摘要：Objective To investigate the relationship between olanzapine induced metabolic disturbance related measures and TCF7L2 gene expression. Methods Thirty adult C57BL/6J mice, in accordance with the random number table, were divided into 3 groups that were olanzapine group (4 mg·kg-1·d-1), olanzapine (4 mg·kg-1·d-1) plus metformin (150 mg·kg-1·d-1) group and control group (saline), with 10 mice in each group. Olanzapine and olanzapine plus metformin and saline were intragastrically administered for 8 weeks. Body weight, fasting glucose and insulin, and oral glucose tolerance test (OGTT) was assessed at baseline and 8th week, homeostasis model assessment-insulin resistance (HOMA-IR), and area under of the curve of glucose(AUCg) were calculated. At the end of 8 weeks, after mice were killed by decapitation, four blood lipid items, including triglyceride, total cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) were measured, and the protein expression levels of TCF7L2 in liver, adipose and skeletal muscle tissue and mRNA and protein expression levels of TCF7L2 in pancreas were detected. Results (1) At the end of 8th week, analysis of variance and multiple comparison revealed that the levels of weight, fasting insulin, HOMA-IR, AUCg and LDL between the 3 groups were different (F=3.717-29.724,all P<0.05). Body weight, fasting insulin, HOMA-IR and LDL of mice in the olanzapine group were significantly higher compared to the placebo group (t=-2.639,-7.164,-6.238,-2.234, all P<0.05), no significant difference was found in AUCg between olanzapine group and placebo group (P>0.05);Body weight, fasting insulin, HOMA-IR, AUCg, LDL in the metformin plus olanzapine group were significantly lower than the olanzapine group (t=2.948, 6.051, 5.520, 3.874, 2.471, all P<0.05);No significant difference were found between olanzapine plus metformin group and placebo group, except AUCg, which was significant lower in the olanzapine plus metformin group compared to the placebo group (t=-2.587,P=0.015).There was no significantly difference of fasting glucose between the 3 groups (F=0.37, P=0.69). (2) At the end of 8th week, one-way ANOVA analysis showed that there was a significant difference of TCF7L2 protein expression among the 3 groups (F=20.842, 13.345, 20.149,all P<0.01). The protein expression levels of TCF7L2 in liver, skeletal muscle and adipose tissues in the olanzapine group(0.50 ± 0.08,0.46 ± 0.09,0.45 ± 0.14)were significantly higher than the placebo group (0.32±0.07,0.30±0.10,0.26±0.09;t=-5.154,-3.946,-3.874,all P<0.01),which were markedly lower in the olanzapine plus metformin group(0.30 ± 0.07,0.26 ± 0.08,0.14 ± 0.09)compared with the olanzapine group (t=5.945, 0.915, 2.418, all P<0.01). No significantly