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Erschienen in: Acta Diabetologica 1/2016

01.02.2016 | Original Article

Prediction of type 1 diabetes in Sardinian schoolchildren using islet cell autoantibodies: 10-year follow-up of the Sardinian schoolchildren type 1 diabetes prediction study

verfasst von: Fernanda Velluzzi, Gianni Secci, Vincenzo Sepe, Catherine Klersy, Marion Shattock, Richard Foxon, Marco Songini, Stefano Mariotti, Mattia Locatelli, Gian Franco Bottazzo, Andrea Loviselli, The Sardinian Autoimmunity Study Group

Erschienen in: Acta Diabetologica | Ausgabe 1/2016

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Abstract

Aims

Stable genetic background makes individuals from the Mediterranean island of Sardinia ideal to define the predictive power of islet-related autoantibodies (IRAs): glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase-like antibodies (IA-2A), islet cell antibodies (ICA) to identify T1DM progressors. The aims of the present study were: (1) determination of IRAs reference limits in healthy non-diabetic Sardinian schoolchildren (SSc). (2) Predictive power evaluation of IRAs as single or combined determination to identify islet to identify T1DM progressors.

Methods

Between 1986 and 1994, 8448 SSc were tested for IRAs. All were followed up for 10 years. The predictive power of single or combination of IRAs was determined as hazard ratio (HR), sensitivity, specificity, area under the ROC curve, negative and positive predictive value (NPV, PPV).

Results

All 43 progressors to T1DM, but three showed at least one autoantibody positivity. HR for any single-autoantibody positivity was 55.3 times greater when compared to SSc negative for all IRAs. Any single autoantibody performed at least 64.9 % sensitivity with PPV always lower than 16 %. The best performing combination was ICA, plus IA-2A (showing 52.6 % sensitivity, 99.8 % specificity, 0.76 area under the ROC curve, 51.3 % PPV and 99.8 % NPV.

