Horm Metab Res 2001; 33(11): 639-644
DOI: 10.1055/s-2001-18691
Original Basic
© Georg Thieme Verlag Stuttgart · New York

Interleukin-1β Inhibits Proinsulin Conversion in Rat β-Cells Via a Nitric Oxide-Dependent Pathway

Y. Zambre, C. Van Schravendijk, Z. Ling
  • Diabetes Research Center, Faculty of Medicine, Vrije Universiteit Brussel, Brussels, Belgium
Further Information

Publication History

Publication Date:
04 December 2001 (online)

Exposure of pancreatic β-cells to interleukin-1β (IL-1β) alters their protein expression and phenotype. Previous work has shown that IL-1β inhibited proinsulin conversion in rat islets, but the mechanism of this inhibition remained unknown. To investigate this phenomenon further, we examined purified rat β-cells for IL-1β-induced inhibition of proinsulin conversion and nitric oxide (NO)-dependency of this inhibitory process. Rat β-cells were cultured for 24 h with or without IL-1β and the inducible-nitric-oxide-synthase (iNOS) inhibitor NG-methyl-L-arginine (NMA). Exposure to IL-1β suppressed proinsulin-1 and proinsulin-2 synthesis by more than 50 %. Conversion of both proinsulin isoforms was also delayed. The suppressive effects of IL-1β on proinsulin synthesis and conversion were prevented by addition of NMA. Exposure to IL-1β also decreased the expression of the proinsulin convertase (PC) PC2. This decrease in PC2 expression was NO-dependent. In conclusion, IL-1β inhibition of proinsulin conversion in rat β-cells occurs via an NO-mediated pathway.

