Diabetologia

, Volume 35, Issue 12, pp 1159–1164 | Cite as

Cellular and humoural autoimmunity markers in Type 2 (non-insulin-dependent) diabetic patients with secondary drug failure

  • A. V. Zavala
  • L. E. Fabiano de Bruno
  • A. I. Cardoso
  • A. H. Mota
  • M. Capucchio
  • E. Poskus
  • L. Fainboim
  • J. C. Basabe
Originals

Summary

In some cases patients with Type 2 (non-insulin-dependent) diabetes mellitus fail to respond to treatment with oral hypoglycaemic agents. These patients may respond in the same way as Type 1 (insulin-dependent) diabetic patients. Cellular immune aggression (defined as the capacity of peripheral mononuclear cells to inhibit stimulated insulin secretion by dispersed rat islet cells), insulin autoantibodies, C-peptide response and HLA antigens were determined in 31 Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents and in 22 control subjects. Nine (29.03%) of the 31 Type 2 diabetic patients showed positive cellular immune aggression (2 SD below control group) and 22 (70.97%) presented no cellular immune aggression. There was a relationship between positive cellular immune aggression and each of the following parameters: age, body mass index and microangiopathy. No correlation was found between positive cellular immune aggression and glycaemia, HbA1, blood lipids or atherosclerosis. Patients with positive cellular immune aggression showed a significantly lower glucagon-stimulated C-peptide response vs those with no cellular immune aggression. Within a sub-group of patients who had never been treated with insulin, insulin autoantibodies were present in four of six patients with positive cellular immune aggression. DR2 antigen was found with decreased frequency in patients whereas no DR3/DR4 heterozygotes were observed. Our data support the hypothesis that a group of Type 2 diabetic patients with secondary failure to oral hypoglycaemic agents presented autoimmunity towards pancreatic Beta cells.

Key words

Secondary drug failure C-peptide anti-Beta-cell autoimmunity humoural and cellular markers HLA 

