吡格列酮对NOD鼠糖尿病的预防作用及其机制探讨

Preventive effects of pioglitazone and its mechanisms in the non-obese diabetic mouse

目的探讨吡格列酮(PIO)对NOD鼠糖尿病发病率和胰岛炎的影响及其作用机制。方法4周龄NOD雌鼠随机分为2组,分别摄食0.02%PIO混合饲料(PIO,n=26)和普通饲料(对照组,n=25),观察30周龄时的糖尿病累积发病率。各组另取12周龄未患病NOD鼠(n=15)胰腺H-E染色观察胰岛炎;ELISA法测血清、脾细胞培养上清干扰素γ(IFN-γ)和白细胞介素4(IL-4)水平;RT-PCR检测脾脏IL-4、IFN-γ mRNA的表达水平。结果30周龄时,PIO组发病率较对照组明显降低(P<0.05)。12周龄时,PIO组胰岛炎平均积分低于对照组(P<0.05);血清、脾上清IL-4水平,脾脏IL-4 mRNA表达水平显著性高于对照组(P<0.05);PIO血清、脾上清IL-4/IFN-γ比值水平高于对照组(P<0.05)。结论PIO通过上调IL-4水平,促使免疫平衡向Th2方向偏移,从而使NOD鼠胰岛炎减轻,而在一定程度上预防和延缓NOD鼠糖尿病的发生。

Objective To explore the effects and mechanisms of pioglitazone on insulitis and diabetes in NOD mice. Methods Female NOD mice at 4 weeks of age were randomly derided into two groups, including 0.02% pioglitazone-mixed diet （pioglitazone group, n = 26）, and pioglitazone-free diet （control group, n= 25）. Pioglitazone was given in diet from 4 to 30 weeks of age. The accumulative diabetes incidence was followed-up to 30 weeks of age in each group of NOD mice. Pancreata were removed from NOD mice at 12 weeks of age in each group （n= 15） to score insulitis severity by routine H-E staining. Their spleens were for cell culture and total RNA extraction. IL-4 and IFN-γ levels in sera and supernatants of splenocytes were measured by ELISA. Spleen IL-4 and IFN-γ mRNA levels were detected by RT-PCR. Results At 30 weeks of age, the incidence of diabetes was 80.0% （20/ 25） in the control group and 53.8% （14/26） in the pioglitazone group. There was a significant reduction of diabetes incidence in NOD mice treated with pioglitazone （P〈0.05）. The insulitis score of pioglitazone group was lower than that of controls （P〈0.05）. IL-4 levels in sera and supernatants of splenocytes and spleen IL-4 mRNA levels were higher in pioglitazone group than in control group （P〈 0.05）. The ratios of IL-4/IFN-γ in sera and supernatants of splenocytes were higher in pioglitazone group than in control group （P〈0.05）. Conehmions Pioglitazone upregulates IL-4, induces a Th2- like response, and subsequently to some extent, lessens insulitis and reduces diabetes incidence in female NOD mice.