type 2 diabetes mellitus is ordinarily associated with dyslipidemia , which presents a synergistic risk factor for cardiovascular disease . statins , the 3-hydroxy-3-methylglutaryl - coenzyme a ( hmg - coa ) reductase inhibitors , are inhibitors of cholesterol synthesis . statin therapy is effective for reduction of cardiovascular events   and is commonly recognized as being safe and well tolerated . furthermore , statin therapy has a close relationship with different doses of statin in cardiovascular patients . intensive - dose statin therapy provides a significant benefit for preventing cardiovascular events compared with moderate - dose statin therapy . more recently , some studies   have reported that statin therapy may affect glucose homoeostasis in type 2 diabetes patients . some studies provided that statins therapy have been linked to increased risk of developing diabetes mellitus [ 7 , 8 ] , some studies reported that statin therapy had no effect on insulin sensitivity [ 911 ] , and others indicated a beneficial effect on glucose metabolism [ 12 , 13 ] . the mechanisms by which statins may affect glycemic control have been under discussion , but not clear . the target of the present study is to investigate the effect of simvastatin on fpg in stz - induced diabetic rats . this research may provide an alternative to the problem of statin therapy . toward this goal , we observed the different effect between simvastatin intervention rats and simvastatin treatment rats , especially on fpg levels of various periods . glucose , total cholesterol ( tc ) , high - density lipoprotein cholesterol ( hdl - c ) , low - density lipoprotein cholesterol ( ldl - c ) , and triglyceride ( tg ) test kits were detected using automatic biochemistry analyzer . the standard diet was obtained from animal experimental central , shandong university ( jinan city , shandong province ) ; and the high - fat diet purchased from beijing ke ' ao xieli company ( beijing city ) . the high - fat diet was purchased from standard diet ( sd ) consists of 6% fat , 64% carbohydrate and 23% protein , and high - fat diet ( hfd ) consists of 25% fat , 48% carbohydrate , and 20% protein . forty male wistar rats , weighing 180200  g , were obtained from animal experimental central , shandong university ( jinan city , shandong province , china ) . guides for the care and use of laboratory animals were approved by the local ethics committee at the medical college of shandong university . rats were housed in wire - floored cages under a 12  h light - dark cycle for at least 7 days prior to treatment and were fed with standard laboratory chow and tap water ad libitum . rats were fasted overnight prior to the study and housed in mesh - bottomed cages to minimize coprophagia . except for the last hour , food was withdrawn from 12 to 14 hours before the experiment , and diabetes was induced by a single intraperitoneal injection of a prepared solution of stz ( 35  mg / kg ) in 0.1  mol / l citrate buffer ( ph 4.5 ) . successful induction of diabetes was confirmed by measuring the fpg concentration in rats 24  h after injection of stz . the fasting blood glucose level above 11.1  mmol / l was considered diabetic and included in the present study . wistar rats were fed with standard diet for one week , and then the rats were randomly divided into four groups , with ten rats in each group as follows : group a : normal control rats , group b : diabetic model rats , group c : simvastatin intervention rats , and group d : simvastatin treatment rats . the normal control rats ( n = 10 ) were fed with standard diet , receiving vehicle solution ( citrate buffer , 1  ml / kg / day ) ; group b , group c , and group d rats ( n = 24 ) were injected with stz ( 35  mg / kg bodyweight , i.p . ) after high - fat diet for 4 weeks . successful induction of diabetes was confirmed by measuring the fpg concentration in rats 24  h after injection of stz . the fasting blood glucose level above 11.1 the simvastatin intervention rats received simvastatin ( 10  mg / kg / day ) from the whole experiment and continued for 12 weeks , and simvastatin treatment rats were treated with simvastatin after successful induction of diabetes and continued for 8 weeks . the following parameters were assayed in each of the study groups during variance period : daily fluid and food consumption , weekly body weight , and blood glucose concentration . food consumption was determined by subtracting leftovers from the diet provided to rats at 2-day intervals . the levels of fasting blood glucose , total cholesterol ( tc ) , high - density lipoprotein cholesterol ( hdl - c ) , low - density lipoprotein cholesterol ( ldl - c ) , and triglyceride ( tg ) were assayed and compared with each group . student 's t - test was applied to compare probabilities of data between two groups . table 1 displays significant differences in fluid and food intakes and bodyweight change between normal control and diabetic model rats . compared with normal control rats , there is a significantly increased fluid and food intakes and decreased bodyweight in diabetic rats . intervention with simvastatin rats tended to increase the bodyweight to that seen in diabetic rats , and the effect was less pronounced in the group of rats treated with simvastatin . table 2 shows that , in diabetic rats , there was a significant increase ( p < 0.05 ) in tc and tg levels , and significant decrease in hdl - c , and the tendency of tc , tg , and hdl - c levels was even worse at the end of the experiment . compared to untreated diabetic rats , the levels of tc and tg significantly decreased ( p < 0.05 ) and the levels of hdl - c increased ( p < 0.05 ) in simvastatin intervention rats . compared to untreated diabetic rats the tc , tg , and hdl - c levels had no significant change in simvastatin treatment rats at 4 weeks , while there was a significant increase ( p < 0.05 ) in tc and tg levels , and significant decrease in hdl - c at 12 weeks .   as summarized in table 2 and figure 1 , at the end of 4 weeks and 12 weeks , the fasting blood glucose levels were significantly higher in diabetic animals when compared with control rat values , which is indicating that there was a successful induction of diabetic model rats . compared with diabetic rats , at the end of 4 weeks , treatment of diabetic rats with simvastatin slightly increased fpg ( p > 0.05 ) simvastatin intervention rats were significantly increased fpg ( p < 0.05 ) and easily induced diabetic rats . at the end of 12 weeks , simvastatin intervention rats were still higher at the level of fpg , while the fpg levels were slightly decreased compared with the end of 4 weeks . at the end of 12 weeks , the simvastatin treatment rats had a significantly higher fpg levels compared with the diabetic rats ( p < 0.05 ) . statins can enhance the expression of low - density lipoprotein ( ldl ) receptors in the liver and consequently lower the levels of blood ldl cholesterol through inhibiting cholesterol synthesis in the liver . stains , including both water - soluble and lipid - soluble statins , have been shown to protect against the injury in cardiovascular and renal diseases [ 16 , 17 ] . besides their well - established role in lowering cholesterol levels , recent research has demonstrated that statins might have relevant effect on glucose metabolism in animal models and in humans . however , several studies on the effect of statin on glucose metabolism are controversial . some [ 1820 ] have shown that simvastatin had a benefit effect on insulin resistance ; some [ 21 , 22 ] have reported no benefit on insulin action , and others [ 2325 ] have identified a deterioration in glucose homoeostasis . water - soluble statins , such as rosuvastatain , are hepatocyte specific and are not probably taken up by pancreatic cells and adipocytes . lipid - soluble statins , such as simvastatin , enter extrahepatic cells easily and may suppress isoprenoid protein synthesis , consequently attenuating the action of insulin levels . the present study is to investigate the effect of simvastatin on glucose metabolism from the prediabetic rats models . toward this goal , we observed the different effect between simvastatin intervention rats and simvastatin treatment rats , especially on fpg levels of various periods . this study shows that the rats with simvastatin intervention at a dose of 10  mg / kg have increased the levels of fpg , and consequently the diabetic model rats were easily induced . similarly , we observed that fpg was slightly increased in diabetic rats after eight weeks with simvastatin treatment . in addition to the classic function of lowering the cholesterol levels , our study demonstrated that statin could also impact the glucose homeostasis on stz - induced diabetic rats . despite the levels of tc and tg decreased and total cholesterol / hdl ratio increased compared with control group , both intervention and treatment with simvastatin rats did not improve the glucose homeostasis , especially on fpg . these results suggest that the rats with simvastatin intervention were more easily induced , the diabetic model rats and the diabetic rats , those treated with simvastatin could also increase the levels of fpg . therefore simvastatin could not decrease the