Type 1 Diabetes-related Autoantibodies in Different Forms of Diabetes

Author(s): Elin Pettersen Sørgjerd*.

Journal Name: Current Diabetes Reviews

Volume 15 , Issue 3 , 2019

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Abstract:

Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.

Keywords: Autoimmune diabetes, LADA, GADA; IA-2A, IAA, ZnT8A, Type 2 diabetes, Type 1 diabetes.

[1]
MacCuish AC, Irvine WJ, Barnes EW, Duncan LJ. Antibodies to pancreatic islet cells in insulin-dependent diabetics with coexistent autoimmune disease. Lancet 1974; 2: 1529-31.
[2]
Baekkeskov S, Aanstoot HJ, Christgau S, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990; 347: 151-6.
[3]
Wenzlau JM, Juhl K, Yu L, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci USA 2007; 104: 17040-5.
[4]
Palmer JP, Asplin CM, Clemons P, et al. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 1983; 222: 1337-9.
[5]
Rabin DU, Pleasic SM, Shapiro JA, et al. Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases. J Immunol 1994; 152: 3183-8.
[6]
Wenzlau JM, Hutton JC. Novel diabetes autoantibodies and prediction of type 1 diabetes. Curr Diabetes Rev 2013; 13: 608-15.
[7]
Regnell SE, Lernmark A. Early prediction of autoimmune (type 1) diabetes. Diabetologia 2017; 60: 1370-81.
[8]
Lampasona V, Liberati D. Islet Autoantibodies. Curr Diabetes Rev 2016; 16: 53.
[9]
Itariu BK, Stulnig TM. Autoimmune aspects of type 2 diabetes mellitus - a mini-review. Gerontology 2014; 60: 189-96.
[10]
van Deutekom AW, Heine RJ, Simsek S. The islet autoantibody titres: their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes mellitus. Diabet Med 2008; 25: 117-25.
[11]
Krischer JP, Lynch KF, Schatz DA, et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia 2015; 58: 980-7.
[12]
Ilonen J, Lempainen J, Hammais A, et al. Primary islet autoantibody at initial seroconversion and autoantibodies at diagnosis of type 1 diabetes as markers of disease heterogeneity. Pediatr Diabetes 2017.
[13]
Bosi E, Boulware DC, Becker DJ, et al. Impact of age and antibody type on progression from single to multiple autoantibodies in type 1 diabetes relatives. J Clin Endocrinol Metab 2017; 102: 2881-6.
[14]
Bingley PJ, Boulware DC, Krischer JP. Type 1 Diabetes TrialNet Study G. The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes. Diabetologia 2016; 59: 542-9.
[15]
Sorgjerd EP, Skorpen F, Kvaloy K, Midthjell K, Grill V. Time dynamics of autoantibodies are coupled to phenotypes and add to the heterogeneity of autoimmune diabetes in adults: the HUNT study, Norway. Diabetologia 2012; 55: 1310-8.
[16]
Knip M, Korhonen S, Kulmala P, et al. Prediction of type 1 diabetes in the general population. Diabetes Care 2010; 33: 1206-12.
[17]
Incani M, Serafini C, Satta C, et al. High prevalence of diabetes-specific autoimmunity in first-degree relatives of Sardinian patients with type 1 diabetes. Diabetes Metab Res Rev 2017; 33.
[18]
Till AM, Kenk H, Rjasanowski I, et al. Autoantibody-defined risk for Type 1 diabetes mellitus in a general population of schoolchildren: results of the Karlsburg Type 1 Diabetes Risk Study after 18 years. Diabet Med 2015; 32: 1008-16.
[19]
Velluzzi F, Secci G, Sepe V, et al. 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. Acta Diabetol 2016; 53: 73-9.
[20]
Ruige JB, Batstra MR, Aanstoot HJ, et al. Low prevalence of antibodies to GAD65 in a 50- to 74-year-old general Dutch population. The Hoorn Study. Diabetes Care 1997; 20: 1108-10.
[21]
Lundgren VM, Isomaa B, Lyssenko V, et al. GAD antibody positivity predicts type 2 diabetes in an adult population. Diabetes 2010; 59: 416-22.
[22]
Siljander HT, Veijola R, Reunanen A, Virtanen SM, Akerblom HK, Knip M. Prediction of type 1 diabetes among siblings of affected children and in the general population. Diabetologia 2007; 50: 2272-5.
[23]
Sorgjerd EP, Thorsby PM, Torjesen PA, Skorpen F, Kvaloy K, Grill V. Presence of anti-GAD in a non-diabetic population of adults; time dynamics and clinical influence: results from the HUNT study. BMJ 2015; 3: e000076.
[24]
