Nitric Oxide Synthase in Pancreatic Islets During Trauma and Parenteral Feeding

Abstract: The influence of trauma (acute pancreatitis) or total parenteral nutrition (TPN) on pancreatic islet hormone secretion in relation to islet expression of inducible nitric oxide synthase (iNOS) was investigated. Acute pancreatitis resulted in an impaired glucose-stimulated insulin secretion (GSIS) which was found to be parallelled by a marked expression of iNOS and an exaggerated NO production in the pancreatic islets. A characteristic feature of long term TPN-treatment is hyperlipidemia and euglycaemia, since the major component of TPN solution is intralipid (IL). TPN treatment impairs GSIS at least in part through a reduced cyclic AMP production in parallel with an exclusive expression of iNOS, which was reflected in an increased NO production accompanied by enhanced cyclic GMP formation by islets. Agents stimulating cyclic AMP/Protein kinase A (PKA) i.e. PACAP27 and PACAP38 were capable of not only inhibiting neuronal constitutive NOS (ncNOS) but also counteracting the expression of iNOS induced by intralipid infusion. The suppressed NO production in the presence of PACAPs was reflected in a suppressed cyclic GMP and a marked increase in cyclic AMP production by pancreatic islets. A short-term study revealed that a "hyperglycaemic or hyperlipidemic period" as short as 24 hours stimulated the expression and activity of iNOS in the islets. Finally the effect of ghrelin (gastric hormone) on islet hormone secretion and NOS isoenzymes activities was also studied. The inhibitory action of ghrelin on GSIS and the stimulatory effect on the glucagon secretion was accompanied by an increased ncNOS activity. However, such effects of ghrelin were only observed at slightly higher and supra-physiological concentrations (in vitro study). Furthermore, TPN-animals displayed extreme low plasma and tissue levels of ghrelin. Thus, ghrelin does not seem to have any significant role in the reduced GSIS and iNOS expression seen during TPN-treatment. Taken together the data suggest that, besides trauma, hyperglycaemia and hyprelipidemia are able to induce pathophysiological changes in pancreatic islets (iNOS expressing and reduced GSIS) implicating that the nutritional state should be regarded as an important factor for the normal function of islets.