Defective Glucose-Stimulated Insulin Release in the Diabetic Goto-Kakizaki (GK) Rat Coincides with Reduced Activity of the Islet Carbon Monoxide Signaling Pathway

The Goto-Kakizaki (GK) rat displays a markedly reduced in-sulin response to glucose, a defect that is thought to be cou-pled to an impaired glucose signaling in the -cell. We have examinedwhether carbonmonoxide (CO), derived from-cell heme oxygenase (HO), might be involved in the secretory dys-function. Immunocytochemical labeling of constitutive HO (HO-2) showed no overt difference in fluorescence pattern in islets from GK vs. Wistar controls. However, isolated islets fromGK rats displayed amarkedly impairedHOactivitymea-sured asCOproduction (50%), and immunoblotting revealed an approximately 50 % reduction of HO-2 protein expression compared with Wistar controls. Furthermore, there was a prominent expression of inducible HO (HO-1) in GK islets. Incubation of isolated islets showed that the glucose-stimu-lated CO production and the glucose-stimulated insulin re