肝脏胰岛素抵抗在自发性糖尿病OLETF大鼠发病中的作用

The role of Hepatic insulin resistance in the pathogenesis of spontaneously diabetic OLETF rats

目的通过观察包括肝脏脂肪沉积等在内的肝脏胰岛素抵抗(IR)指标在自发性2型糖尿病OLETF大鼠发病中的作用,探讨通过改善肝脏IR防治2型糖尿病的可行性。方法 OLETF大鼠20只作为糖尿病组,LETO鼠10只作为正常对照组。定期口服葡萄糖耐量试验。分别于8、32、40周龄分批宰杀大鼠。检测血清各项血脂指标。分离肝脏,HE染色观察肝脏结组织学变化;根据HE结果,对32周龄及40周龄的OLETF组大鼠肝脏以冰冻切片进行脂肪及糖原的特异性染色,以进一步明确空泡样变性病变。结果 OLETF组在23周龄首次出现糖耐量异常(IGT)4例,并有1例糖尿病发生;至40周龄时,OLETF组糖尿病发病率达92.9%。LETO组无IGT或糖尿病发生。自32周起,LETO组血清三酰甘油、胆固醇和游离脂肪酸均显著低于OLETF组(P<0.05)。随着糖尿病病程进展,OLETF组大鼠肝脏空泡化加重,进一步完善脂肪及糖原特异性染色,提示肝脏脂肪浸润及糖原堆积渐进性加重;LETO组大鼠肝脏结构随着周龄延长无明显变化。结论肝脏IR在自发性糖尿病大鼠发病中发挥重要作用,改善肝脏IR可作为防治2型糖尿病的可能机制之一。

Objective To study the effects of hepatic insulin resistance,including the lipid deposition in livers,on preventing diabetes in Otsuka Long-Evans Tokushima Fatty （OLETF） rats,and explore the probability of new mechanism in preventing diabetes in laboratory animals.Methods Twenty male spontaneous diabetic OLETF rats were treated as OLETF （group OLETF）.Ten male Long-Evans Tokushima Otsuka （LETO） rats were used as normal control group（group LETO）.Blood glucose is determined by oral glucose tolerance test.Rats were sacrificed at 8,32 and 40 weeks and liver tissue isolated.Serum triglyceride,serum cholesterol,and serum free fatty acid （FFA） were determined.The morphological changes of livers were measured by HE stain.Based on HE results,frozen liver sections of OLETF rats of 32-week-old and 40-week-old respectively were stained with fatty Sudan Ⅲ as well as PAS before and after amylase digestion,the purpose of which is to further clarify the nature of the lesions.Results OLETF rats developed diabetes since 23 weeks of age and the incidence rate of diabetes became higher with the time goes by until got to 92.9% at 40 weeks of age when the research came to the end.No rats have developed diabetes or IGT in group LETO.The serum triglyceride,serum cholesterol,serum FFA was significantly lower in group LETO than that of group OLETF since 32 weeks （P 〈 0.05）.With the week age increasing,liver vacuolation in group OLETF became serious and it was suggested that there appeared a gradual increase on liver fat infiltration and glycogen accumulation with a further improvement on the specific staining of fat and glycogen;while there was no significant damage in the liver structure of group LETO.Conclusion Hepatic insulin resistance may play an important part in the onset of T2DM,and the improvement of hepatic insulin resistance may work as a probable mechanism of preventing diabetes.