difference were founded between olanzapine plus metformin group and placebo group,except in the adipose tissue, which was significant lower compared to the placebo group (t=6.292,P=0.023). No significant differences were found between the 3 groups of TCF7L2 mRNA and protein expression level in pancreas(F=0.346, 0.102, both P>0.05). Changes of weight gain, fasting insulin, HOMA-IR and AUCg before and after drug administration were positive correlated with protein expression of TCF7L2 in liver (r=0.457,0.592,0.636, 0.460), skeletal muscle tissue (r=0.459, 0.499, 0.503, 0.399)and adipose tissues(r=0.377, 0.639, 0.584, 0.364; all P<0.05 or P<0.01). The change of HOMA-IR plays an import role in the TCF7L2 protein expression of liver, skeletal muscle (R2=0.405, 0.253;respectively), and change of fasting insulin exerts most impact on the TCF7L2 expression in adipose tissue (R2=0.408). Conclusion Olanzapine induced weight gain, insulin resistance and glucose intolerance may be correlated with the change of TCF7L2 protein expression in liver, skeletal muscle and adipose tissues.%目的：探讨奥氮平引起的代谢异常相关指标与TCF7L2基因表达的关系。方法将30只成年雄性小鼠采用随机数字表法分为奥氮平组、奥氮平+二甲双胍组、安慰剂组，每组10只。奥氮平组予以奥氮平4 mg·kg-1·d-1灌胃，奥氮平+二甲双胍组给予奥氮平4 mg·kg-1·d-1和二甲双胍缓释片150 mg·kg-1·d-1干预，安慰剂组采用生理盐水灌胃8周。于基线及第8周末测体重、空腹血糖、空腹胰岛素以及口服葡萄糖耐量试验（oral glucose tolerance test，OGTT）。计算稳态模型的胰岛素抵抗指数（homeostasis model assessment-insulin resistance, HOMA-IR）及葡萄糖曲线下面积（area under of the curve of glucose，AUCg）。第8周末处死小鼠，测血脂4项[甘油三酯、总胆固醇、高密度脂蛋白(high density lipoprotein, HDL)、低密度脂蛋白(low density lipoprotein，LDL)]，取小鼠肝脏、骨骼肌、脂肪及胰腺组织测TCF7L2的表达水平。结果（1）体重和糖脂代谢指标：第8周末，奥氮平组、奥氮平+二甲双胍组和安慰剂组小鼠体重、空腹胰岛素、HOMA-IR、AUCg和LDL组间差异有统计学意义（F=3.717~29.724,均P<0.05）；奥氮平组小鼠体重、空腹胰岛素、HOMA-IR和LDL均显著高于安慰剂组（t=-2.639、-7.164、-6.238、-2.234，均P<0.05），奥氮平组AUCg与安慰剂组相比差异无统计学意义；奥氮平+二甲双胍组小鼠体重、空腹胰岛素、HOMA-IR、AUCg及LDL均显著低于奥氮平组（t=2.948、6.051、5.520、3.874、2.471，均P<0.05）；第8周末，奥氮平+二甲双胍组除AUCg（t=-2.587，P=0.015）显著低于安慰剂组外，其余上述指标2组间差异均无统计学意义。3组小鼠空腹血糖差异均无统计学意义(F=0.370，P=0.694)。（2）TCF7L2蛋白表达：服药8周后，3组小鼠肝脏、骨骼肌及脂肪组织的TCF7L2蛋白表达水平差异均有统计学意义（F=20.842、13.345、20.149，均P<0.01），其中奥氮平组（0.50±0.08、0.46±0.09、0.45±0.14）小鼠肝脏、骨骼肌和脂肪组织的TCF7L2蛋白表达显著高于安慰剂组（0.32±0.07、0.30±0.10、0.26±0.09；t=-5.154、-3.946、-3.874，均P<0.01），而奥氮平+二甲双胍组（0.30±0.07、0.26±0.08、0.14±0.09）小鼠肝脏、骨骼肌和脂肪组织的TCF7L2蛋白表达水平显著低于奥氮平组（t=5.945、0.915、2.418，均P<0.01），奥氮平+二甲双胍组脂肪组织TCF7L2蛋白表达显著低于安慰剂组（t=6.292，P=0.023），2组间肝脏和骨骼肌组织TCF7L2蛋白表达差异无统计学意义；3组间胰腺组织TCF7L2的mRNA和蛋白表达水平差异均无统计学意义（F=0.346、0.102，均P>0.05）。（3）服药前后体重、空腹胰岛素、HOMA-IR及AUCg的改变与肝脏组织(r=0.457，0.592，0.636，0.460)，骨骼肌组织（r=0.459,0.499,0.503,0.399）和脂肪组织(r=0.377,0.639,0.584,0.364)的TCF7L2蛋白表达水平均呈正相关（均P<0.01或P<0.05）。服药前后HOMA-IR的变化对肝脏和骨骼肌组织中TCF7L2蛋白表达影响最大（决定系数分别为R2=0.405、0.253），空腹胰岛素改变对脂肪组织中TCF7L2蛋白表达影响最大(R2=0.408)。结论奥氮平引起的体重增加、胰岛素抵抗及糖耐量异常可能与肝脏、骨骼肌和脂肪组织中TCF7L2蛋白表达水平改变有关。
