Elucidation of mechanism for diabetogenesis in Wistar Fatty rats

第一年，我们检测了Wistar fat大鼠的高血糖和高胰岛素血症是否与葡萄糖激酶（GK）、6磷酸果糖-2-激酶（PFK2）和PEPCK基因的表达紊乱有关。Wistar fat大鼠与Wistar Lean大鼠的GK、PFK2和PEPCK活性及mRNA水平均无显著差异。接下来，我们在Wistar fat大鼠中研究了AD-4833对肝脏中GK、PFK2和PEPCK基因表达以及血液中中间体水平的影响，据报道AD-4833可以增强胰岛素反应。AD-4833处理导致血糖和胰岛素水平降低，但GK、PFK2和PEPCK基因的表达没有改变。相比之下，中间水平受到该药的影响。甘油水平降低，乳酸和丙酮酸水平升高。综上所述，在Wistar脂肪大鼠中引起高血糖的机制似乎不是kgk、PFK2或PEPCK的基因缺陷。AD-4833的作用机制似乎也不是对这些酶的影响。第二年，我们研究了AD-4833对Wistar fat大鼠脂肪细胞中胰岛素刺激的葡萄糖转运活性的影响。这个实验还在进行中。在动物模型研究的同时，还研究了引起NIDDM的人类遗传因素。研究了胰岛启动子区与NIDDM的关系。结果发现序列变异导致启动子活性缺陷。目前正在研究这种启动子变异的生理意义。GK启动子缺陷作为Wistar脂肪大鼠高血糖的原因的可能性也计划进行研究。

In the first year, whether hyperglycemia and hyperinsulinemia in Wistar Fatty rats are associated with disturbed expression of glucokinase(GK), 6phosphofructo-2-kinae(PFK2) and PEPCK genes was examined. Either activities or mRNA levels of GK, PFK2 and PEPCK were not significantly different between Wistar Fatty rats and their littermates, Witar Lean rats. Next, the effects of AD-4833, which, reportedly, enhances the insulin response, on the expression of GK, PFK2 and PEPCK genes in liver, and intermediates levels in blood were studied in Wistar Fatty rats. AD-4833 treatment resulted in the decrease of blood sugar and insulin levels, but expression of GK, PFK2 and PEPCK genes was not changed. In contrast, intermediate levels were affected by this drug. Glycerol levels were decreased, and lactate and pyruvate levels were increased. Taken these, the mechanisms to cause hyperglycemia in Wistar Fatty rats do not seem to be gene defects ofk GK, PFK2 or PEPCK.Mechanisms of AD-4833 do not seem to be the effects on these enzymes, either. In the next year, the effect of AD-4833 on the insulin-stimulated glucose transport activity in adipocytes isolated from Wistar Fatty rats was studied. This experiment is still in progress. Human genetic factors to cause NIDDM were also sutdied in pararell with the study in animal model. Islet promotor region was studied regarding the association with NIDDM.Consequently, sequence variants were found, which resulted in defects of promotor activities. The physiological significance of this promotor variants are now being studied. The possibilitiy of GK promotor defect as the cause of hyperglycemia in Wistar Fatty rats are also planned to be studied.