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目的探讨4-苯基丁酸(4-PBA)对2型糖尿病(T2DM)大鼠胰岛β细胞内质网应激(ERS)诱导的细胞凋亡的保护作用。方法高脂饮食喂养加小剂量链脲佐菌素(STZ)腹腔注射建立SD大鼠T2DM模型,造模成功后取其中10只给予4-PBA灌胃20d。放射免疫法检测各组大鼠游离脂肪酸(FFA)、血糖及胰岛素的变化。醛品红染色观察胰岛形态改变,RT-PCR检测内质网相关蛋白(Caspase-3、GRP78、CHOP)的mRNA表达变化。结果高脂对照组(n=10)和T2DM组(n=8)大鼠血清FFA比正常对照组(n=10)显著增加,4-PBA治疗后显著下降(n=8)。4-PBA治疗升高了T2DM造成的血清胰岛素水平降低,并降低了T2DM引起的高血糖。醛品红染色显示,T2DM大鼠胰岛萎缩,数量显著下降,胰岛细胞胞质内出现空泡,4-PBA治疗后胰岛数量相比T2DM组有所增多。与对照组相比,T2DM组Caspase-3和CHOP的mRNA表达升高,4-PBA治疗后显著降低。结论 4-PBA通过CHOP途径减轻ERS对胰岛β细胞的损伤,抑制胰岛细胞的过度凋亡,保护胰岛β细胞功能,从而延缓2型糖尿病的发展。
Objective To investigate the protective effects of 4-phenylbutyric acid (4-PBA) on pancreatic β-cell endoplasmic reticulum stress (ERS) -induced apoptosis in type 2 diabetes mellitus (T2DM) rats. Methods T2DM model of SD rats was established by intraperitoneal injection of high-fat diet plus small dose of streptozotocin (STZ). Ten rats were given 4-PBA for 20 days after successful modeling. Radioimmunoassay was used to detect the changes of free fatty acids (FFA), blood glucose and insulin in each group. The morphological changes of islets were observed by aldehyde magenta staining. The mRNA expression of endoplasmic reticulum-associated protein (Caspase-3, GRP78, CHOP) was detected by RT-PCR. Results Compared with normal control group (n = 10), serum FFA of high-fat control group (n = 10) and T2DM group (n = 8) increased significantly and decreased significantly after 4-PBA treatment (n = 8). 4-PBA treatment increased serum insulin levels caused by T2DM and decreased T2DM-induced hyperglycemia. Aldehyde magenta staining showed that islet atrophy and the number of cells in T2DM rats were significantly decreased, vacuoles were found in the cytoplasm of pancreatic islets, and the number of islets increased after 4-PBA treatment. Compared with the control group, mRNA expression of Caspase-3 and CHOP increased in T2DM group and decreased significantly after 4-PBA treatment. Conclusions 4-PBA can reduce the damage of pancreatic islet β-cells by the CHOP pathway, inhibit the excessive apoptosis of islet cells and protect the function of pancreatic β-cells, thus delaying the development of type 2 diabetes mellitus.