References

  • 1 Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM.  Diabetologia. 1996;  19 1005-1029
  • 2 Rabinovitch A. Roles of cytokines in IDDM pathogenesis and islet β-cell destruction.  Diabetes Reviews. 1993;  1 215-240
  • 3 Rabinovitch A. An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus. Diabetes Metab.  Rev. 1998;  14 129-151
  • 4 Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello C A, Svenson M, Nielsen J H. Affinity purified human interleukin-1 is cytotoxic to isolated islets of Langerhans.  Diabetologia. 1986;  29 63-67
  • 5 Ling Z, In’t Veld P A, Pipeleers D G. Interaction of interleukin-1 with islet β-cells. Distinction between indirect, aspecific cytotoxicity and direct, specific functional suppression.  Diabetes. 1993;  42 56-65
  • 6 Ling Z, Meng-Chi C, Smismans A, Pavlovic D, Schuit F, Eizirik D L, Pipeleers D. Intercellular differences in interleukin-1β-induced suppression of insulin synthesis and stimulation of noninsulin protein synthesis by rat pancreatic β-cells.  Endocrinology. 1998;  139 1540-1545
  • 7 Ling Z, Van de Casteele M, Eizirik D L, Pipeleers D G. Interleukin-1β-induced alteration in β-cell phenotype can reduce cellular sensitivity to conditions causing necrosis but not to cytokine-induced apoptosis.  Diabetes. 2000;  49 340-345
  • 8 Corbett J A, Lancaster J R, Sweetland M A, McDaniel M L. Interleukin-1β-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. Role of nitric oxide in Interleukin-1β-induced inhibition of insulin secretion.  J Biol Chem. 1991;  266 21 351-21 354
  • 9 Corbett J A, McDaniel M L. Does nitric oxide mediate autoimmune destruction of β-cells? Possible therapeutic interventions in IDDM.  Diabetes. 1992;  41 897-903
  • 10 Southern C, Schulster D, Green I C. Inhibition of insulin secretion by interleukin-1β and tumor necrosis factor-α via an L-arginine dependent nitric oxide generating mechanism.  FEBS Lett. 1990;  276 42-44
  • 11 Welsh N, Eizirik D L, Bendtzen K, Sandler S. Interleukin-1β-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme acotinase.  Endocrinology. 1991;  129 3167-3173
  • 12 Eizirik D L, Pavlovic D. Is there a role for nitric oxide in β-cell dysfunction and damage in IDDM?.  Diabetes/Metabolism Rev. 1997;  13 293-307
  • 13 Eizirik D L, Sandler S, Welsh N, Cetkovic-Cvrlje M, Nieman A, Geller D A, Pipeleers D G, Bendtzen K, Hellerström C. Cytokines suppress human islet function irrespective of their effective on nitric oxide generation.  J Clin Invest. 1994;  93 1968-1974
  • 14 Eizirik D L, Delaney C A, Green M HL, Cunningham J M, Thorpe J R, Pipeleers D G, Hellerström C, Green I C. Nitric oxide donors decrease the function and survival of human pancreatic islets.  Mol Cell Endocrinol. 1996;  118 71-83
  • 15 Eizirik D L, Pipeleers D G, Ling Z, Welsh N, Hellerström C, Anderson A. Major species differences between humans and rodents in the susceptibility to pancreatic β-cell injury.  Proc Natl Acad Sci USA. 1994;  91 9253-9256
  • 16 Hostens K, Pavlovic D, Zambre Y, Ling Z, Van Schravendijk C, Eizirik D L, Pipeleers D. Exposure of human islets to cytokine combinations results in elevated proinsulin release.  J Clin Invest. 1999;  104 67-72
  • 17 Hansen B S, Nielsen J H, Linde S, Spinas G A, Welinder B S, Mandrup-Poulsen T, Nerup J. Effect of interleukin-1 on the biosynthesis of proinsulin and insulin in isolated rat pancreatic islets.  Biomed Biochim Acta. 1988;  47 305-309
  • 18 Pavlovic D, Chen M -C, Bouwens L, Eizirik D L, Pipeleers D. Contribution of ductal cells to cytokine responses by human pancreatic islets.  Diabetes. 1999;  48 29-33
  • 19 Lefebvre V H, Otonkoski T, Ustinov J, Huotari M -A, Pipeleers D G, Bouwens L. Culture of adult human islet preparations with hepatocyte growth factor and 804G matrix is mitogenic for Duct cells but not for B-cells.  Diabetes. 1998;  47 134-137
  • 20 Alarcon C, Lincoln B, Rhodes C J. The biosynthesis of the subtilisin-related proprotein convertase PC3, but not that of PC2 convertase is regulated by glucose in parallel to proinsulin biosynthesis in rat pancreatic islets.  J Biol Chem. 1993;  268 4276-4280
  • 21 Martin S K, Carroll R, Benig M, Steiner D F. Regulation by glucose of the biosynthesis of PC2, PC3 and proinsulin in (ob/ob) mouse islets of Langerhans.  FEBS Lett. 1994;  356 279-282
