GLUCOREGULATORY PEPTIDE HORMONES

当胰岛β细胞丢失时，胰岛素抵抗患者就会患上糖尿病。 正常的对葡萄糖的反应能力和对前 存在胰岛素抵抗。找出贝塔细胞缺陷 结果在NIDDM中，我们计划在大鼠身上表征分子， 正常β细胞代偿的代谢和生理成分 1)高血糖钳夹反应，2)地塞米松反应 治疗，以及3)肥胖，并将这些与不同类型的β细胞进行比较 不能补偿这些相同因素的大鼠模型(如ZDF-DRT大鼠， GK大鼠、Zucker FA/FA大鼠和亚糖尿病链脲佐菌素大鼠 治疗)。功能测量包括1)胰岛素对5的反应， 10、20 mM葡萄糖、甘油醛和琥珀酸单甲酯定位 一块，2)葡萄糖运输代谢、利用、 氧化和葡糖激活酶活性进一步定位这种封闭，3) 胰岛β细胞原、GLUT-2、葡萄糖激酶和G蛋白的定量测定 确定关键蛋白表达是否受损的Alpha mRNA，4) 百分GLUT-2和含β-葡萄糖激活剂的形态计量学分析 细胞质量通过免疫细胞化学，5)β细胞体积，以确定 受损的β细胞团的扩张和形态计量学评估 通过电子显微镜观察线粒体的完整性。纵向 测量将从前六周开始每周进行一次， 直到糖尿病发作后六周。希望能找到一种 不同糖尿病大鼠模型的一致性差异 正常的代偿反应的重要组成部分，可能指向 致病基因。

Insulin resistant individuals become diabetic when beta-cells lose their normal ability to respond to glucose and to compensate for the pre- existing insulin resistance. To identify the beta-cell defect that results in NIDDM, we plan to characterize in rats the molecular, metabolic and physiologic components of the normal beta-cell compensatory response induced 1) by hyperglycemic clamping, 2) by dexamethasone treatment, and 3) by obesity and compare these with beta-cells of various rat models that cannot compensate these same factors (eg ZDF-drt rats, GK rats, Zucker fa/fa rats and rats after subdiabetic streptozotocin treatment). Functional measurement include 1) insulin responses to 5, 10, 20 mM glucose, glyceraldehyde and monomethyl succinate to localize a block, 2) measurements of glucose transport metabolism, utilization, oxidation and glucokinase activity further to localize such a block, 3) quantitation of beta-cell proinsulin, GLUT-2, glucokinase and G protein alpha mRNA to determine if expression of key proteins is impaired, 4) morphometric analysis of percent GLUT-2 and glucokinase containing beta- cell mass by immunocytochemistry, 5) beta-cell volume to determine if expansion of the beta-cell mass impaired and 6) morphometric assessment of mitochondrial integrity by electronmicroscopy. Longitudinal measurements will be made a weekly intervals from six weeks before and until six weeks after the onset of diabetes. The hope is to find a consistent difference in various diabetic rat models of seemingly crucial component of the normal compensatory response that might point to the pathogenic locus.