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 insulin response to glucose, a defect that is thought to be coupled to an impaired glucose signaling in the beta-cell. We have examined whether carbon monoxide (CO), derived from beta-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.
Mosén
Henrik
H
Department of Pharmacology, Institute of Physiological Sciences, University of Lund, BMC F13, S-221 84 Lund, Sweden. henrik.mosen@farm.lu.se
Salehi
Albert
A
Alm
Per
P
Henningsson
Ragnar
R
Jimenez-Feltström
Javier
J
Ostenson
Claes-Göran
CG
Efendic
Suad
S
Lundquist
Ingmar
I
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006427:Hemin / Q000737:chemistry; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008856:Microscopy, Fluorescence; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D001786:Blood Glucose; D007328:Insulin; D006427:Hemin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D005947:Glucose