 12 h,24h were lower than those of group TXT(0ug/ml),and the insulin secretion in group TXT(0.01ug/ml)cultured for1 h,3h,6h,12 h,24h were lower than those of other groups.The SI of group TXT(0.01ug/ml)cultured for 1h,3h,6h,12 h,24h were lower than those of other groups.At the same concentration of TXT,the SI of group TXT(0.005ug/ml)cultured for 12 h,24h were lower than those at 1h,and the SI of group TXT(0.01ug/ml)cultured for 3h,6h,12 h,24h were lower than those at 1h.Conclusions:1 Application of 4 cycles of docetaxel reduced the secretion of insulin in normal rats,increased insulin resistance and blood glucose.2 Application of 1 cycle docetaxel damaged the diabetes mellitus rats' islets function.3 Docetaxel increased the level of alanine aminotransferase and aspartate aminotransferas in rats,damaged the liver,increased blood glucose.4 Docetaxel increased the level of total cholesterol and triglycerides in rats,affected insulin secretion and sensitivity,and further increased blood glucose.5 In vitro,TXT in higher concentration decreaseds insulin secretion from islets.