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

Department of Pharmacology, Institute of Physiological Sciences (H.M., A.S., R.H., J.J.-F., I.L.) and Department of Pathology (P.A.), University of Lund, S-221 84 Lund, Sweden; and Department of Molecular Medicine (C.-G.O., S.E.), Karolinska Institute, S-171 76 Stockholm, Sweden

Address all correspondence and requests for reprints to: Henrik Mosén, M.D., Department of Pharmacology, Institute of Physiological Sciences, University of Lund, BMC F13, S-221 84 Lund, Sweden. E-mail: henrik.mosen{at}farm.lu.se.

The Goto-Kakizaki (GK) rat displays a markedly reduced insulin response to glucose, a defect that is thought to be coupled to an impaired glucose signaling in the ß-cell. We have examined whether carbon monoxide (CO), derived from ß-cell heme oxygenase (HO), might be involved in the secretory dysfunction. Immunocytochemical labeling of constitutive HO (HO-2) showed no overt difference in fluorescence pattern in islets from GK vs. Wistar controls. However, isolated islets from GK rats displayed a markedly impaired HO activity measured as CO production (–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-stimulated CO production and the glucose-stimulated insulin response were considerably reduced in GK islets compared with Wistar islets. Addition of the HO activator hemin or gaseous CO to the incubation media brought about a similar amplification of glucose-stimulated insulin release in GK and Wistar islets, suggesting that distal steps in the HO-CO signaling pathway were not appreciably affected. We conclude that the defective insulin response to glucose in the GK rat can be explained, at least in part, by a marked impairment of the glucose-HO-CO signaling pathway as manifested by a prominent decrease in glucose stimulation of islet CO production and a reduced expression of HO-2. A possible role of HO-1 expression as a compensatory mechanism in the GK islets is presently unclear.

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