Effects Of Gliclazide In Combination With Ezetimibe On Blood Glucose, Blood Lipid And Myocardial Fibrosis In Type2Model Diabetic Rats

Objective: To investigate effects of gliclazide in combination with ezetimibe on bloodglucose, blood lipid and myocardial fibrosis in type2diabetic rats.Methods:46male Wistar rats were used, of which8rats were randomly chosen asnormal group (group C), and the remaining were made for type2diabetic model. Thehigh-fat diet combined with intraperitoneal injection of streptozotocin (STZ,35mg/kg)was used to induce the model. The rats that are suitable for the type2diabetic criteriawere randomly divided into model group (group M, n=7), gliclazide group (group G,n=8), ezetimibe group (group E, n=7), and gliclazide combined with ezetimibe group(group G+E, n=7). All drugs were intragastrically administered for6weeks. Changes inbody weight, fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glucosearea under the curve (AUC), glycosylated hemoglobin (HbAlc), fasting insulin (FINS),insulin sensitivity index (ISI), Homa insulin resistance index (Homa-IR), blood lipid ofrats were tested in all groups. Levels of myocardial TGF-β1and CTGF were measuredwith ELISA. Myocardial HYP contents were measured by alkaline hydrolysis.Myocardial pathological changes were observed through HE and Masson staining. CVF of myocardium was analysed by IPP. The mRNA expression of MMP-2and TIMP-1inmyocardium was detected by RT-PCR. The protein expression of MMP-2and TIMP-1in myocardium was detected by Western blotting.Results:(1) Compared with model group, all treatments slowed weights (P<0.01), except for theprotein expression of group E，others decreased contents of FBG, AUC, HbAlc,Homa-IR, FINS significantly (P<0.01or P<0.05), increased ISI (P<0.01), decreasedlevels of TG, TC and LDL-C (P<0.05or P<0.01). Compared with monotherapy,combination therapy increased levels of HDL-C (P<0.05), and decreased FBG, HbAlc,FINS, Homa-IR, ISI, TG, TC and LDL-C (P<0.05or P<0.01).(2) Compared with model group, all treatments improved myocardial fibrosis andpathology injury to varying degrees, and decreased LVWI and myocardial CVF (P<0.01). Compared with monotherapy, combination therapy showed better effects onthose parameters (P<0.05or P<0.01).(3) Compared with model group, all treatments decreased levels of myocardial HYP,TGF-β1, and CTGF (P<0.01). Compared with monotherapy, combination therapydecreased those parameters either (P<0.05or P<0.01).(4) Compared with model group, all treatments decreased mRNA and proteinexpression of MMP-2and TIMP-1and their ratios (P<0.01). Compared withmonotherapy, combination therapy exerted better effects on those parameters (P<0.05orP<0.01) except for TIMP-1expression of group G.Conclusion:1) Gliclazide and ezetimibe lower blood sugar and blood lipid, increase level of seruminsulin, and the combination has stronger effects on those parameters.2) The combination has synergistic effect on myocardial fibrosis, and its mechanismmay be related to the decreased myocardial contents of TGF-β1and CTGF, and to the down-regulation of TIMP-1mRNA and protein expression.