Study On Fatty Liver Disease Of Macroangiopathy In Rat Model Of Type 2 Diabetes Mellitus And The Effect Of Rosiglitazone Interence

Objective: Nonalcoholic fatty liver disease(NAFLD), which is often associated with obese individuals and patients with hyperinsulinemia, dyslipidemia, hepertension or type 2 diabetes, is a clinicopathological syndrome. NAFLD divide into simple steatosis, steatophetatitis and hepatic cirrhosis in pathology. The exact pathogenesis of NAFLD has not been fully illustrated, but insulin resistance (IR) and relative disorder of metabolism whose center is sterol regulatory element binding protein-1c (SREBP-1c) and peroxisome proliferators-activated receptor-γcoactivator-1(PGC-1α) family sever as an important function to take place to development in NAFLD. Rosiglitazone belongs to thiazolidinediones (TZDs), a kind of novel oral insulin sensitizer, which plays important roles in reducing IR and reducing serum insulin level and hyperglycemia. In recent years, many researches have found Rosiglitazone also has the functions like improving the dyslipidemia, relieving the accumulation of liver fat, and the level of the inflammably change in pathological. Metformin not only can reduces hyper glycemia by increasing glyconeogenesis and glycogenolysis, but also plays significant part in improving the dyslipidemia. Therefore, The rats model of type 2 diabetic for studying was set up by feeding female SD rats with a high-sucrose-high-fat diet and by injecting streptozotin(STZ) to them intrapenitoneally. On this condition, the abnormal metabolism and the morphological alteration of rat liver are to observe in insulin resistance and type 2 diabetic rats under light microscopy and electron microscope, investigate the relation between SREBP-1c or PGC-1αand insulin resistance and illustrate the pathophysiological mechanism of NAFLD the functional mechanism of rosiglitazone in improving NAFLD.Methods: SD rats were randomly assigned into two groups: normal control group(NC) and insulin resistance group(IR). NC group rats were fed with the normal diet, while IR group were fed with high-fat and high-sucrose diet. For 8 weeks, insulin resistance was evaluated by euglycemic insulin clamp. Then, IR rats were randomly devided into two groups: IR group and diabetic group(DM). Little dosage STZ (25 mg/kg), was injected to DM group in abdominalcavity, so pancreases was impaired partially, which bring out pancreases secrete obstacle. At 8 week, IR group was randomly devided into two groups: insulin resistance control group(IR) and insulin resistance group treated with rosiglitazone(TIR), and DM group was randomly devided two groups: diabetic contor group (3mg·kg-1d-1) (DM) and diabetic group treated with rosiglitazone (3mg·kg-1d-1) (TDM). Whole experiment last 18 weeks. Body weight, fasting blood glucose, and fasting serum insulin were measured after 18 weeks. When the experiment of 26th was finished, TG, TC, LDL, HDL, ALT and AST was measured. Liver tissue was observed by naked eyes and microscope. Liver tissue was stained with HE staining , observed by electronic microscope and detected expression of SREBP-1c and PGC-1αgene by reverse transcription polymerase chain reaction (RT-PCR).Results: 1 In IR group, fed with high sucrose and fat diet fasting blood glucose had no difference with NC group (P>0.05), and body weight was higher than NC group (P<0.01); FINs, TC, TG significent were higher than NC group (P<0.01, P <0.05, P <0.05); glucose infusion rate (GIR): IR group was obviously lower htan NC group (P<0.01). After DM group was injected a low dose of STZ intrapenitoneally, after 2 weeks fasting blood glucose level was markedly increased compared with NC group (P<0.01), and TC, TG significant were higher than NC group. Fins were lower than IR group but was higher than NC group (P<0.05).2 After 18 weeks, compared with NC , there was not significant difference in fasting blood glucose in IR group, but DM group was significantly high. FINS, TC, TG, LDL, ALT in IR group and DM group were higher than NC group (P<0.01); FINs, TC, TG, LDL, ALT in TIR group nad TDM group were significantly lower than control groups.3 The pathological morphological change of liver: There was significant difference between NC group and experimental group. Hepatic intralobules was on fat deposit, portal area and hepatic lobules had no inflammatory cell infusion in NC group. There were portal area inflammatory, intralobular inflammatory, seriously piecemeal necrosis and bridging necrosis in DM group. Liver tissue panlobular microvesicular and macrovesicular steatosis and accasional foci of inflammation were improved obviously by rosiglitazone in TIR and TDM group.4 Electron microscope shows: many mitochondrials and rough endoplasmic leticulum in liver cell of NC group were not abnormal. Mitochondrial of DM and IR group was slight swelling some disappeared and some was disorder. There were so many ellipse shape fat droplets in cytoplasm. Rough endoplasmic leticulum taken off pellets. There is slightly inflammatory dead band in cytoplasm. Mitochondria were slightly swelling, and mitochondrial crista were fusion and disappear in TIR and TDM group.5 The expression of SREBP-1c gene was significantly increased in IR and DM group(P<0.01). After treated by rosiglitazone, it obviously decreased(P<0.01), and the expression of PGC-1αgene was significantly higher than IR group and DM group(P<0.01).6 SREBP-1c was significantly positive correlation with TG, FINS, LDL and ALT. PGC-1αwas significantly negative correlation with TG and LDL.Conclusions: 1 Rats in IR group showed obesity, hyperlipid, hyperinsulinmia. We successfully assessed the insulin sensitivity by high insulin euglycemic clamp technique in rats fed with high sucrose and fat diet. IR was found, then type 2 diabetes was set up by injecting them streptozotin intrapenitoneally. This model accompanied with hyperglycemia, hyperinsulinmia and insulin resistance is similar to type 2 diabetes of human. It is a suitable model to study the NAFLD of type 2 diabetes mellitus.2 Pathological changes of liver cells were found by Electron microscope and light microscope.3 The expression of SREBP-1c gene was significantly increased in IR and DM group, but the expression of PGC-1αgene was decreased. The metabolic abnormalities of type 2 diabetes mellitus are the risk factors of the developing of NAFLD.4 Rosiglitazone can improve diabetic NAFLD by lightening the inflammatory reaction, which implicates rosiglitazone can obviously improve pathological changs of liver by effecting inflammation factor. So, rosiglitazone have unique effect in protect macrovascular, and can more early improve and prevent the occurrence diabetic NAFLD.