Acta Diabetologica

, Volume 50, Issue 2, pp 233–239 | Cite as

First-degree relatives of persons with type 1 diabetes: insulin resistance and enterovirus infection are associated with different patterns of islet cell autoimmunity

  • Ileana Cubas-Dueñas
  • Eduardo Cabrera-Rode
  • Luis Sarmiento
  • Gisela Molina
  • Magilé Fonseca
  • Celeste Arranz
  • Emma Domínguez
  • Pedro González
  • Manuel Vera
  • Oscar Díaz-Horta
Original Article

Abstract

Type 1 diabetes (T1D) results from the interaction of genetic and environmental factors. Previous studies indicate an association between detection of Enterovirus (EV) genome in blood and the clinical onset of T1D. Insulin resistance can also represent a risk factor for progression to clinically overt T1D. This study aimed at evaluating whether there is association between both EV infection and insulin resistance with islet autoantibodies in first-degree relatives of persons with type 1 diabetes. We collected sera from 94 first-degree relatives with (32) or without (64) islet cell antibodies (ICA) from the Cuban T1D prediction program. Blood glucose and insulin concentrations were determined. Antibodies to GAD65 and IA-2 were determined by radioimmunoassay. Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). EV-RNA was detected in serum using a highly sensitive reverse transcriptase-polymerase chain reaction method. The occurrence of EV-RNA was higher in ICA-positive relatives than in ICA-negative ones [15.6% (5/32) vs. 1.6% (1/62), P = 0.016]. GAD65 autoantibodies were more frequent in subjects with insulin resistance [34.5% (10/29) vs. 13.9% (9/65), P = 0.028] as defined by the HOMA-IR value. GAD65 autoantibodies also positively correlated with HOMA-IR (r.bis = 0.28, P < 0.01). IA-2 autoantibodies did correlate neither with EV-RNA nor with insulin resistance. There was no association between the presence of EV-RNA and insulin resistance. Our data suggest that enterovirus infection and insulin resistance are two independent events associated with ICA and GAD65 autoantibodies, respectively. These observations support the multifactorial nature of T1D.

Keywords

Insulin resistance Enterovirus infection Islet cell antibodies GAD65 autoantibodies IA-2 autoantibodies 