  • 22 Pipeleers D G, In’t Veld P A, Van De Winkel M, Maes E, Schuit F C, Gepts W. A new in vitro model for the study of pancreatic A and B cells.  Endocrinology. 1985;  117 806-816
  • 23 Pipeleers D G, Schuit F C, Van Schravendijk C FH, Van De Winkel M. Interplay of nutrients and hormones in the regulation of glucagon release.  Endocrinology. 1985;  117 817-823
  • 24 Green L, Wagner D, Glogowski J, Skipper P L, Wishnok J S, Tannenbaum S R. Analysis of nitrate, nitrite and (15N)nitrate in biological fluids.  Anal Biochem. 1982;  126 131-138
  • 25 Zambre Y, Ling Z, Hou X, Foriers A, Van Den Bogaert B, Van Schravendijk C, Pipeleers D. Effect of glucose on production and release of proinsulin conversion products by cultured human islets. J.  Clin Endocrinol Metab. 1998;  83 1234-1238
  • 26 Linde S, Welinder B S, Nielsen J H. Analysis of proinsulin and its conversion products by reversed-phase high-performance liquid chromatography.  J Biochem. 1993;  614 185-204
  • 27 Schuit F C, In’t Veld P A, Pipeleers D G. Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells.  Proc Natl Acad Sci. 1988;  85 3865-3869
  • 28 Spinas G A, Hansen B S, Linde S, Kastern W, Mandrup-Poulsen T, Nielsen J H, Nerup J. Interleukin-1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans.  Diabetologia. 1987;  30 474-480
  • 29 Gishizky M L, Grodsky G M. Differential kinetics of rat insulin I and II processing in rat islets of Langerhans.  FEBS Lett. 1987;  223 227-231
  • 30 Sizonenko S V, Halban P A. Differential rates of conversion of rat proinsulins I and II: Evidence for slow cleavage at the B-chain/C-peptide junction of proinsulin II.  Biochem J. 1991;  278 621-625
  • 31 Corbett J A, Sweetland M A, Wang J L, Lancaster J RJ, McDaniel M L. Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans.  Proc Natl Acad Sci. 1993;  90 1731-1735
  • 32 Flodström M, Eizirik D. Interferon-gamma induced interferon regulatory factor-1 (IRF-1) expression in rodent and human islet cells precedes nitric oxide production.  Endocrinology. 1997;  138 2747-2753
  • 33 Delaney C A, Pavlovic D, Hoorens A, Pipeleers D G, Eizirik D L. Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells.  Endocrinology. 1997;  138 2610-2614
  • 34 Furuta M, Carroll R, Martin S, Swift H H, Ravazzola M, Orci L, Steiner D F. Incomplete processing of proinsulin to insulin accompanied by elevation of des-31,32 proinsulin intermediates in islets of mice lacking active PC2.  J Biol Chem. 1998;  273 3431-3437
  • 35 Neerman-Arbez M, Sizonenko S V, Halban P A. Slow cleavage at the proinsulin B-chain/connecting peptide junction associated with low levels of endoprotease PC1/3 in transformed β-cells.  J Biol Chem. 1993;  268 16 098-16 100
  • 36 Ishii T, Sunami O, Saitoh N, Nishio H, Takeuchi T, Hata F. Inhibition of skeletal muscle sarcoplasmic reticulum Ca2+-ATPase by nitric oxide.  FEBS Lett. 1998;  440 218-222
  • 37 Pernollet M -G, Lantoine F, Devynck M -A. Nitric oxide inhibits ATP-dependent Ca2+- uptake into platelet membrane vesicles.  Biochem Biophys Res Commun. 1996;  222 780-785
  • 38 Sambrook J F. The involvement of calcium in transport of secretory proteins from the endoplasmic reticulum.  Cell. 1990;  61 197-199
  • 39 Kuznetsov G, Brostrom M A, Brostrom C O. Demonstration of a calcium requirement for secretory protein processing and export. Differential effects of calcium and dithiothreitol.  J Biol Chem. 1992;  267 3932-3939
  • 40 Wileman T, Kane L P, Carson G R, Terhorst C. Depletion of cellular calcium accelerates protein degradation in the endoplasmic reticulum.  J Biol Chem. 1991;  266 4500-4507
  • 41 Guest P C, Bailyes E M, Hutton J C. Endoplasmic reticulum Ca2+ is important for the proteolytic processing and intracellular transport of proinsulin in the pancreatic β-cells.  Biochem J. 1997;  323 445-450
  • 42 Willmott N J, Galione A, Smith P A. Nitric oxide induces intracellular Ca2+ mobilization and increases secretion of incorporated 5-hydroxytryptamine in rat pancreatic beta-cells.  FEBS Lett. 1995;  371 99-104

Dr. Zhidong Ling

Diabetes Research Center
Vrije Universiteit Brussel

Laarbeeklaan 103
1090 Brussels
Belgium


Phone: + 32 (2) 477 45 41

Fax: + 32 (2) 477 45 45

Email: zling@mebo.vub.ac.be