Total Parenteral Nutrition-Stimulated Activity of Inducible Nitric Oxide Synthase in Rat Pancreatic Islets is Suppressed by Glucagon-Like Peptide-1

Abstract

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.

Key words

Pancreatic Islets - Hormones - Isoforms of Nitric Oxide Synthase - Cyclic Nucleotides

References

• 1 Felber J P, Vanotti A. Effects of fat infusions on glucose tolerance and insulin plasma levels.  Med Exp. 1964;  10 153-156
• 2 Unger R H. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications.  Diabetes. 1995;  44 863-870
• 3 Sako Y, Grill V E. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation.  Endocrinology. 1990;  127 1580-1589
• 4 Zhou Y P, Grill V E. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.  J Clin Invest. 1994;  93 870-876
• 5 Milburn Jr J L, Hirose H, Lee Y H, Nagasawa Y, Ogawa A, Ohneda M, Beltran del Rio H, Newgard C B, Johnson J H, Unger R H. Pancreatic beta-cells in obesity. Evidence for induction of functional, morphologic, and metabolic abnormalities by increased long chain fatty acids.  J Biol Chem. 1995;  270 1295-1299
• 6 Shimabukuro M, Ohneda M, Lee V, Unger R H. Role of nitric oxide in obesity-induced β-cell disease.  J Clin Invest. 1997;  100 290-295.
• 7 de Kreutzenberg S, Lisato G, Riccio A, Giunta F, Bonato R, Petolillo M, Tiengo A, Del Prato S. Metabolic control during total parenteral nutrition: use of an artificial endocrine pancreas.  Metabolism. 1988;  37 510-513
• 8 Panagiotidis G, Alm P, Lundquist I. Inhibition of nitric oxide synthase increases arginine-induced insulin release.  Eur J Pharmacol. 1992;  229 277-278
• 9 Panagiotidis G, Åkesson B, Alm P, Lundquist I. The nitric oxide system in the endocrine pancreas induces differential effects of the secretion of insulin and glucagon.  Endocrine. 1994;  2 787-792
• 10 Panagiotidis G, Åkesson B, Rydell E, Lundquist I. Influence of nitric oxide synthase inhibition, nitric oxide and hydroperoxide on insulin release induced by various secretagogues.  Br J Pharmacol. 1995;  114 289-296
• 11 Lundquist I, Panagiotidis G, Stenström A. Effect of L-DOPA administration on islet monoamine oxidase activity and glucose-induced insulin release in the mouse.  Pancreas. 1991;  6 522-527
• 12 Panagiotidis G, Lindström P, Stenström A, Lundquist I. Glucose modulation of islet monoamine oxidase activity in lean and obese hyperglycemic mice.  Metabolism. 1993;  42 1398-1404
• 13 Panagiotidis G, Stenström A, Lundquist I. In vivo action of cyclic AMP modulating secretagogues on islet monoamine oxidase activity and insulin release.  Endocrine. 1994;  2 571-576
• 14 Salehi A, Carlberg M, Henningsson R, Lundquist I. Islet constitutive nitric oxide synthase: biochemical determination and regulatory function.  Am J Physiol. 1996;  270 C1634-C1641
• 15 Åkesson B, Mosén H, Panagiotidis G, Lundquist I. Interaction of the islet nitric oxide system with L-arginine-induced secretion of insulin and glucagon in mice.  Br J Pharmacol. 1996;  119 758-764
• 16 Salehi A, Parandeh F, Lundquist I. Signal transduction in islet hormone release: interaction of nitric oxide with basal and nutrient-induced hormone responses.  Cell Signal. 1998;  10 645-651
• 17 Henningsson R, Lundquist I. Arginine-induced insulin release is decreased and glucagon increased in parellel with islet NO production.  Am J Physiol. 1998;  275 E500-506
• 18 Åkesson B, Henningsson R, Salehi A, Lundquist I. Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice.  J Endocrinol. 1999;  163 39-48
• 19 Henningsson R, Alm P, Lindström E, Lundquist I. Chronic blockade of NO synthase paradoxically increases islet NO production and modulates islet hormone release.  Am J Physiol. 2000;  279 E95-E107
• 20 Fan B-G, Salehi A, Axelson J, Sternby B, Lundquist I, Andrén-Sandberg Å, Ekelund M. Total perenteral nutrition influences both endocrine and exocrine function of rat pancreas.  Pancreas. 1997;  2 147-153
• 21 Henningsson R, Alm P, Lundquist I. Evalution of islet heme oxygenase-CO and nitric oxide synthase-NO pathways during acute endotoxemia.  Am J Physiol. 2001;  280 C1242-C1254
• 22 Roth B, Ekelund M, Fan B-G, Hägerstrand I, Salehi A, Lundquist I, Nilsson-Ehle P. Biochemical and ultra-structural reactions to parenteral nutrition with two different fat emulsions in rats.  Intensive Care Med. 1998;  24 716-724