References

  1. 1.
    Sarmiento-Pérez L, Cabrera-Rode E (eds) (2007) Enterovirus infections and type 1 diabetes mellitus. Nova Science Publishers, New York, pp 1–187Google Scholar
  2. 2.
    American Diabetes Association (2011) Diagnosis and classification of diabetes mellitus. Diabetes Care 34(Suppl 1):S62–S69CrossRefGoogle Scholar
  3. 3.
    Couper JJ, Donaghue KC (2009) Diabetes stages in children and adolescents. Pediatric Diabetes 10(Suppl 12):13–16PubMedCrossRefGoogle Scholar
  4. 4.
    Wenzlau JM, Moua O, Sarkar SA, Yu L, Rewers M, Eisenbarth GS et al (2008) S1C30A8 is a major target of humoral autoimmunity in type 1 diabetes and a predictive marker in prediabetes. Ann NY Acad Sci 1150:256–259PubMedCrossRefGoogle Scholar
  5. 5.
    Richer M, Horwits M (2008) Viral infections in the pathogenesis of autoimmune diseases: focus on type 1 diabetes. Front Biosci 13:4241–4257PubMedCrossRefGoogle Scholar
  6. 6.
    Uriarte A, Cabrera Rode E, Ventura R, Vargas J (1990) Abnormalities of specific pancreatic immunity in children infected by Echo-4 virus. Rev Cubana Pediatria 3:359–362Google Scholar
  7. 7.
    Uriarte A, Molina G, Cabrera Rode E, Ventura R, Vargas J, Vera M (1991) Prospective study in children with high risk of type 1 diabetes after infection by echo 4 virus (1986–1989). Rev Cubana Endocrinol 2:34–43Google Scholar
  8. 8.
    Díaz Horta O, Bello M, Cabrera Rode E, Suárez J, Mas P, García I et al (2001) Echovirus 4 and type 1 diabetes mellitus. Autoimmunity 34:275–281PubMedCrossRefGoogle Scholar
  9. 9.
    Cabrera-Rode E, Sarmiento L, Tiberti C, Molina G, Barrios J, Hernandez D et al (2003) Type 1 diabetes islet associated antibodies in subjects infected by echovirus 16. Diabetologia 46:1348–1353PubMedCrossRefGoogle Scholar
  10. 10.
    Cabrera-Rode E, Sarmiento L, Molina G, Perez C, Arranz C, Galvan JA et al (2005) Islet cell related antibodies and type 1 diabetes associated with echovirus 30 epidemic: a case report. J Med Virol 76:373–377PubMedCrossRefGoogle Scholar
  11. 11.
    Sarmiento L, Cabrera-Rode E, Lekuleni L, Cuba I, Molina G, Fonseca M et al (2007) Occurrence of enterovirus RNA in serum of children with newly diagnosed type 1 diabetes and islet cell autoantibody-positive subjects in a population with a low incidence of type 1 diabetes. Autoimmunity 40:540–545PubMedCrossRefGoogle Scholar
  12. 12.
    Fourlanos S, Narendran P, Byrnes GB, Colman PG, Harrison LC (2004) Insulin resistance is a risk factor for progression to type 1 diabetes. Diabetologia 47:1661–1667PubMedCrossRefGoogle Scholar
  13. 13.
    Bingley PJ, Mahon JL, Gale EA (2008) Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT). Diabetes Care 31:146–150PubMedCrossRefGoogle Scholar
  14. 14.
    Cabrera-Rode E, Marichal S, Parlá J, Arranz C, González R, Pérez C et al (2010) Frequency and characteristics of metabolic syndrome and insulin resistance in the first-degree relatives of persons with type 1 diabetes. Endocrinol Nutr 57:311–321PubMedCrossRefGoogle Scholar
  15. 15.
    Cabrera-Rode E, Molina G, Arranz C, Vera M, Gonzalez P, Suarez R et al (2006) Effect of standard nicotinamide in the prevention of type 1 diabetes in first degree relatives of persons with type 1 diabetes. Autoimmunity 39:333–340PubMedCrossRefGoogle Scholar
  16. 16.
    Pilcher C, Elliott RB (1984) Improved sensitivity of islet cell cytoplasmic antibody assay in diabetics. Lancet 1:1352PubMedCrossRefGoogle Scholar
  17. 17.
    Schmidli RS, Colman PG, Bonifacio E (1995) Disease sensitivity and specificity of 52 assays for glutamic acid decarboxylase antibodies. The second international GADAb workshop. Diabetes 44:636–640PubMedCrossRefGoogle Scholar
  18. 18.
    Bonifacio E, Lampasona V, Genovese S, Ferrari M, Bosi E (1995) Identification of protein tyrosine phosphatase-like IA2 (islet cell antigen 512) as the insulin-dependent diabetes-related 37/40 k autoantigen and a target of islet-cell antibodies. J Immunol 155:5419–5426PubMedGoogle Scholar
  19. 19.
    Halonen P, Rocha E, Hierholzen J (1995) Detection of enteroviruses and rhinoviruses in clinical specimens by PCR and liquid-phase hybridization. J Clin Microbiol 33:648–653PubMedGoogle Scholar
  20. 20.
    Yang CF, De L, Yang SJ, Ruiz Gomez J, Cruz JR, Holloway BP et al (1992) Genotype-specific in vitro amplification of sequences of the wild type 3 polioviruses from Mexico and Guatemala. Virus Res 24:277–296PubMedCrossRefGoogle Scholar
  21. 21.
    Kilpatrick DR, Nottay B, Yang CF, Yang SJ, Da Silva E, Penaranda S et al (1998) Serotype-specific identification of polioviruses by PCR using primers containing mixed-base or deoxyinosine residues at positions of codon degeneracy. J Clin Microbiol 36:352–357PubMedGoogle Scholar
