Research On The Effects Of Atorvastation On Glucose Tolerance,bone Metabolism In Rats And Its Mechanisms

Objective:Taking Wistar rats as research objects, we observed the effect of atorvastatin on glucose tolerance,bone metabolism in rats. We investigated its potential mechanism and analyzed its drug safety in order to guide clinical practice.Method:Eight-week-old Wistar rats were randomly divided into four groups:the control group (n=10, normal sodium 2ml/d),the low-dose group (n=10, atorvastatin 5mg/kg/d),the middle-dose group (n=10, atorvastatin 25mg/kg/d) and high-dose group (n=30, atorvastatin 50mg/kg/d). An oral glucose tolerance test (OGTT) was carried out 0,4,8,12 weeks after the administration and 24-hour urine was collected. The levels of blood glucose and serum insulin were measured before, and 15,30,60 and 120 min after glucose intake. The fasting level of serum tumor necrosis factor-a (TNF-α),calcium,phosphorus,alkaline phosphatase (ALP),triglyeride (TG) total cholesterol (TC),high-density lipoprotein (HDL),aspartate aminotransferase (AST),alanine aminotransferase (ALT),creatine kinase (CK) and the level of urinary calcium (Ca),phosphorus (P) and creatinine (Cr) were measured. The HOMA-β,modified beta cell function index (MBCI),the first-phase secretion (represented byΔI30/ΔG30),the second-phase secretion [represented by area under the curve of blood insulin (AUCI)],HOMA-IR,area under the curve of blood glucose (AUCg),simple glucose disposition index (DI),LDL and urinary Ca/Cr,P/Cr were calculated. All rats in the control group,low-dose group,middle-dose group and partial rats (n=10) in the high dose group were scacrificed 8 weeks after administration. The rest rats (n=20) in high-dose group then were randomly divided into two groups:atorvastatin-continued administration group (n=10, atorvastatin 50mg/kg/d); atorvastatin-elution group (n=10, normal sodium 2ml/d) Left femurs from all sacrificed rats were collected for the bone mineral density (BMD) measurement. The tissues from liver,pancreas and muscle stained by hematoxylin and eosin were observed under the microscope to find the pathological changes.Result:1. Before atorvastatin administration, no statistical difference existed in body weight,blood glucose and serum insulin level during OGTT,HOMA-β,MBCI,ΔI30/AG30,AUCI,HOMA-IR,AUCg,DI and fasting serum TNF-α,Ca,P,ALP,TG,TC,HDL,LDL,AST,ALT,CK and urinary Ca/Cr,P/Cr among groups (P>0.05)2. 4 weeks after administration, the blood glucose and serum insulin level at any time point during OGTT,HOMA-β,MBCI,ΔI30/ΔG30,AUCI,HOMA-IR,AUCg,DI and fasting serum TNF-α,Ca,P,ALP and urinary Ca/Cr,P/Cr showed no statistical difference among groups (P>0.05); Compared with the control group, the the fasting level of serum TG,TC and LDL was lower but AST,ALT,CK was higher in the atorvastatin-treated group (P<0.05)3. 8 weeks after administration, no statistical difference was found in the blood glucose at any time point during OGTT,DI,Ca,P and BMD among groups (P>0.05); in contrast with lower level of the serum insulin at any time point during OGTT,HOMA-β,MBCI,ΔI30/ΔG30,AUCI,HOMA-IRand AUCg, fasting serum TNF-a level was higher in high-dose group in comparison with the control group (P<0.05); Compared to the control group, the fasting level of serum ALP,HDL,AST,ALT and CK increased in atorvastatin-treated group accompanied by the decreased level of TG,TC,LDL and urinary Ca/Cr and P/Cr.4. 12 weeks after administration, no statistical difference existed in blood glucose level at any time point during OGTT,DI,TNF-α,Ca,P between two groups (P>0.05).the level of the serum insulin at any time point during OGTT,HOMA-β,MBCI,ΔI30/ΔG30,AUCI,HOMA-IR,AUCg,TG,TC,LDL and urinary Ca/Cr,P/Cr appeared higher and the fasting level of the serum ALP,HDL,AST,ALT,CK appeared lower in atorvastatin-elution group compared with atorvastatin-continued administration group (P<0.05); The tissues collected from liver,pancreas and muscle showed no obvious pathological change under the microscope. Conclusion:1. Atorvastatin showed no obvious effect on blood glucose level at any time point during OGTT,DI and BMD in rats.2. The high-dose atorvastatin inhibited the insulin secretion of pancreatic islet B cell at any time point during OGTT, decreased HOMA-β,MBCI,ΔI30/ΔG30,AUCI,HOMA-IR,AUCg in rats, and increased the fasting level of serum TNF-α.3. Atorvastatin increased the level of serum ALP, meanwhile, decreased the level of urinary Ca/Cr and P/Cr in rats, which probably facilitated the osteogenesis. Atorvastatin decreased the fasting level of serum TG,TC and LDL and increased the fasting level of serum HDL,AST,ALT and CK in rats and caused no obvious pathological change in the tissues collected from liver,pancreas and muscle.