Overexpression of leptin receptors in pancreatic islets of Zuckerdiabetic fatty rats restores GLUT-2 glucokinase andglucose-stimulated insulin secretion

摘要

The high-Km glucose transporter, GLUT-2, and the high-Km hexokinase of β cells, glucokinase (GK), are required for glucose-stimulated insulin secretion (GSIS). GLUT-2 expression in β cells of Zucker diabetic fatty (ZDF) rats is profoundly reduced at the onset of β-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 toperoxisome proliferator-activator receptor α (PPARα) and retinoid Xreceptor, up-regulated GLUT-2 expression in islets of normal rats, butnot in ZDF rats, in which PPARα is very low. Because the fat contentof islets of diabetic ZDF rats remains high unless they are treatedwith leptin, it appears that restoration of GSIS requires normalizationof intracellular nutrient homeostasis, whereas up-regulation of GLUT-2and GK is leptin-independent, requiring only high expression of OB-Rb.