title: Total parenteral nutrition modulates hormone release by stimulating expression and activity of inducible nitric oxide synthase in rat pancreatic islets.
abstract: The expression and activities of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) in relation to insulin and glucagon secretory mechanisms were investigated in islets isolated from rats subjected to total parenteral nutrition (TPN) for 10 d. TPN is known to result in significantly increased levels of plasma lipids during the infusion time. In comparison with islets from freely fed control rats, islets taken from TPN rats at d 10 displayed a marked decrease in glucose-stimulated insulin release (4.65 +/- 0.45 ng/[islet x h] vs 10.25 +/- 0.65 for controls) (p < 0.001) accompanied by a strong iNOS activity (18.3 +/- 1.1 pmol of NO/[min x mg of protein]) and a modestly reduced cNOS activity (11.3 +/- 3.2 pmol of NO/[min x mg of protein] vs 17.7 +/- 1.7 for controls) (p < 0.01). Similarly, Western blots showed the expression of iNOS protein as well as a significant reduction in cNOS protein in islets from TPN-treated rats. The enhanced NO production, which is known to inhibit glucose-stimulated insulin release, was manifested as a strong increase in the cyclic guanosine 5'-monophosphate content in the islets of TPN-treated rats (1586 +/- 40 amol/islet vs 695 +/- 64 [p < 0.001] for controls). Moreover, the content of cyclic adenosine monophosphate (cAMP) was greatly increased in the TPN islets (80.4 +/- 2.1 fmol/islet vs 42.6 +/- 2.6 [p < 0.001] for controls). The decrease in glucose-stimulated insulin release was associated with an increase in the activity of the secretory pathway regulated by the cAMP system in the islets of TPN-treated rats, since the release of insulin stimulated by the phosphodiesterase inhibitor isobutylmethylxanthine was greatly increased both in vivo after iv injection and after in vitro incubation of isolated islets. By contrast, the release of glucagon was clearly reduced in islets taken from TPN-treated rats (33.5 +/- 1.5 pg/[islet x h] vs 45.5 +/- 2.2 for controls) (p < 0.01) when islets were incubated at low glucose (1.0 mmol/L). The data show that long-term TPN treatment in rats brings about impairment of glucose-stimulated insulin release, that might be explained by iNOS expression and a marked iNOS-derived NO production in the beta-cells. The release of glucagon, on the other hand, is probably decreased by a direct "nutrient effect" of the enhanced plasma lipids. The results also suggest that the islets of TPN-treated rats have developed compensatory insulin secretory mechanisms by increasing the activity of their beta-cell cAMP system.
authors.affiliation: Institute of Physiological Sciences, Department of Pharmacology, University of Lund, Sweden. Salehi@farm.lu.se
authors.forename: A
authors.initials: A
authors.lastname: Salehi
authors.forename: M
authors.initials: M
authors.lastname: Ekelund
authors.forename: R
authors.initials: R
authors.lastname: Henningsson
authors.forename: I
authors.initials: I
authors.lastname: Lundquist
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006728:Hormones / Q000378:metabolism*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010289:Parenteral Nutrition, Total; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
chemical_list: D006728:Hormones; D007328:Insulin; D005934:Glucagon; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006152:Cyclic GMP; D005947:Glucose; D015056:1-Methyl-3-isobutylxanthine