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
Avoid common mistakes on your manuscript.
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