Conclusions

Determination of IRAs reference limits in healthy SSc by standard statistical methods is crucial to establish the power of IRAs as progression markers to T1DM. Our data offer a solid rationale for future testing of ICA and IA-2A as routine laboratory markers to identify individuals at high risk of T1DM in the general population.
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Literatur
1.
Zurück zum Zitat Hattersley AT (1997) Genes versus environment in insulin-dependent diabetes: the phoney war. Lancet 349:147–148CrossRefPubMed Hattersley AT (1997) Genes versus environment in insulin-dependent diabetes: the phoney war. Lancet 349:147–148CrossRefPubMed
2.
Zurück zum Zitat Ko KW, Yang SW, Cho NH (1994) The incidence of IDDM in Seoul from 1985 to 1988. Diabetes Care 17:1473–1475CrossRefPubMed Ko KW, Yang SW, Cho NH (1994) The incidence of IDDM in Seoul from 1985 to 1988. Diabetes Care 17:1473–1475CrossRefPubMed
3.
Zurück zum Zitat Soltesz G, Patterson CC, Dahlquist G (2007) Worldwide childhood type 1 diabetes incidence–what can we learn from epidemiology? Pediatr Diabetes 8(Suppl 6):6–14CrossRefPubMed Soltesz G, Patterson CC, Dahlquist G (2007) Worldwide childhood type 1 diabetes incidence–what can we learn from epidemiology? Pediatr Diabetes 8(Suppl 6):6–14CrossRefPubMed
4.
Zurück zum Zitat Green A, Gale EA, Patterson CC (1992) Incidence of childhood-onset insulin-dependent diabetes mellitus: the EURODIAB ACE study. Lancet 339:905–909CrossRefPubMed Green A, Gale EA, Patterson CC (1992) Incidence of childhood-onset insulin-dependent diabetes mellitus: the EURODIAB ACE study. Lancet 339:905–909CrossRefPubMed
5.
Zurück zum Zitat Songini M, Loche M, Muntoni S et al (1993) Increasing prevalence of juvenile onset type 1 (insulin-dependent) diabetes mellitus in Sardinia: the military service approach. Diabetologia 36:547–552CrossRefPubMed Songini M, Loche M, Muntoni S et al (1993) Increasing prevalence of juvenile onset type 1 (insulin-dependent) diabetes mellitus in Sardinia: the military service approach. Diabetologia 36:547–552CrossRefPubMed
6.
Zurück zum Zitat Casu A, Pascutto C, Bernardinelli L, Songini M (2004) Type 1 diabetes among sardinian children is increasing: the Sardinian diabetes register for children aged 0–14 years (1989–1999). Diabetes Care 27:1623–1629CrossRefPubMed Casu A, Pascutto C, Bernardinelli L, Songini M (2004) Type 1 diabetes among sardinian children is increasing: the Sardinian diabetes register for children aged 0–14 years (1989–1999). Diabetes Care 27:1623–1629CrossRefPubMed
7.
Zurück zum Zitat Casu A, Trucco M, Pietropaolo M (2005) A look to the future: prediction, prevention, and cure including islet transplantation and stem cell therapy. Pediatr Clin North Am 52:1779–1804CrossRefPubMed Casu A, Trucco M, Pietropaolo M (2005) A look to the future: prediction, prevention, and cure including islet transplantation and stem cell therapy. Pediatr Clin North Am 52:1779–1804CrossRefPubMed
8.
Zurück zum Zitat Cavalli-Sforza LL, Piazza P (1993) Human genomic diversity in Europe: a summary of recent research and prospects for the future. Eur J Hum Genet 1:3–18PubMed Cavalli-Sforza LL, Piazza P (1993) Human genomic diversity in Europe: a summary of recent research and prospects for the future. Eur J Hum Genet 1:3–18PubMed
9.
Zurück zum Zitat Cappello N, Rendine S, Griffo R et al (1996) Genetic analysis of Sardinia: I. data on 12 polymorphisms in 21 linguistic domains. Ann Hum Genet 60:125–141CrossRefPubMed Cappello N, Rendine S, Griffo R et al (1996) Genetic analysis of Sardinia: I. data on 12 polymorphisms in 21 linguistic domains. Ann Hum Genet 60:125–141CrossRefPubMed
10.
Zurück zum Zitat Bottazzo GF, Loviselli A, Velluzzi F et al (1997) The “Sardinia-IDDM study”: an attempt to unravel the cause of insulin-dependent diabetes mellitus in one of the countries with the highest incidence of the disease in the world. Ann Ist Super Sanita 33:417–424PubMed Bottazzo GF, Loviselli A, Velluzzi F et al (1997) The “Sardinia-IDDM study”: an attempt to unravel the cause of insulin-dependent diabetes mellitus in one of the countries with the highest incidence of the disease in the world. Ann Ist Super Sanita 33:417–424PubMed
11.
Zurück zum Zitat Bottazzo GF, Florin-Christensen A, Doniach D (1974) Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2:1279–1283CrossRefPubMed Bottazzo GF, Florin-Christensen A, Doniach D (1974) Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2:1279–1283CrossRefPubMed
12.
Zurück zum Zitat Palmer JP, Asplin CM, Clemons P et al (1983) Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 222:1337–1339CrossRefPubMed Palmer JP, Asplin CM, Clemons P et al (1983) Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 222:1337–1339CrossRefPubMed
13.
Zurück zum Zitat Baekkeskov S, Aanstoot HJ, Christgau S et al (1990) Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347:151–156CrossRefPubMed Baekkeskov S, Aanstoot HJ, Christgau S et al (1990) Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347:151–156CrossRefPubMed
14.