Dabelea D, Ma Y, Knowler WC, et al. Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program. Diabet Med 2014; 31: 1064-8.
[25]
Mendivil CO, Toloza FJ, Ricardo-Silgado ML, et al. Antibodies against glutamic acid decarboxylase and indices of insulin resistance and insulin secretion in nondiabetic adults: a cross-sectional study. Diabetes Metab Syndr Obes 2017; 10: 179-85.
[26]
Ong YH, Koh WCA, Ng ML, et al. Glutamic acid decarboxylase and islet antigen 2 antibody profiles in people with adult-onset diabetes mellitus: a comparison between mixed ethnic populations in Singapore and Germany. Diabet Med 2017; 34: 1145-53.
[27]
Hawa MI, Buchan AP, Ola T, et al. LADA and CARDS: a prospective study of clinical outcome in established adult-onset autoimmune diabetes. Diabetes Care 2014; 37: 1643-9.
[28]
Radtke MA, Midthjell K, Nilsen TI, Grill V. Heterogeneity of patients with latent autoimmune diabetes in adults: linkage to autoimmunity is apparent only in those with perceived need for insulin treatment: results from the Nord-Trondelag Health (HUNT) study. Diabetes Care 2009; 32: 245-50.
[29]
Kasuga A, Maruyama T, Ozawa Y, et al. Antibody to the M(r) 65,000 isoform of glutamic acid decarboxylase are detected in non-insulin-dependent diabetes in Japanese. J Autoimmun 1996; 9: 105-11.
[30]
Zhou Z, Xiang Y, Ji L, et al. Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): A nationwide, multicenter, clinic-based cross-sectional study. Diabetes 2013; 62: 543-50.
[31]
Haller-Kikkatalo K, Pruul K, Kisand K, Nemvalts V, Reimand K, Uibo R. GADA and anti-ZnT8 complicate the outcome of phenotypic type 2 diabetes of adults. Eur J Clin Invest 2015; 45: 255-62.
[32]
Zaharieva ET, Velikova TV, Tsakova AD, Kamenov ZA. Prevalence of positive diabetes-associated autoantibodies among type 2 diabetes and related metabolic and inflammatory differences in a sample of the bulgarian population. J Diabetes Res 2017; 2017: 9016148.
[33]
Hawa MI, Kolb H, Schloot N, et al. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care 2013; 36: 908-13.
[34]
Steck AK, Vehik K, Bonifacio E, et al. Predictors of progression from the appearance of islet autoantibodies to early childhood diabetes: The Environmental Determinants of Diabetes in the Young (TEDDY). Diabetes Care 2015; 38: 808-13.
[35]
Steck AK, Dong F, Waugh K, et al. Predictors of slow progression to diabetes in children with multiple islet autoantibodies. J Autoimmun 2016; 72: 113-7.
[36]
Endesfelder D, Hagen M, Winkler C, et al. A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children. Diabetologia 2016; 59: 2172-80.
[37]
Achenbach P, Hummel M, Thumer L, Boerschmann H, Hofelmann D, Ziegler AG. Characteristics of rapid vs. slow progression to type 1 diabetes in multiple islet autoantibody-positive children. Diabetologia 2013; 56: 1615-22.
[38]
Pollanen PM, Lempainen J, Laine AP, et al. Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility. Diabetologia 2017; 60: 1284-93.
[39]
Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 2013; 309: 2473-9.
[40]
Lampasona V, Petrone A, Tiberti C, et al. Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes: Non Insulin Requiring Autoimmune Diabetes (NIRAD) 4. Diabetes Care 2010; 33: 104-8.
[41]
Kong YH, Kim MS, Lee DY. Comparison of the prevalence of islet autoantibodies according to age and disease duration in patients with type 1 diabetes mellitus. Ann Pediatr Endocrinol Metab 2013; 18: 65-70.
[42]
Tuomi T, Carlsson A, Li H, et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 1999; 48: 150-7.
[43]
Zampetti S, Campagna G, Tiberti C, et al. High GADA titer increases the risk of insulin requirement in LADA patients: A 7-year follow-up (NIRAD study 7). Eur J Endocrinol 2014; 171: 697-704.
[44]
Pettersen E, Skorpen F, Kvaloy K, Midthjell K, Grill V. Genetic heterogeneity in latent autoimmune diabetes is linked to various degrees of autoimmune activity: Results from the Nord-Trondelag Health Study. Diabetes 2010; 59: 302-10.
[45]
Liu L, Li X, Xiang Y, et al. Latent autoimmune diabetes in adults with low-titer GAD antibodies: Similar disease progression with type 2 diabetes: a nationwide, multicenter prospective study (LADA China Study 3). Diabetes Care 2015; 38: 16-21.
