Summary
A model of the pathogenesis of insulin-dependent diabetes mellitus, i.e. the initial phase of beta-cell destruction, is proposed: in a cascade-like fashion efficient antigen presentation, unbalanced cytokine, secretion and poor beta-cell defence result in beta-cell destruction by toxic free radicals (O2 − and nitric oxide) produced by the beta cells themselves. This entire process is under polygenetic control.
Article PDF
Similar content being viewed by others
Abbreviations
- IDDM:
-
Insulin-dependent diabetes mellitus
- TNF:
-
tumour necrosis factor
- IL-1:
-
interleukin-1
- BB:
-
bio-breeding
- NOD:
-
non-obese diabetic
- IFN:
-
interferon
- APC:
-
antigen presenting cells
- mn SOD:
-
manganosuperoxide dismutase
- NO:
-
nitric oxide
- NOS:
-
nitric oxide synthases
- ONOO− :
-
peroxynitrite
References
Nerup J, Andersen OO, Bendixen G, Egeberg J, Poulsen JE (1971) Antipancreatic cellular hypersensitivity in diabetes mellitus. Diabetes 20: 424–427
Nerup J, Platz P, Andersen OO et al. (1974) HL-A antigens and diabetes mellitus. Lancet I: 864–866
Thomsen M, Platz P, Andersen OO et al. (1975) MLC typing in juvenile diabetes mellitus and ideopathic Addisons disease. Transpl Rev 22: 125–147
Eisenbarth GS (1986) Type 1 diabetes mellitus. A chronic autoimmune disease. N Engl J Med 314: 1360–1368
Mandrup-Poulsen T, Helqvist S, Mølvig J, Wogensen LD, Nerup J (1989) Cytokines as immune effector molecules in autoimmune endocrine diseases with special reference to insulin-dependent diabetes mellitus. Autoimmunity 4: 191–218
Nerup J, Mandrup-Poulsen T, Mølvig J, Helqvist S, Wogensen LD (1989) On the pathogenesis of insulin-dependent diabetes mellitus — a discussion of three recently proposed models. In: Creutzfeldt W, Lefèbvre P (eds) Diabetes mellitus: pathophysiology and therapy. Springer-Verlag, Berlin, pp 39–50
Hanenberg H, Kolb-Bachofen V, Kantwerk-Funke G, Kolb H (1989) Macrophage infiltration precedes and is prerequisite for lymphocytic insulitis in pancreatic islets of pre-diabetic BB rats. Diabetologia 32: 126–134
O'Reilly LA, Hutchings PR, Crocker PR et al. (1991) Characterization of pancreatic islet cell infiltrates in NOD mice: effect of cell transfer and transgene expression. Eur J Immunol 21: 1171–1180
Mandrup-Poulsen T (1988) On the pathogenesis of insulin-dependent diabetes mellitus. Dan Med Bull 35: 438–460
Mølvig J (1992) A model of the pathogenesis of insulin-dependent diabetes mellitus. Dan Med Bull 39: 509–541
Mandrup-Poulsen T, Bendtzen K, Høiriis Nielsen J, Bendixen G, Nerup J (1985) Cytokines cause structural and functional damage to isolated islets of Langerhans. Allergy 40: 424–429
Mandrup-Poulsen T, Bendtzen K, Nerup J, Egeberg J, Nielsen JH (1985) Mechanism of pancreatic islet cell destruction. Dose-dependent cytotoxic effect of soluble blood mononuclear cell mediators on isolated islets of Langerhans. Allergy 41: 250–259
Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello CA, Svenson M, Nielsen JH (1986) Affinity purified human Interleukin 1 is cytotoxic to isolated islets of Langerhans. Diabetologia 29: 63–67
Mandrup-Poulsen T, Bendtzen K, Dinarello CA, Nerup J (1987) Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic β-cell cytotoxicity. J Immunol 39: 4077–4082
Nerup J, Mandrup-Poulsen T, Mølvig J, Helqvist S, Wogensen L, Egeberg J (1988) Mechanisms of pancreatic β-cell destruction in type 1 diabetes. Diabetes Care 11 [Suppl 1]: 16–23
Sandler S, Eizirik DL, Svensson C, Strandell E, Welsh M, Welsh N (1991) Biochemical and molecular actions of interleukin-1 on pancreatic β-cells. Autoimmunity 10: 241–253
Rabinovitch A, Pukel C, Baquerizo H (1988) Interleukin-1 inhibits glucose-modulated insulin and glucagon secretion in rat islet monolayer cultures. Endocrinol 122: 2393–2398
McDaniel ML, Hughes JH, Wolf BA, Easom RA, Turk JW (1988) Descriptive and mechanistic considerations of interleukin 1 and insulin secretion. Diabetes 37: 1311–1315
