Effects of rosiglitazone on antagonizing insulin resistance and adipose liver damnification in hyperlipemic rats / 中国组织工程研究

ABSTRACT

BACKGROUND: Some experiments indicated that applying rosiglitazone on diabetic animals lacking of insulin could not increase insulin and lower blood glucose obviously, which showed that rosiglitazone did not stimulate the excretion of rosiglitazone. The action of rosiglitazone in improving insulin resistance and the effects on the functions of liver and kidneys need more investigations.OBJECTIVE: To investigate whether rosiglitazone can improve the insulin resistance of rats with hyperlipemia, and analyze the possible mechanism.SETTINGS Guangzhou Hospital of Traditional Chinese Medicine; Guangzhou Institute of Traditional Chinese Medicine and Materia MedicaDESIGN: A stratified randomized controlled animal trial.MATERIALS Sixty-four Sprague-Dawley (SD) rats (Batch No. 2002A024), SPF grade, half male and half female,weighing 150 to 180 g, aged 6 to 8 weeks were purchased from Guangdong Medical Experimental Animal Center.Normal feed (total quantity of heat 6.9 kJ/g) was enriched with 23% protein, 53% carbohydrate and 5% fat. High fat emulsion (total quantity of heat 15.5 kJ/g) was enriched with 200 g/L lard, 200 g/L cholesterol, 10 g/L bile salt ox,200 g/L propylene glycol, 200 g/L tween-80. High fat and sugar feed (total quantity of heat 21.0 kJ/g) was enriched with 15% protein, 51% carbohydrate and 30% fat after adding 100 g/L glucose, 200 g/L lard and 100 g/L yolk powder then mixing and baking. Rosiglitazone was from GlaxoSmithKline Co Ltd. (Tianjin) (5 mg/tab, Batch No.02110012). Gliclazide was from Servier International and Tianjin Hua Jin Pharmaceutical Factory (100 mg/tab, Batch No.00232).METHODS: The experiment was carried out in Guangzhou University of Traditional Chinese Medicine from April to July in 2003. ① Sixty-four Sprague-Dawley rats, 16 of which were randomly sampled as the normal control group and had been fed with normal feed for 6 weeks. The others were modeled after medical literatures, each one was administered with high fat emulsion (10 mL/kg) by gavage once a day for 14 days. Rats whose FBG≥6.1 mmol/L or 2hBG≥7.8 mmol/L were selected, randomized into 3 groups according to body mass and blood glucose, i.e., negative control (model)group, rosiglitazone group and gliclazide group, there were 16 rats in each group. Except the normal control group, rats in the rosiglitazone group and gliclazide group were gavaged with rosiglitazone for 5 mg/kg and gliclazide for 100 mg/kg respectively, and those in the model group were gavaged with distilled water. All of the rats were fed with high-fat feed once a day for 28 days. From the 21st day, high fat emulsion was added once a day for 7 days. After fasting for 18 hours from the last administration, all the rats were recorded for FBG and administered dextrose 2.78 mol/10 mL .kg or dextrose and drug mixture 10 mL/kg by body mass. Two hours'later, 2hBG was recorded. ② Blood samples were collected from orbital plexus and serum was prepared for detecting the biochemical indexes and immunological indexes in serum, i.e., fasting serum glucose(FSG), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST),blood urea nitrogen (BUN), creatinine (Cr), tumor necrosis factor alpha (TNF-α) and fasting insulin (FINS). The insulin sensitivity index (ISI) was calculated ISI=ln [1/ (FINS content×FBG content)]. After the rats were killed, their liver suspension was prepared for measuring the levels of TG, superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA).MAIN OUTCOME MEASURES: ① FBG and 2hBG; ② FSG, blood lipids, TNF-α, FINS and ISI in serum; ③ TG, GSH, SOD and MDA in liver cells; ④ ALT, AST, BUN and Cr in serum. RESULTS: ① Results of FBG and 2hBG The FBG and 2hBG in the rosiglitazone group [(3.2±0.3), (6.3±1.2) mmol/L]were lower than those in the modelcontrol group [(3.8±0.5), (8.1±2.1) mmol/L, P ＜ 0.01]. The FBG in the gliclazide group [(3.3±0.7) mmol/L] was lower than that in the model control group. ② Results of FSG, blood lipids, TNF-α, FINS and ISI The FSG, TNF-α and FINS in the rosiglitazone group were (4.2±1.2) mmol/L, (246±45) μg/L and (133±45) pmol/L respectively, which were lower than those in the model control group [(6.6±1.5) mmol/L, (294±65) μg/L, (264±76) pmol/L,P ＜ 0.05-0.01], whereas ISI was higher than that in the model control group (-6.33±0.46, -7.46±0.95, P ＜ 0.01). The FSG and TNF-α in the gliclazide group [(4.1±1.1) mmol/L, (251±62) μg/L] were lower than those in the model control group (P ＜ 0.05-0.01). ③ Results of TG content, GSH deposit, SOD activity and MDA content in liver cells The TG and MDA contents in liver cells in the rosiglitazone group [(1.00±0.38), (40±17) mmol/g] were lower than those in the model control group [(2.40±0.60), (171±63) mmol/g, P＜ 0.01], the GSH deposit and SOD activity [(51±14) mg/g, (583.45±50.01 ) nkat/g] were higher than those in the model control group [(2.40±0.60) mg/g, (450.09±66. 68) nkat/g, P ＜ 0.05-0.01].The TG and MDA contents in the gliclazide group [(1.20±0.38), (100±30) mmol/g] were lower than those in the model control group, whereas the GSH deposit [(46±15) mg/g] was higher than that in the model control group. ④ Results of ALT, AST, BUN and Cr in serum The serum contents of BUN and Cr in the rosiglitazone group [(14.3±3.8) mmol/L,(33±9) μmol/L] were lower than those in the model control group [(19.2±5.6) mmol/L, (45±13) μmol/L, P ＜ 0.05].CONCLUSION: Both rosiglitazone and gliclazide can improve the insulin resistance induced by high fat feed.Rosiglitazone is superior to gliclazide in decreasing the high insulin level, decreaseing serum levels of BUN and Cr,improving reduced GSH deposit and enhancing SOD activity.