• 23 Salehi A, Fan B-G, Ekelund M, Nordin G, Lundquist I. TPN-evoked dysfunction of islet lysosomal activity mediates impairment of glucose-stimulated insulin release.  Am J Physiol. 2001;  281 E171-E179
• 24 Salehi A, Ekelund M, Henningsson R, Lundquist I. Total parenteral nutrition modulates hormone release by stimulating expression and activity of inducible nitric oxide synthase in rat pancreatic islets.  Endocrine. 2001;  16 97-104
• 25 Gotoh M, Maki T, Kiyoizumi T, Satomi S, Monaco A P. An improved method for isolation of mouse pancreatic islets.  Transplantation. 1985;  40 437-438
• 26 Heding L. A simplified insulin radioimmunoassay method. In: Donato L, Milhaud G, Sirchis J (eds) Labelled proteins in tracer studies. Brussels; Euratom Belgium 966: 345-350
• 27 Bradford M MA. A rapid and sensitive method for quantification of microgram quantities of protein utilizing the principle of protein-dye binding.  Anal Biochem. 1978;  84 309-312
• 28 Alm P, Ekström P, Henningsson R, Lundquist I. Morphological evidence for the existence of nitric oxide and carbon monoxide pathways in the rat islets of Langerhans: An immunocytochemical and confocal microscopic study.  Diabetologia. 1999;  42 978-986
• 29 Corbett J A, McDaniel M L. Does nitric oxide mediate autoimmune destruction of β-cells?.  Diabetes. 1992;  41 897-903
• 30 Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM.  Diabetologia. 1996;  39 1005-1029
• 31 Eizirik D L, Flodström M, Karlsen A E, Welsh N. The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells.  Diabetologia. 1996;  39 875-890
• 32 Laychock S G, Modica M E, Cavanaugh C T. L-arginine stimulates cyclic guanosine 3′,5 ′-monophosphate formation in rat islets of Langerhans and RIN m5F insulinoma cells: evidence for L-arginine: nitric oxide synthase.  Endocrinology. 1991;  129 3043-3052
• 33 Schmidt H H, Warner T D, Ishii K, Sheng H, Murad F. Insulin secretion from pancreatic B cells caused by L-arginine-derived nitrogen oxides.  Science. 1992;  255 721-723
• 34 Tsuura Y, Ishida H, Shinomura T, Nishimura M, Seino Y. Endogenous nitric oxide inhibits glucose-induced insulin secretion by suppression of phosphofructokinase activity in pancreatic islets.  Biochem Biophys Res Com. 1998;  252 34-38
• 35 Jones P M, Persaud S J, Bjaaland T, Pearson J D, Howell S. Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans.  Diabetologia. 1992;  35 1020-1027
• 36 Henningsson R, Alm P, Ekström P, Lundquist I. Heme oxygenase and carbon monoxide: regulatory roles in islet hormone release. A biochemical, immunohistochemical, and confocal microscopical study.  Diabetes. 1999;  48 66-76
• 37 Åkesson B, Lundquist I. Influence of nitric oxide modulators on cholinergically stimulated hormone release from mouse islets.  J Physiol. 1999;  515 463-473
• 38 Åkesson B, Lundquist I. Nitric oxide and hydroperoxide affect islet hormone release and Ca²⁺ efflux.  Endocrine. 1999;  11 99-107
• 39 Knowles R G, Moncada S. Nitric oxide synthases in mammals.  Biochem J. 1994;  298 249-258
• 40 Eizirik D L, Pavlovic D. Is there a role for nitric oxide in β-cell dysfunction and damage in IDDM?.  Diabet Metab Rev. 1997;  13 293-307
• 41 Cunningham J M, Green I C. Cytokines, nitric oxide and insulin secreting cells.  Growth Reg. 1994;  4 173-180
• 42 Salehi A, Parandeh F, Lundquist I. The nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester potentiates insulin secretion stimulated by glucose and L-arginine independently of its action on ATP-sensitive K⁺ channels.  Biosc Rep. 1998;  18 19-28
• 43 Stamler S, Simon D I, Osborne J A, Mullins M E, Jaraki O, Michel T, Singel D J, Loscalzo J. S-Nitrosylation of proteins with nitric oxide, synthesis, and characterization of biologically active compounds.  Proc Natl Acad Sci USA. 1992;  89 444-448
• 44 Ammon H PT, Mark M. Thiols and pancreatic β-cell function. A review.  Cell Biochem Funct. 1985;  3 157-171
• 45 Trovati M, Anfossi G. Insulin, insulin resistance, and platelet function: similarities with insulin effects on cultured vascular smooth muscle cells.  Diabetologia. 1998;  41 609-622
• 46 Duhe R J, Nielsen M D, Dittman A H, Villacres E C, Choi E-J, Storm D R. Oxidation of critical cysteine residues of type I adenylyl cyclase by o-iodosobenzoate or nitric oxide reversibly inhibits stimulation by calcium and calmodulin.  J Biol Chem. 1994;  269 7290-7298