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目的：观察血糖波动对2 型糖尿病大鼠心肌组织形态的影响并探讨其可能机制。方法：选取45 只雄性Sprague-Dawley(SD) 大鼠，按随机数字法分成正常对照组(CON组)和糖尿病组(DM 组)。DM组给予4 周高糖高脂饲料喂养后，予小剂量链脲佐菌素 35 mg/Kg腹腔注射建立2 型糖尿病大鼠模型。将成模大鼠按随机数字法分成糖尿病对照组(CDM 组)和波动血糖组(FDM 组)。 FDM组大鼠每天定时皮下注射短效胰岛素并错时给予葡萄糖，建立糖尿病血糖波动模型，CON组、CDM组予等量生理盐水皮下注射。每周测血糖值2 天，4次/天，动态观测各组大鼠外形、进食量、饮水量等变化。造模成功12 周后取腹主动脉血测定糖化血红蛋白(HbAlc)，取大鼠心脏组织行Masson 染色观察心肌纤维化水平，免疫印记法分别检测心肌组织AKT、p-AKT蛋白的表达，免疫组织化学法分析各组大鼠心肌细胞中Caspase-3 蛋白的表达。结果：①与CON组相比，FDM 组、CDM组大鼠HbA1c、血糖变异系数(CV)水平升高，差异具有统计学意义(P<0.05)；与CDM 组相比，FDM 组HbA1c 水平差异无统计学意义(P>0.05)，CV 值进一步升高，差异具有统计学意义(P<0.05)。②与CON组相比，CDM 组、FDM组大鼠心肌组织形心肌纤维化水平升高，差异具有统计学意义(P<0.05)；与CDM组相比，FDM组心肌组织心肌纤维化水平进一步升高，差异具有统计学意义(P<0.05)。③与CON组相比，FDM组、CDM组大鼠心肌p-AKT蛋白表达水平均减少，差异具有统计学意义(P<0.05)；与CDM组相比，FDM 组p-AKT蛋白表达水平均进一步减少，差异具有统计学意义(P<0.05)。而三组大鼠心肌组织AKT 蛋白表达水平差异无统计学意义(P>0.05)。④ 与CON 组相比，FDM组、CDM组大鼠心肌Caspase-3 蛋白表达水平均升高，差异具有统计学意义(P<0.05)；与CDM组相比，FDM 组Caspase-3 蛋白表达水平进一步升高，差异具有统计学意义(P<0.05)。结论：血糖波动可加重2 型糖尿病大鼠的心肌纤维化，其机制可能与抑制AKT活化有关。

英文摘要:

Objective:To investigate the effects of blood glucose fluctuation on myocardium in rats and explore the related mechanisms.Methods:Forty-five male Sprague Dawley rats were firstly randomly divided into the diabetes mellitus group (DM group) and the control group (CON group). The CON group was fed a standard diet, and the DMgroup was fed with a high sugar and fat diet for 4 weeks. Then, the DM group received single intraperitoneal (i.p.) injections of streptozotocin at 35 mg/kg. Three days later, blood samples from the tail vein were collected and measured. The diabetic rats exhibited elevated blood glucose levels (≥ 16.7 mmol/L) lasting 3 days, confirming diabetes. Then the diabetic rats were randomly divided into continuous high blood glucose group (CDMgroup) and fluctuating blood glucose group (FDM group). FDM group was induced by daily subcutaneous insulin and glucose feeding at different time points. 12 weeks later, aorta blood was collected to measure glycosylated hemoglobin A1c (HbA1C). Myocardial fibrosis was measured by Masson's trichrome staining. The levels of Akt and p-Akt expressions were determined by western blot. The levels of Caspase-3 were determined by immunohistochemistry.Results:① The HbA1c level was significantly increased in the CDM and FDM groups compared with the CON group (both P<0.05), and no significant difference was found between CDMand FDMgroups (P>0.05). The CV value of blood glucose in FDM and CDM groups were increased compared with the CON group (both P<0.05), which was significantly higher in the FDM group compared with the CDM group (P<0.05). ② Masson's trichrome staining showed that the percentage area of fibrosis in the CDM group were higher than that of the CON group (P<0.05), but the ratio in FDM group was significantly higher than that of the CDM group (P<0.05). ③ The expression levels of AKT showed no significant difference between three groups (P>0.05). However, the expression levels of p-AKT were significantly decreased in the CDM and FDM groups compared with the CON group (P<0.05), and levels in the FDMgroup was significantly lower than of the CDM group (P<0.05). ④ The expression levels of Caspase-3 were significantly increased in the CDM and FDM groups compared with the CON group (P<0.05), which was significantly higher in the FDMgroup than that in the CDMgroup (P<0.05).Conclusion:Blood glucose fluctuation could aggravate the fibrosis in heart, and which was possibly related to the inhibition of AKT activity.

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