Nitric oxide (NO) and carbon monoxide (CO): A novel class of messenger molecules regulating insulin and glucagon secretion

Sammanfattning: During the last decade it has been shown that nitric oxide (NO) and carbon monoxide (CO) are produced in our own body, and that they constitute a novel class of messenger molecules. In 1992 a constitutive NO-producing NO-synthase (cNOS) was found in the islets of Langerhans, and in 1997 we could show for the first time that the islets also contained a CO-producing constitutive heme oxygenase (HO-2). The aim of this thesis was to elucidate the role of NO and CO in the regulation of islet hormone release. Glucagon secretion and glucose-stimulated insulin secretion was stimulated by CO produced from the HO-2 enzyme, which we found to reside in all four endocrine cell types of the islets. The effects of CO in transduction signalling was found to include cyclic GMP (cGMP) production as well as NOS inhibition. Islet CO-production was found to be stimulated by glucose. The inducible HO-1 enzyme was induced in vivo by LPS (lipopolysaccharide), concomitant with inducible NOS (iNOS), and might be part of an islet defence against the oxidative stress exerted by NO. L-arginine- and glucose-stimulated insulin secretion was inhibited by cNOS-derived-NO in parallel with islet NO-production and independent of membrane depolarisation events. In contrast, glucagon secretion was stimulated by NO. By measuring both cNOS and iNOS activity in the islets we could show that the NOS-inhibitor NG-mono-methyl-L-arginine (L-NMMA) in low concentrations stimulated islet cNOS-derived-NO-production, and that NG-nitro-L-arginine methyl ester (L-NAME) during long-term oral administration did inhibit islet cNOS activity, but that the total islet NO-production was paradoxically increased because of a compensatory induction of iNOS. Islet iNOS, which by immunocytochemistry and confocal microscopy was found in most b-cells, and a small percentage of a- and PP-cells after in vivo LPS treatment, was also rapidly induced by hyperglycaemia as well as after starvation. In animal models of NIDDM insulin hypersecretion was correlated to low cNOS and iNOS activity, while failing insulin secretion was correlated to high NO-production within the islets. In situations of excessive NO-production the islet adenylate cyclase-cyclic AMP system was upregulated, similar to the HO-system, probably as a counterbalance to the NO-induced suppression of insulin secretion. Glucagon, as well as CO, was found to inhibit islet NOS activity. It seems as if a functional NO system is essential in the islets by stimulating glucagon secretion and inhibiting excessive insulin secretion, constituting a fail-safe instrument to finely tune the influence of insulin secretion on the blood glucose level.