Wang M Y, Koyama K, Shimabukuro M, Mangelsdorf D, Newgard C B, Unger R H
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11921-6. doi: 10.1073/pnas.95.20.11921.
The high-Km glucose transporter, GLUT-2, and the high-Km hexokinase of beta cells, glucokinase (GK), are required for glucose-stimulated insulin secretion (GSIS). GLUT-2 expression in beta cells of Zucker diabetic fatty (ZDF) rats is profoundly reduced at the onset of beta-cell dysfunction of diabetes. Because ZDF rats are homozygous for a mutation in their leptin receptor (OB-R) gene and are therefore leptin-insensitive, we expressed the wild-type OB-R gene in diabetic islets by infusing a recombinant adenovirus (AdCMV-OB-Rb) to determine whether this reversed the abnormalities. Leptin induced a rise in phosphorylated STAT3, indicating that the transferred wild-type OB-R was functional. GLUT-2 protein rose 17-fold in AdCMV-OB-Rb-treated ZDF islets without leptin, and leptin caused no further rise. GK protein rose 7-fold without and 12-fold with leptin. Preproinsulin mRNA increased 64% without leptin and rose no further with leptin, but leptin was required to restore GSIS. Clofibrate and 9-cis-retinoic acid, the partner ligands for binding to peroxisome proliferator-activator receptor alpha (PPARalpha) and retinoid X receptor, up-regulated GLUT-2 expression in islets of normal rats, but not in ZDF rats, in which PPARalpha is very low. Because the fat content of islets of diabetic ZDF rats remains high unless they are treated with leptin, it appears that restoration of GSIS requires normalization of intracellular nutrient homeostasis, whereas up-regulation of GLUT-2 and GK is leptin-independent, requiring only high expression of OB-Rb.
高 Km 葡萄糖转运体 GLUT-2 和 β 细胞的高 Km 己糖激酶葡萄糖激酶（GK）是葡萄糖刺激的胰岛素分泌（GSIS）所必需的。在 Zucker 糖尿病脂肪（ZDF）大鼠的 β 细胞功能障碍开始时，GLUT-2 在其中的表达显著降低。由于 ZDF 大鼠的瘦素受体（OB-R）基因发生突变，为纯合子，因此对瘦素不敏感，我们通过注入重组腺病毒（AdCMV-OB-Rb）在糖尿病胰岛中表达野生型 OB-R 基因，以确定这是否能逆转异常情况。瘦素诱导磷酸化 STAT3 升高，表明转移的野生型 OB-R 具有功能。在未添加瘦素的情况下，AdCMV-OB-Rb 处理的 ZDF 胰岛中 GLUT-2 蛋白增加了 17 倍，添加瘦素后未进一步升高。GK 蛋白在未添加瘦素时增加了 7 倍，添加瘦素后增加了 12 倍。前胰岛素原 mRNA 在未添加瘦素时增加了 64%，添加瘦素后未进一步升高，但恢复 GSIS 需要瘦素。氯贝丁酯和 9-顺式视黄酸是与过氧化物酶体增殖物激活受体α（PPARα）和视黄酸 X 受体结合的配体，它们上调正常大鼠胰岛中的 GLUT-2 表达，但在 ZDF 大鼠胰岛中不起作用，因为 ZDF 大鼠中的 PPARα 非常低。由于除非用瘦素治疗，糖尿病 ZDF 大鼠胰岛的脂肪含量仍然很高，因此似乎恢复 GSIS 需要细胞内营养稳态正常化，而 GLUT-2 和 GK 的上调不依赖于瘦素，只需要 OB-Rb 的高表达。