Voorbij HAM, Jeucken PHM, Kabel PJ, de Haan M, Drexhage HA (1989) Dendritic cells and scavenger macrophages in pancreatic islets of prediabetic BB rats. Diabetes 38: 1623–1629
Jiang Z, Woda BA (1991) Cytokine gene expression in the islets of the diabetic Biobreeding/Worcester rat. J Immunol 146: 2990–2994
Held W, MacDonald HR, Weissman IL, Hess MW, Mueller C (1990) Genes encoding tumor necrosis factor α and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci USA 87: 2239–2243
Oschilewski U, Kiesel U, Kolb H (1985) Administration of silica prevents diabetes in BB-rats. Diabetes 34: 197–199
Lee KU, Amano K, Yoon JW (1988) Evidence for initial involvement of macrophage in development of insulitis in NOD mice. Diabetes 37: 989–991
Haskins K, McDuffie M (1990) Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T-cell clone. Science 249: 1433–1436
Mandrup-Poulsen T, Egeberg J, Nerup J, Bendtzen K, Nielsen JH, Dinarello CA (1987) Ultra-structural studies of time-course and cellular specificity of interleukin 1 mediated islet cytotoxicity. Acta Path Microbiol Immunol Scand (C) 95: 55–63
Helqvist S, Zumsteg UW, Spinas GA et al. (1991) Repetitive exposure of pancreatic islets to interleukin-1β. An in vitro model of prediabetes? Autoimmunity 10: 311–318
Wogensen LD, Kolb-Bachofen V, Christensen P (1990) Functional and morphological effects of interleukin-1β on the perfused rat pancreas. Diabetologia 33: 15–23
Wogensen L, Reimers J, Nerup J (1992) Repetitive in vivo treatment with human recombinant Interleukin 1β modify beta-cell function in normal rats. Diabetologia 35: 331–339
Helqvist S, Bouchelouche P, Andersen HU, Nerup J (1989) Modulation of calciumflux influences interleukin 1β effects on insulin release from isolated islets of Langerhans. Acta Endocrinol (Copenh) 121: 447–455
Eizirik DL, Welsh N, Hellerström C (1993) Predominance of stimulatory effects of interleukin-1β on isolated human pancreatic islets. J Clin Endo Metab 76: 399–403
Zumsteg U, Reimers JI, Pociot F et al. (1993) Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats. Diabetologia 36: 759–766
Andersen HU, Mandrup-Poulsen T, Egebjerg J, Helqvist S, Nerup J (1989) Genetically determined differences in newborn rat islet sensitivity to interleukin-1 in vitro: no association with the diabetes prone phenotype in the BB-rat. Acta Endocrinol (Copenh) 120: 92–98
Spinas GA, Mandrup-Poulsen T, Mølvig J et al. (1986) Low concentrations of interleukin-1 stimulate and high concentrations inhibit insulin release from isolated rat islets of Langerhans. Acta Endocrinol (Copenh) 113: 551–558
Palmer JP, Helqvist S, Spinas GA et al. (1989) Interaction of β -cell activity and IL-1 concentration and exposure time in isolated rat islets of Langerhans. Diabetes 38: 1211–1216
Helqvist S, Bouchelouche PN, Johannesen J, Nerup J (1990) Interleukin 1β increases the cytosolic free sodium concentration in isolated rat islets of Langerhans. Scand J Immunol 32: 53–58
Mandrup-Poulsen T, Spinas GA, Prowse SJ et al. (1987) Islet cytotoxicity of interleukin 1: influence of culture conditions and islet donor characteristics. Diabetes 36: 641–647
Sinkowitch L (1985) Intracellular pH modulates the generation of superoxide radicals by human neutrophils. J Clin Invest 76: 1079–1089
Helqvist S, Polla BS, Johannesen J, Nerup J (1991) Heat shock protein induction in rat pancreatic islets by recombinant human interleukin 1β. Diabetologia 34: 150–156
Asayama K, Kooy NW, Burr IM (1986) Effect of vitamin E deficiency and selenium deficiency on insulin secretory reserve and free radical scavenging systems in islets; decrease of islet manganosuperoxide dismutase. J Clin Lab Med 107: 464–495
Sumoski W, Baquerizo H, Rabinovitch A (1989) Oxygen free radical scavengers protect rat islet cells from damage by cytokines. Diabetologia 32: 792–796