Zurück zum Zitat Payton MA, Hawkes CJ, Christie MR (1995) Relationship of the 37,000- and 40,000-M(r) tryptic fragments of islet antigens in insulin-dependent diabetes to the protein tyrosine phosphatase-like molecule IA-2 (ICA512). J Clin Invest 96:1506–1511PubMedCentralCrossRefPubMed Payton MA, Hawkes CJ, Christie MR (1995) Relationship of the 37,000- and 40,000-M(r) tryptic fragments of islet antigens in insulin-dependent diabetes to the protein tyrosine phosphatase-like molecule IA-2 (ICA512). J Clin Invest 96:1506–1511PubMedCentralCrossRefPubMed
15.
Zurück zum Zitat 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 37/40K autoantigen and a target of islet-cell antibodies. J Immunol 155:5419–5426PubMed 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 37/40K autoantigen and a target of islet-cell antibodies. J Immunol 155:5419–5426PubMed
16.
Zurück zum Zitat Seissler J, Hatziagelaki E, Scherbaum WA (2001) Modern concepts for the prediction of type 1 diabetes. Exp Clin Endocrinol Diabetes 109(Suppl 2):S304–S316CrossRefPubMed Seissler J, Hatziagelaki E, Scherbaum WA (2001) Modern concepts for the prediction of type 1 diabetes. Exp Clin Endocrinol Diabetes 109(Suppl 2):S304–S316CrossRefPubMed
17.
18.
Zurück zum Zitat LaGasse JM, Brantley MS, Leech NJ et al (2002) Successful prospective prediction of type 1 diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State Diabetes Prediction Study. Diabetes Care 25:505–511CrossRefPubMed LaGasse JM, Brantley MS, Leech NJ et al (2002) Successful prospective prediction of type 1 diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State Diabetes Prediction Study. Diabetes Care 25:505–511CrossRefPubMed
19.
Zurück zum Zitat Strebelow M, Schlosser M, Ziegler B, Rjasanowski I, Ziegler M (1999) Karlsburg type I diabetes risk study of a general population: frequencies and interactions of the four major type I diabetes-associated autoantibodies studied in 9419 schoolchildren. Diabetologia 42:661–670CrossRefPubMed Strebelow M, Schlosser M, Ziegler B, Rjasanowski I, Ziegler M (1999) Karlsburg type I diabetes risk study of a general population: frequencies and interactions of the four major type I diabetes-associated autoantibodies studied in 9419 schoolchildren. Diabetologia 42:661–670CrossRefPubMed
20.
Zurück zum Zitat Norris JM, Yin X, Lamb MM et al (2007) Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA 298:1420–1428CrossRefPubMed Norris JM, Yin X, Lamb MM et al (2007) Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA 298:1420–1428CrossRefPubMed
21.
Zurück zum Zitat Loviselli A, Velluzzi F, Mossa P et al (2001) The Sardinian Autoimmunity Study: 3. Studies on circulating antithyroid antibodies in Sardinian schoolchildren: relationship to goiter prevalence and thyroid function. Thyroid 11:849–857CrossRefPubMed Loviselli A, Velluzzi F, Mossa P et al (2001) The Sardinian Autoimmunity Study: 3. Studies on circulating antithyroid antibodies in Sardinian schoolchildren: relationship to goiter prevalence and thyroid function. Thyroid 11:849–857CrossRefPubMed
22.
Zurück zum Zitat Songini M, Bernardinelli L, Clayton D et al (1998) The Sardinian IDDM study: 1. Epidemiology and geographical distribution of IDDM in Sardinia during 1989 to 1994. Diabetologia 41:221–227CrossRefPubMed Songini M, Bernardinelli L, Clayton D et al (1998) The Sardinian IDDM study: 1. Epidemiology and geographical distribution of IDDM in Sardinia during 1989 to 1994. Diabetologia 41:221–227CrossRefPubMed
23.
Zurück zum Zitat Palmer JP, Wilkin TJ, Kurtz AB, Bonifacio E (1990) The third international workshop on the standardisation of insulin autoantibody measurement. Diabetologia 33:60–61CrossRefPubMed Palmer JP, Wilkin TJ, Kurtz AB, Bonifacio E (1990) The third international workshop on the standardisation of insulin autoantibody measurement. Diabetologia 33:60–61CrossRefPubMed
24.
Zurück zum Zitat Bonifacio E, Lernmark A, Dawkins RL (1988) Serum exchange and use of dilutions have improved precision of measurement of islet cell antibodies. J Immunol Methods 106:83–88CrossRefPubMed Bonifacio E, Lernmark A, Dawkins RL (1988) Serum exchange and use of dilutions have improved precision of measurement of islet cell antibodies. J Immunol Methods 106:83–88CrossRefPubMed
25.
Zurück zum Zitat Petersen JS, Hejnaes KR, Moody A et al (1994) Detection of GAD65 antibodies in diabetes and other autoimmune diseases using a simple radioligand assay. Diabetes 43:459–467CrossRefPubMed Petersen JS, Hejnaes KR, Moody A et al (1994) Detection of GAD65 antibodies in diabetes and other autoimmune diseases using a simple radioligand assay. Diabetes 43:459–467CrossRefPubMed
26.
Zurück zum Zitat Seissler J, Morgenthaler NG, Achenbach P et al (1996) Combined screening for to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM. The DENIS Study Group. Deutsche Nikotinamid Interventions-Studie. Diabetologia 39:1351–1356CrossRefPubMed Seissler J, Morgenthaler NG, Achenbach P et al (1996) Combined screening for to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM. The DENIS Study Group. Deutsche Nikotinamid Interventions-Studie. Diabetologia 39:1351–1356CrossRefPubMed
27.
