Ohneda M, Johnson J H, Lee Y H, Nagasawa Y, Unger R H
Gifford Laboratories, Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas.
Am J Physiol. 1994 Dec;267(6 Pt 1):E968-74. doi: 10.1152/ajpendo.1994.267.6.E968.
Zucker diabetic fatty (ZDF) rats develop non-insulin-dependent diabetes mellitus concomitantly with loss of glucose responsiveness and GLUT-2, the high-Michaelis constant glucose transporter of beta-cells. To determine the integrity of beta-cell glucose metabolism distal to the level of glucose transport and phosphorylation, we examined the insulin responses of isolated pancreata to 5, 10, and 20 mM D-glyceraldehyde and monomethylsuccinate, as well as to glucose. The insulin response of diabetic pancreata to glucose was 90% below the response prior to the onset of diabetes, whereas the responses to glyceraldehyde and succinate had declined to 65 and 44%, respectively, below the prediabetic responses. D-[14C]glyceraldehyde oxidation by diabetic islets was 74% below that of islets from lean nondiabetic controls. We conclude that 1) the insulin responses to glyceraldehyde and monomethylsuccinate, as well as to glucose, are impaired in the diabetes of ZDF rats and 2) the impairment of the glucose response was greater than that of the glyceraldehyde response, which was, in turn, greater than that of the monomethylsuccinate response; this decrescendo pattern of impairment is consistent with defects at multiple sites in glucose metabolism; if the defect were entirely due to a postmetabolic signaling defect, the impairment to glucose and its metabolites should be comparable.
Zucker糖尿病脂肪（ZDF）大鼠会同时发展出非胰岛素依赖型糖尿病，伴有葡萄糖反应性丧失以及β细胞的高米氏常数葡萄糖转运体GLUT-2的丧失。为了确定葡萄糖转运和磷酸化水平远端的β细胞葡萄糖代谢的完整性，我们检测了分离胰腺对5、10和20 mM D-甘油醛、单甲基琥珀酸以及葡萄糖的胰岛素反应。糖尿病胰腺对葡萄糖的胰岛素反应比糖尿病发作前的反应低90%，而对甘油醛和琥珀酸的反应分别降至糖尿病前期反应的65%和44%以下。糖尿病胰岛对D-[14C]甘油醛的氧化比瘦的非糖尿病对照的胰岛低74%。我们得出结论：1）ZDF大鼠糖尿病中，胰腺对甘油醛、单甲基琥珀酸以及葡萄糖的胰岛素反应受损；2）葡萄糖反应的受损程度大于甘油醛反应，而甘油醛反应又大于单甲基琥珀酸反应；这种递减的受损模式与葡萄糖代谢多个位点的缺陷一致；如果缺陷完全是由于代谢后信号缺陷，那么对葡萄糖及其代谢产物的损害应该是相当的。