  22. 22.
    Sarmiento L, Avalos I, Ramos Y, Mas P, Bello M, Palomera R (2000) Rapid detection of enterovirus by direct method of polymerase chain reaction. Rev Cubana Med Trop 52:15–20Google Scholar
  23. 23.
    Trinder P (1969) Determination of glucose oxidase with one alternative oxygen acceptor. Ann Clin Biochem 6:24–27Google Scholar
  24. 24.
    Arranz Calzado C, González Suárez R (1988) Utilización de un método rápido para la separación de la hormona libre y unida en el radioinmunoensayo de insulina. Rev. Cubana Invest Biomed 7:150–156Google Scholar
  25. 25.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in men. Diabetologia 28:412–419PubMedCrossRefGoogle Scholar
  26. 26.
    Arranz C, González RM, Álvarez A, Rodríguez B, Reyes A (2010) Reference criteria for insulin secretion indicators and of the lipid parameters in a hospital mixed population. Rev Cubana Endocrinol 21:1–12Google Scholar
  27. 27.
    Chen PY, Popovich PM (2002) Correlation: parametric and nonparametric measures. Sage Publications, Thousand Oaks, CAGoogle Scholar
  28. 28.
    Salminen KK, Vuorinen T, Oikarinen S, Helminen M, Simell S, Knip M et al (2004) Isolation of enterovirus strains from children with preclinical type 1 diabetes. Diabet Med 21:156–164PubMedCrossRefGoogle Scholar
  29. 29.
    Coutant R, Carel JC, Lebon P, Bougneres PF, Palmer P, Cantero-Aguilar L (2002) Detection of enterovirus RNA sequences in serum samples from autoantibody-positive subjects at risk for diabetes. Diabet Med 19:968–969PubMedCrossRefGoogle Scholar
  30. 30.
    Moya-Suri V, Schlosser M, Zimmermann K, Rjasanowski I, Gurtler L, Mentel R (2005) Enterovirus RNA sequences in sera of school children in the general population and their association with type 1-diabetes-associated autoantibodies. J Med Microbiol 54:879–883PubMedCrossRefGoogle Scholar
  31. 31.
    Lönnrot M, Salminen K, Knip M, Savola K, Kulmala P, Leinikki P et al (2000) Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group. J Med Virol 61:214–220PubMedCrossRefGoogle Scholar
  32. 32.
    Sadeharju K, Hamalainen AM, Knip M, Lonnrot M, Koskela P, Virtanen SM et al (2003) Enterovirus infections as a risk factor for type I diabetes: virus analyses in a dietary intervention trial. Clin Exp Immunol 132:271–277PubMedCrossRefGoogle Scholar
  33. 33.
    Isermann B, Ritzel R, Zorn M, Schilling T, Nawroth PP (2007) Autoantibodies in diabetes mellitus: current utility and perspectives. Exp Clin Endocrinol Diabetes 115:483–490PubMedCrossRefGoogle Scholar
  34. 34.
    Hela J, Sauter P, Sane F, Goffard A, Gharbi J, Hober D (2010) Enterovirus and type 1 diabetes: towards a better understanding of the relationship. Rev Med Virol 20:265–280CrossRefGoogle Scholar
  35. 35.
    Pallansch M, Raymond P (2001) Enteroviruses: polioviruses, coxsackieviruses, echoviruses and newer enteroviruses. In: Knipe D, Howlen P, Griffin D (eds) Fields virology, 3rd edn. Lippincott Raven Publisher, Philadelphia, pp 123–775Google Scholar
  36. 36.
    Filippi CM, von Herrath MG (2000) Viral trigger for type 1 diabetes: pros and cons. Diabetes 57:2863–2871CrossRefGoogle Scholar
  37. 37.
    Björk E, Kämpe O, Karlsson FA, Pipeleers DG, Anderson A, Hellerström C et al (1992) Glucose regulation of the autoantigen GAD65 in human pancreatic islet. J Clin Endocrinol Metab 75:1574–1576PubMedCrossRefGoogle Scholar
  38. 38.
    Achenbach P, Warncke K, Reiter J, Naserke HE, Williams AJK, Bingley PJ et al (2004) Stratification of type 1 diabetes risk on the basis of islet autoantibodies characteristics. Diabetes 53:384–392PubMedCrossRefGoogle Scholar
  39. 39.
    Bruining GJ (2000) Association between infant growth before onset of juvenile type-1 diabetes and autoantibodies to IA-2. Netherlands Kolibrie study group of childhood diabetes. Lancet 356:655–656PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Ileana Cubas-Dueñas
    • 1
  • Eduardo Cabrera-Rode
    • 1
  • Luis Sarmiento
    • 2
  • Gisela Molina
    • 1
  • Magilé Fonseca
    • 2
  • Celeste Arranz
    • 3
  • Emma Domínguez
    • 3
  • Pedro González
    • 4
  • Manuel Vera
    • 3
  • Oscar Díaz-Horta
    • 1
  1. 1.Department of Immunology and Genetics on DiabetesNational Institute of EndocrinologyHavanaCuba
  2. 2.Department of Virology“Pedro Kouri” Tropical Medicine InstituteHavanaCuba
  3. 3.National Institute of EndocrinologyHavanaCuba
  4. 4.“William Soler” HospitalHavanaCuba

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