Zawalich W S, Zawalich K C, Kelley G G, Shulman G I
Yale University School of Nursing, New Haven, CT 06536-0740, USA.
Biochem Biophys Res Commun. 1995 Apr 26;209(3):974-80. doi: 10.1006/bbrc.1995.1593.
The sequence of events that culminate in the development of diabetes in the fa/fa Zucker diabetic fatty (ZDF) rat is unclear. In the present series of experiments islets from 5 week old prediabetic fa/fa male rats were isolated and their phosphoinositide (PI) hydrolysis and insulin secretory responses compared to those obtained from lean nondiabetic age- and weight-matched control rats. Peak first and second phase insulin secretory responses to 20mM glucose averaged 77 +/- 10 (mean +/- SE, n = 7) and 491 +/- 47 pg/islet/min from lean, nondiabetic control islets. The comparable responses from fa/fa prediabetic rat islets were significantly greater, 264 +/- 51 and 810 +/- 78 pg/islet/min. In a parallel fashion 3H-inositol efflux and inositol phosphate responses from prediabetic rat islets were also greater than comparable control responses. These findings demonstrate that significant increases in the phospholipase C-mediated hydrolysis of islet PI pools and insulin release in response to hyperglycemic stimulation can be detected prior to the emergence of diabetes in the fa/fa ZDF rat. These early changes in beta cell responsiveness to glucose may contribute to the hyperinsulinemia and subsequent insulin resistance characteristic of this animal model of non-insulin dependent diabetes mellitus.
导致fa/fa Zucker糖尿病脂肪（ZDF）大鼠发生糖尿病的一系列事件尚不清楚。在本系列实验中，分离出5周龄糖尿病前期fa/fa雄性大鼠的胰岛，并将其磷酸肌醇（PI）水解和胰岛素分泌反应与年龄和体重匹配的非糖尿病瘦型对照大鼠的胰岛进行比较。来自非糖尿病瘦型对照胰岛对20mM葡萄糖的第一和第二阶段胰岛素分泌反应峰值平均为77±10（平均值±标准误，n = 7）和491±47 pg/胰岛/分钟。来自fa/fa糖尿病前期大鼠胰岛的相应反应明显更高，为264±51和810±78 pg/胰岛/分钟。以类似方式，糖尿病前期大鼠胰岛的3H-肌醇流出和肌醇磷酸反应也高于相应的对照反应。这些发现表明，在fa/fa ZDF大鼠出现糖尿病之前，可以检测到磷脂酶C介导的胰岛PI池水解和胰岛素释放对高血糖刺激的显著增加。β细胞对葡萄糖反应性的这些早期变化可能导致该非胰岛素依赖型糖尿病动物模型的高胰岛素血症及随后的胰岛素抵抗。