Southern C, Schulster D, Green IC (1990) Inhibition of insulin secretion by interleukin-1β and tumor necrosis factor-α via an L-arginine-dependent nitric oxide generating mechanism. FEBS lett 276: 42–44
Fehsei K, Jalowy A, Qi S, Burkart V, Hartmann B, Kolb H (1993) Islet cell DNA is a target of inflammatory attack by nitric oxide. Diabetes 42: 496–500
Marietta MA (1993) Nitric oxide synthase structure and mechanism. J Biol Chem 268: 12231–12234
Lyons CR, Orloff GJ, Cunningham JM (1992) Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J Biol Chem 267: 6370–6374
Stadler J, Stefanovic-Racic M, Billiar TR et al. (1991) Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide. J Immunol 147: 3915–3920
Beasley D, Schwartz JH, Brenner BM (1991) Interleukin 1 induces prolonged L-arginine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells. J Clin Invest 87: 602–608
Andersen HU, Zumsteg U, Mose Larsen P et al. (1992) 2-D protein map of islets of Langerhans: effects of interleukin-1β and nicotinamide. Diabetologia 35 [Suppl 1]: A212 (Abstract)
Karlsen AE, Boel E, Cuartero BG et al. (1993) Cloning of an IL-1 inducible nitric oxide synthase isoform from rat islets also detected in cytokine exposed human islets and RIN cells. Endothelium 1 [Suppl]: S26
Gerling IC, Karlsen AE, Champman HD et al. (1994) The inducible nitric oxide synthase gene, Nos2, maps to mouse chromosome 11. Mammalian Genome, 5: 318–320
Kolb H, Kolb-Bachofen V (1992) Type 1 (insulin-dependent) diabetes mellitus and nitric oxide. Diabetologia 35: 796–797
Mandrup-Poulsen T, Corbett JA, McDaniel ML, Nerup J (1993) What are the types and cellular sources of free radicals in the pathogenesis of type 1 (insulin-dependent) diabetes mellitus? Diabetologia 36: 470–471
Kröncke K-D, Funda J, Berschick B, Kolb-Bachofen V (1991) Macrophage cytotoxicity towards isolated rat islet cells: neither lysis nor its protection by nicotinamide are beta-cell specific. Diabetologia 34: 232–238
Corbett JA, Wang JL, Sweetland MA, Lancaster Jr. JR, McDaniel ML (1992) IL-1β induces the formation of nitric oxide by β-cells purified from rodent islets of Langerhans: evidence for the β-cell as a source and site of action of nitric oxide. J Clin Invest 90: 2384–2391
Kleeman R, Rothe H, Kolb-Bachofen V et al. (1993) Transcription and translation of inducible nitric oxide synthase in the pancreas of prediabetic BB rats. FEBS lett 328: 9–12
Andersen HU, Jørgensen KH, Egeberg J, Mandrup-Poulsen T, Nerup J (1993) Nicotinamide reduces interleukin-1-induced nitric oxide production and inhibition of insulin release in rat islets of Langerhans. Acta Endocrinol (Copenh) 128 [Suppl 1] 4
Hammonds P, Beggs M, Beresford G, Espinal J, Clarke J, Mertz RJ (1990) Insulin-secreting β-cells possess specific receptors for interleukin-1β. FEBS lett 261: 97–100
Brawn K, Fridovich I (1981) DNA strand scission by enzymatically generated oxygen radicals. Arch Biochem Biophys 206: 414–419
Corbett JA, Lancaster Jr. JR, Sweetland MA, McDaniel ML (1991) 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 266: 21351–21354
Welsh N, Eizirik DL, Bendtzen K, Sandler S (1991) Interleukin-1β-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase. Endocrinology 129: 3167–3173
Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci (USA) 87: 1620–1624
Beckman JS, Carson M, Smith CD, Koppenol WH (1993) ALS, SOD and peroxynitrite. Nature 364: 584
Ghosh S, Palmer SM, Rodrigues NR et al. (1993) Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nature Genetics 4: 404–409
Crisa L, Mardes JP, Rossini AA (1992) Autoimmune diabetes in the BB-rat. Diabetes Metab Rev 8: 9–37
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nerup, J., Mandrap-Poulsen, T., Helqvist, S. et al. On the pathogenesis of IDDM. Diabetologia 37 (Suppl 2), S82–S89 (1994). https://doi.org/10.1007/BF00400830
Issue Date:
DOI: https://doi.org/10.1007/BF00400830