References

  1. 1.
    Krall L, Bradley M (1962) Secondary failure in the treatment of diabetes mellitus with tolbutamide and with phenformine. Diabetes 11 [Suppl]: 88A (Abstract)Google Scholar
  2. 2.
    Mehnert H (1962) Clinical and experimental finding after five years treatment of diabetes with sulfonylureas. Diabetes 11 [Suppl]: 80A (Abstract)Google Scholar
  3. 3.
    Himsworth H (1986) Diabetes mellitus: a differentiation into insulin sensitive and insulin-insensitive types. Lancet I: 127–128Google Scholar
  4. 4.
    Liu C, Coulston A, Reaven G (1983) Does day long absolute hypoinsulinemia characterize the patients with non-insulin dependent diabetes mellitus? Metabolism 32: 754–756CrossRefPubMedGoogle Scholar
  5. 5.
    Gleichmann H, Zorcher B, Grenlich B et al. (1984) Correlation of islet cell antibodies and HLA-DR phenotypes with diabetes mellitus in adults. Diabetologia 27: 90–92CrossRefPubMedGoogle Scholar
  6. 6.
    Landin-Olsson M, Nilsson KO, Lernmark Å, Sundkvist G (1990) Islet cell antibodies and fasting C-peptide predict insulin requirement at diagnosis of diabetes mellitus. Diabetologia 33: 561–568PubMedGoogle Scholar
  7. 7.
    Groop L, Bottazzo G, Doniach D (1986) Islet cell antibodies identify latent type I diabetes in patients aged 35–75 at diagnosis. Diabetes 35: 237–241PubMedGoogle Scholar
  8. 8.
    Groop L, Pelkonen R, Roakimiej S, Bottazzo G, Doniach D (1986) Secondary failure treatment with oral antidiabetic agents in non-insulin-dependent diabetes. Diabetes Care 9: 129–132PubMedGoogle Scholar
  9. 9.
    Madsbad S, Krarup T, Christensen C (1981) Practical clinical value of the C-peptide response to glucagon stimulation in the choice of treatment in diabetes mellitus. Acta Med Scan 210: 153–155PubMedGoogle Scholar
  10. 10.
    Lacy PE, Kostianovsky M (1967) Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 16: 35–39PubMedGoogle Scholar
  11. 11.
    Ono J, Takaki R, Fukuma M (1977) Preparation of single cells from pancreatic islets, of adult rats by the use of dispase. Endocrinology Jpn 24: 265–270Google Scholar
  12. 12.
    Boitard C, Debray-Sachs M, Plouplard A, Assan R, Hamburger J (1981) Lymphocytes from diabetics suppress insulin release in vitro. Diabetologia 21: 41–46PubMedGoogle Scholar
  13. 13.
    Herbert V, Lau K, Gottlieb C, Bleicher SJ (1965) Coated charcoal immunoassay of insulin. J Clin Endocr Metab 25: 1375–1384PubMedGoogle Scholar
  14. 14.
    Linde S, Hansen B, Lernmark Å (1983) Preparation of stable radioiodinated polypeptide hormones and proteins using polyacrylamide gel electrophoresis. In: Langone JJ, Van Vunakis H (eds) Methods in enzymology, Vol 92. Academic Press, Orlando San Diego New York Austin London Montreal Sydney Tokyo Toronto, pp 305–309Google Scholar
  15. 15.
    Linde S, Hansen B, Sonne O, Holst JJ, Gliemann J (1981) Tyrosine A14 [125I] monoiodoinsulin. Preparation, biologic properties and long-term stability. Diabetes 30: 1–8Google Scholar
  16. 16.
    Palmer JP, Asplin CM, Clemons P et al. (1983) Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 222: 1337–1339PubMedGoogle Scholar
  17. 17.
    Terasaki PI, McClelland JD (1964) Microdroplet assay of human serum cytotoxins. Nature 204: 998–1000Google Scholar
  18. 18.
    Van Road JJ, Van Heeusen A, Pleon JS (1976) Simultaneous detection of two cell population by two-colour fluorescence and its application to the recognition of beta-cell determinants. Nature 262: 295–297PubMedGoogle Scholar
  19. 19.
    Rattcliffe JT (1969) Elements of mathematical statistics. Oxford University Press, LondonGoogle Scholar
  20. 20.
    Ruiz M, Puchulu F, Christensen A (1988) Genetic and humoral markers in IDDM patients and their families. In: Camerini-Davalos RA, Cole HS (eds) Advances in experimental medicine and biology: prediabetes, Vol 246. Plenum Press, New York London, pp 241–247Google Scholar
  21. 21.
    Basabe JC (1989) The immune system and islet function. In: Larkins R, Zimmet P, Chisholm D (eds) Diabetes 1988. Elsevier Science Publishers, Amsterdam, pp 37–44Google Scholar
  22. 22.
    Basabe JC, Fabiano de Bruno LE, Arata M (1988) Diabetic lymphocytes transfer and beta cell function. In: Camerini-Davalos RA, Cole HS (eds) Advances in experimental medicine and biology: prediabetes, Vol 246. Plenum Press, New York London, pp 101–108Google Scholar
  23. 23.
    Boitard C, Chatenaud LM, Debray-Sachs M (1982) In vitro inhibition of pancreatic beta-cell function by lymphocytes from diabetics with associated autoimmune disease: a T-cell phenomenon. J Immunol 129: 2529–2531PubMedGoogle Scholar
  24. 24.
    Wogensen L, Reimers J, Mandrup-Poulsen T, Nerup J (1991) Repeated intraperitoneal injections of interleukin 1 β induce glucose intolerance in normal rats. Acta Endocrinol (Copenh) 124: 470–478Google Scholar
  25. 25.
    Mandrup-Poulsen T, Helquist S, Molvig J, Wogensen L, Nerup J (1989) Cytokines as immune effector molecules in autoimmune diseases with special reference to insulin dependent diabetes mellitus. Autoimmunity 4: 191–218PubMedGoogle Scholar
  26. 26.
    Boitard C, Sai P, Debray-Sachs M, Assan R, Hamburger J (1984) Antipancreatic immunity: “in vitro” studies of cellular and humoral immune reactions directed toward pancreatic islet. Clin Exp Immunol 55: 571–580PubMedGoogle Scholar
  27. 27.
    Lang F, Maugendre D, Houssaint E, Charbonnel B, Sai P (1987) Cytoadherence of lymphocytes from type 1 diabetic subjects to insulin-secreting cells; marker of anti beta-cell cellular immunity. Diabetes 36: 1356–1364PubMedGoogle Scholar
  28. 28.
    Segain J, Valentin A, Bardet S et al. (1989) In vitro relationship of CD4 cells from type I diabetic patients and xenogenic beta-cell membranes. Diabetes 38: 634–640PubMedGoogle Scholar
  29. 29.
    Binder C, Faber O (1978) Residual β-cell function in children with diabetes. C-Peptide levels gives reliable information about the beta-cell reserve. Diabetes 27: 226–229PubMedGoogle Scholar
  30. 30.
    Wolf E, Spencer KM, Cudworth AG (1983) The genetic susceptibility to type 1 (insulin-dependent) diabetes: analysis of the HLA-DR association. Diabetologia 24: 224–230CrossRefPubMedGoogle Scholar
  31. 31.
    Groop L, Miettinen A, Groop P-H, Meri S, Koskimies S, Bottazzo GF (1988) Organ-specific autoimmunity and HLA-DR antigens as markers for beta-cell destruction in patients with type II diabetes. Diabetes 37: 99–103PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • A. V. Zavala
    • 1
  • L. E. Fabiano de Bruno
    • 3
  • A. I. Cardoso
    • 4
  • A. H. Mota
    • 2
  • M. Capucchio
    • 2
  • E. Poskus
    • 4
  • L. Fainboim
    • 2
  • J. C. Basabe
    • 3
  1. 1.Cátedra de Nutrición, Hospital de Clínicas “General José de San Martín”Universidad de Buenos AiresBuenos AiresArgentina
  2. 2.Laboratorio de Inmunogenética, Hospital de Clínicas “General José de San Martín”Universidad de Buenos AiresBuenos AiresArgentina
  3. 3.Centro de Investigaciones Endocrinólogicas (CEDIE)Hospital General de Niños “Dr. R. Gutierrez”Buenos AiresArgentina
  4. 4.Instituto de Estudios de la Inmunidad Humoral (CONICET-UBA)Buenos AiresArgentina

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