fpg levels and improve the insulin sensitivity . what is more , simvastatin therapy is associated with a slightly increased risk of diabetes . in this paper , we demonstrated the different effect on fpg between intervention and treatment with simvastatin rats . importantly , the simvastatin intervention rats were more easily induced to be diabetic rats and had a higher fpg compared with simvastatin treatment group . besides , the results indicated that simvastatin intervention rats were more inclined to have an adverse effect on glucose homeostasis , especially on fpg , compared with simvastatin treatment rats . the biological significance of elevated fpg identified in simvastatin intervention group remains unknown , but some studies   would suggest that the abnormality in fpg may translate into the clinical syndrome of diabetes with a rise in glycosylated hemoglobin ( hba1c ) . in addition , it has provided that there is a graded relationship between fpg and the extent of coronary artery disease severity . current estimates indicate that simvastatin intervention rats , with prediabetic status , may easily develop diabetic rats induced by stz . it is noteworthy that , in our current study , the mean fpg value in simvastatin treatment rats increased which is in the impaired fasting glucose range . the precise mechanisms by which statins may exert any influence on glucose metabolism are unclear . statins have the potential to alter glycemic control by decreasing various metabolites such as isoprenoid , farnesyl pyrophosphate , geranylgeranyl pyrophosphate , and ubiquinone ( coq10 ) , all of which are dependent on mevalonic acid production . reduction in coq10 may result in delayed atp production in pancreatic beta cells and thereby impair insulin release . simvastatin has been shown to inhibit glucose - induced increase in intracellular calcium in pancreatic beta cells leading to the inhibition of insulin secretion in a dose - dependent manner . thus , this study shows that simvastatin intervention that effectively increased fpg may promote the development of type 2 diabetes mellitus . the limitations of the research showed that our diabetic rats were followed up for 8 weeks in this experimental study this is an obviously short period considering the natural history of diabetes mellitus . we do not know whether this association would continue , worse , or get better through a long period of followup . the biological importance of elevated fpg in simvastatin intervention and treatment rats identified in this study remains unknown , but data from the jupiter trial   would suggest that the elevated fpg may translate into the clinical syndrome of diabetes with a rise in hba1c . besides , it has been demonstrated that there is a graded relationship between fpg and the levels of coronary artery disease severity . the present estimates indicate that most individuals with prediabetic status may eventually develop clinical diabetes mellitus . our observational study demonstrated that statin therapy is associated with a rise of fpg levels over a mean period of 12 weeks in simvastatin intervention rats . considering the prevalence of statin usage in current clinical practice , this significant observation merits further investigation . clinicians should realize this potential adverse association of statin use on fpg , and careful monitoring is advised .
objective . to investigate 
 the effect of simvastatin on glucose homeostasis in streptozotocin induced type 2 diabetic rats . methods . 
 forty male wistar rats were randomly divided into four groups . 
 normal control rats were fed with standard diet , others were fed with high - fat diet . 
 diabetic rats were induced by a single intraperitoneal injection of stz . 
 the simvastatin intervention rats were fed with simvastatin during the experiment process , and the simvastatin treatment rats were fed with simvastatin after diabetes rats were induced . 
 we measured body weight , fasting plasma glucose , cholesterol , high - density lipoprotein cholesterol , and triglyceride after an overnight fast . 
 results . 
 the fpg was higher in diabetic rats when compared to normal control ones ; the simvastatin intervention rats had a higher fpg compared to the diabetic rats and were more easily be induced to diabetes at the end of 4 weeks , fpg level of simvastatin treatment rats was increased compared with diabetic model rats after 12 weeks . 
 conclusion . 
 these data indicate that simvastatin intervention rats may cause hyperglycemia by impairing the function of islet  cells and have an adverse effect on glucose homeostasis , especially on fpg level .