[46]
Vehik K, Lynch KF, Schatz DA, et al. Reversion of beta-cell autoimmunity changes risk of type 1 diabetes: TEDDY Study. Diabetes Care 2016; 39: 1535-42.
[47]
Desai M, Cull CA, Horton VA, et al. GAD autoantibodies and epitope reactivities persist after diagnosis in latent autoimmune diabetes in adults but do not predict disease progression: UKPDS 77. Diabetologia 2007; 50: 2052-60.
[48]
Borg H, Gottsater A, Fernlund P, Sundkvist G. A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes 2002; 51: 1754-62.
[49]
Huang G, Yin M, Xiang Y, et al. Persistence of glutamic acid decarboxylase antibody (GADA) is associated with clinical characteristics of latent autoimmune diabetes in adults: A prospective study with 3-year follow-up. Diabetes Metab Res Rev 2016; 32: 615-22.
[50]
Brooks-Worrell BM, Boyko EJ, Palmer JP. Impact of islet autoimmunity on the progressive beta-cell functional decline in type 2 diabetes. Diabetes Care 2014; 37: 3286-93.
[51]
Landin-Olsson M. Latent autoimmune diabetes in adults. Ann N Y Acad Sci 2002; 958: 112-6.
[52]
Torn C, Mueller PW, Schlosser M, Bonifacio E, Bingley PJ. Diabetes antibody standardization program: Evaluation of assays for autoantibodies to glutamic acid decarboxylase and islet antigen-2. Diabetologia 2008; 51: 846-52.
[53]
Schlosser M, Mueller PW, Torn C, Bonifacio E, Bingley PJ. Diabetes Antibody Standardization Program: Evaluation of assays for insulin autoantibodies. Diabetologia 2010; 53: 2611-20.
[54]
Lampasona V, Schlosser M, Mueller PW, et al. Diabetes antibody standardization program: First proficiency evaluation of assays for autoantibodies to zinc transporter 8. Clin Chem 2011; 57: 1693-702.
[55]
Seissler J, de Sonnaville JJ, Morgenthaler NG, et al. Immunological heterogeneity in type I diabetes: Presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease. Diabetologia 1998; 41: 891-7.
[56]
Curnock RM, Reed CR, Rokni S, Broadhurst JW, Bingley PJ, Williams AJ. Insulin autoantibody affinity measurement using a single concentration of unlabelled insulin competitor discriminates risk in relatives of patients with type 1 diabetes. Clin Exp Immunol 2012; 167: 67-72.
[57]
Krause S, Chmiel R, Bonifacio E, et al. IA-2 autoantibody affinity in children at risk for type 1 diabetes. Clin Immunol 2012; 145: 224-9.
[58]
Mayr A, Schlosser M, Grober N, et al. GAD autoantibody affinity and epitope specificity identify distinct immunization profiles in children at risk for type 1 diabetes. Diabetes 2007; 56: 1527-33.
[59]
Hampe CS, Kockum I, Landin-Olsson M, et al. GAD65 antibody epitope patterns of type 1.5 diabetic patients are consistent with slow-onset autoimmune diabetes. Diabetes Care 2002; 25: 1481-2.
[60]
Kobayashi T, Tanaka S, Okubo M, Nakanishi K, Murase T, Lernmark A. Unique epitopes of glutamic acid decarboxylase autoantibodies in slowly progressive type 1 diabetes. J Clin Endocrinol Metab 2003; 88: 4768-75.
[61]
Achenbach P, Hawa MI, Krause S, et al. Autoantibodies to N-terminally truncated GAD improve clinical phenotyping of individuals with adult-onset diabetes: Action LADA 12. Diabetologia 2018; 61: 1644-9.
[62]
Schloot NC, Pham MN, Hawa MI, et al. Inverse relationship between organ-specific autoantibodies and systemic immune mediators in type 1 diabetes and type 2 diabetes: Action LADA 11. Diabetes Care 2016; 39: 1932-9.
[63]
Fleiner HF, Bjoro T, Midthjell K, Grill V, Asvold BO. Prevalence of thyroid dysfunction in autoimmune and type 2 diabetes: the population-based HUNT study in Norway. J Clin Endocrinol Metab 2016; 101: 669-77.
[64]
Nederstigt C, Corssmit EP, de Koning EJ, Dekkers OM. Incidence and prevalence of thyroid dysfunction in type 1 diabetes. J Diabetes Complications 2016; 30: 420-5.
[65]
Sacks DB, Arnold M, Bakris GL, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care 2011; 34: e61-99.


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Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [199 - 204]
Pages: 6
DOI: 10.2174/1573399814666180730105351
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