Total parenteral nutrition-stimulated activity of inducible nitric oxide synthase in rat pancreatic islets is suppressed by glucagon-like peptide-1.
Long-term total parenteral nutrition (TPN) is associated with elevated plasma lipids and a marked decrease of glucose-stimulated insulin release. Since nitric oxide (NO) has been shown to modulate negatively the insulin response to glucose, we investigated the influence of TPN-treatment on isoforms of islet NO-synthase (NOS) activities in relation to the effect of glucagon-like peptide-1 (GLP-1), a known activator of glucose-stimulated insulin release. Isolated islets from TPN rats incubated at basal glucose (1 mmol/l) showed a modestly increased insulin secretion accompanied by an enhanced accumulation of islet cAMP and cGMP. In contrast, TPN islets incubated at high glucose (16.7 mmol/l) displayed an impaired insulin secretion and a strong suppression of islet cAMP content. Moreover, islet inducible NOS (iNOS) as well as islet cGMP content were greatly increased in these TPN islets. A dose-response study of GLP-1 with glucose-stimulated islets showed that GLP-1 could overcome and completely restore the impaired insulin release in TPN islets, bringing about a marked increase in islet cAMP accumulation concomitant with heavy suppression of both glucose-stimulated increase in islet cGMP content and the activities of constitutive NOS (cNOS) and iNOS. These effects of GLP-1 were mimicked by dibutyryl-cAMP. The present results show that the impaired insulin response of glucose-stimulated insulin release seen after TPN treatment is normalized by GLP-1. This beneficial effect of GLP-1 is most probably exerted by a cAMP-induced suppression of both iNOS and cNOS activities in these TPN islets.
Salehi
A
A
Department of Physiological Sciences, Division of Pharmacology, University of Lund, Sweden. salehi@farm.lu.se
Ekelund
M
M
Lundquist
I
I
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000201:enzymology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010289:Parenteral Nutrition, Total; D010446:Peptide Fragments / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D006152:Cyclic GMP; D005947:Glucose