Zurück zum Zitat Verge CF, Stenger D, Bonifacio E et al (1998) Combined use of (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes: combinatorial islet autoantibody workshop. Diabetes 47:1857–1866CrossRefPubMed Verge CF, Stenger D, Bonifacio E et al (1998) Combined use of (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes: combinatorial islet autoantibody workshop. Diabetes 47:1857–1866CrossRefPubMed
28.
Zurück zum Zitat Reed AH, Henry RJ, Mason WB (1971) Influence of statistical method used on the resulting estimate of normal range. Clin Chem 17:275–284PubMed Reed AH, Henry RJ, Mason WB (1971) Influence of statistical method used on the resulting estimate of normal range. Clin Chem 17:275–284PubMed
29.
Zurück zum Zitat American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33(Suppl 1): S62–S69 American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33(Suppl 1): S62–S69
30.
Zurück zum Zitat Frongia O, Mastinu F, Sechi GM (1997) Prevalence and 4-year incidence of insulin-dependent diabetes mellitus in the province of Oristano (Sardinia, Italy). Acta Diabetol 34:199–205CrossRefPubMed Frongia O, Mastinu F, Sechi GM (1997) Prevalence and 4-year incidence of insulin-dependent diabetes mellitus in the province of Oristano (Sardinia, Italy). Acta Diabetol 34:199–205CrossRefPubMed
31.
Zurück zum Zitat Bruining GJ, Molenaar JL, Grobbee DE et al (1989) Ten-year follow-up study of islet-cell antibodies and childhood diabetes mellitus. Lancet 1:1100–1103CrossRefPubMed Bruining GJ, Molenaar JL, Grobbee DE et al (1989) Ten-year follow-up study of islet-cell antibodies and childhood diabetes mellitus. Lancet 1:1100–1103CrossRefPubMed
32.
Zurück zum Zitat Schatz D, Krischer J, Horne G et al (1994) Islet cell antibodies predict insulin-dependent diabetes in United States school age children as powerfully as in unaffected relatives. J Clin Invest 93:2403–2407PubMedCentralCrossRefPubMed Schatz D, Krischer J, Horne G et al (1994) Islet cell antibodies predict insulin-dependent diabetes in United States school age children as powerfully as in unaffected relatives. J Clin Invest 93:2403–2407PubMedCentralCrossRefPubMed
33.
Zurück zum Zitat Levy-Marchal C, Dubois F, Noel M, Tichet J, Czernichow P (1995) Immunogenetic determinants and prediction of IDDM in French schoolchildren. Diabetes 44:1029–1032CrossRefPubMed Levy-Marchal C, Dubois F, Noel M, Tichet J, Czernichow P (1995) Immunogenetic determinants and prediction of IDDM in French schoolchildren. Diabetes 44:1029–1032CrossRefPubMed
34.
Zurück zum Zitat Genovese S, Bingley PJ, Bonifacio E et al (1994) Combined analysis of IDDM-related autoantibodies in healthy schoolchildren. Lancet 10. 344(8924):756CrossRef Genovese S, Bingley PJ, Bonifacio E et al (1994) Combined analysis of IDDM-related autoantibodies in healthy schoolchildren. Lancet 10. 344(8924):756CrossRef
35.
Zurück zum Zitat Bonifacio E, Genovese S, Braghi S et al (1995) Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity. Diabetologia 38(7):816–822CrossRefPubMed Bonifacio E, Genovese S, Braghi S et al (1995) Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity. Diabetologia 38(7):816–822CrossRefPubMed
36.
Zurück zum Zitat Bingley PJ, Bonifacio E, Williams AJ et al (1997) Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes 46(11):1701–1710CrossRefPubMed Bingley PJ, Bonifacio E, Williams AJ et al (1997) Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes 46(11):1701–1710CrossRefPubMed
37.
Zurück zum Zitat Samuelsson U, Sundkvist G, Borg H, Fernlund P, Ludvigsson J (2001) Islet autoantibodies in the prediction of diabetes in school children. Diabetes Res Clin Pract 51:51–57CrossRefPubMed Samuelsson U, Sundkvist G, Borg H, Fernlund P, Ludvigsson J (2001) Islet autoantibodies in the prediction of diabetes in school children. Diabetes Res Clin Pract 51:51–57CrossRefPubMed
38.
Zurück zum Zitat Kulmala P, Rahko J, Savola K et al (2001) Beta-cell autoimmunity, genetic susceptibility, and progression to type 1 diabetes in unaffected schoolchildren. Diabetes Care 24:171–173CrossRefPubMed Kulmala P, Rahko J, Savola K et al (2001) Beta-cell autoimmunity, genetic susceptibility, and progression to type 1 diabetes in unaffected schoolchildren. Diabetes Care 24:171–173CrossRefPubMed
41.
Zurück zum Zitat Jimenez-Gonzalez M, Jaques F, Rodriguez S et al (2013) Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model. Diabetologia 56:838–846CrossRefPubMed Jimenez-Gonzalez M, Jaques F, Rodriguez S et al (2013) Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model. Diabetologia 56:838–846CrossRefPubMed
Metadaten
Titel
Prediction of type 1 diabetes in Sardinian schoolchildren using islet cell autoantibodies: 10-year follow-up of the Sardinian schoolchildren type 1 diabetes prediction study
verfasst von
Fernanda Velluzzi
Gianni Secci
Vincenzo Sepe
Catherine Klersy
Marion Shattock
Richard Foxon
Marco Songini
Stefano Mariotti
Mattia Locatelli
Gian Franco Bottazzo
Andrea Loviselli
The Sardinian Autoimmunity Study Group
Publikationsdatum
01.02.2016
Verlag
Springer Milan
Erschienen in
Acta Diabetologica / Ausgabe 1/2016
Print ISSN: 0940-5429
Elektronische ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-015-0751-y

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