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Autoantibodies and Type 1 Diabetes (T1D)

Test codes: 

  • 13621 (GAD-65 Antibody, IA-2 Antibody, Insulin Autoantibody, and ZnT8 Antibody)
  • 34878 (GAD-65 Antibody)
  • 36178 (Insulin Autoantibody)
  • 36741 (Islet Cell Antibody Screen with Reflex to Titer)
  • 37933 (IA-2 Antibody)
  • 93022 (ZnT8 Antibody)

T1D results from the immune destruction of insulin-producing β cells. Patients with established T1D do not produce any insulin and require insulin-based treatments to survive. In contrast, T2D patients produce insulin. However, their bodies develop insulin resistance and resist the normal effects of insulin. In the presence of insulin resistance, the pancreas makes extra insulin to maintain normal blood sugar. Eventually, despite the extra amount of insulin, the body’s insulin resistance worsens until the pancreas cannot sufficiently produce insulin to meet the body’s needs, and the patient develops elevated blood glucose.

LADA is diagnosed in patients positive for at least one diabetes autoantibody. It could be considered a slowly progressing variant of type 1 diabetes, as patients typically show prolonged preservation of insulin production and a slower onset of the clinical syndrome compared to classic T1D. The LADA phenotype is heterogeneous and associated with variable titers of islet autoantibodies (IAbs), body mass indices (BMIs), and rates of progression to insulin dependence. Usually, insulin treatment is not necessary at diagnosis, and it takes months to years to become insulin dependent.1

The incidence of T1D is rising worldwide, with annual increases of 2% to 5%.2-4 T1D affects pediatric and adult patients. Pediatric T1D has a bimodal distribution and peaks at ages 4 to 6 and ages 10 to 14.5

Epidemiological data show that T1D is diagnosed more frequently in adulthood than in childhood at a median of more than 35 years of age.6-8 Despite this, misdiagnosis of T1D in adults is common and increasingly likely with age, which increases the likelihood for developing diabetic ketoacidosis (DKA) at presentation.

Studies show that a family history of T1D substantially increases the lifetime risk of developing the condition (Table 1), suggesting a heritable component; however, 90% of people who develop T1D do not have a family history.4

Table showing Lifetime risk of T1D development based on family history (click the link to enlarge the image of the table).

The most frequent clinical presentation consists of increased thirst, frequent urination, and weight loss,11 but up to 30% of all children with T1D present with diabetic ketoacidosis (DKA).12 DKA is a medical emergency that requires ICU hospitalization and predisposes the patient to poorer health consequences, including higher lifetime HbA1c and adverse impacts on memory and intelligence quotient. Up to 50% of children under 3 years of age with poor socioeconomic backgrounds present with DKA,13 likely because 90% of T1D patients do not have a family history.4 This means that patients and their families may not recognize the severity of the situation until urgent hospitalization is required.

The introduction of islet autoantibody (IAb) screening for T1D has resulted in a growing number of IAb-positive patients being monitored for progression towards clinical diabetes. In research studies, such monitoring has been shown to significantly reduce the incidence of DKA at T1D diagnosis.14-19

Four stages of type 1 diabetes (T1D) are defined by autoantibodies and blood glucose levels (Table 2).20 Autoantibody screening over the past few decades has helped identify individuals at high risk of developing T1D. It has also helped understand that immune system-mediated destruction of β cells begins long before the onset of symptoms and abnormal blood sugar levels. As a result, clinical guidelines have been established that provide pre-symptomatic and symptomatic staging of T1D.

Table showing pre-symptomatic and symptomatic staging of T1D

T1D IAbs are markers of ongoing damage to insulin-producing ß cells. The first IAb detected in T1D was called islet cell autoantibody (ICA). ICA lacked specificity because it had many targets and was too frequent in the general population. Thus, ICA has been replaced by 4 IAbs with better specificity. The IAbs currently used are IAA (insulin autoantibody), IA-2A (tyrosine phosphatase islet antigen-2 autoantibody), GADA (glutamic acid decarboxylase autoantibody), and ZnT8A (zinc transporter type 8 autoantibody).24

Among these biomarkers, IAA is the only ß-cell–specific IAb. T1D IAbs often appear in a particular sequence, with IAA or GADA developing first, sometimes as early as 6 months of age, followed by IA2A and ZnT8A. 

The American Diabetes Association (ADA) supports using IAb screening to diagnose T1D.25 Clinical trials have consistently shown a reduction in diabetic ketoacidosis (DKA) rate and HbA1c levels in children who tested positive after screening for T1D with IAb. Experts recommend repeating IAb testing within 3 months to confirm seroconversion and to monitor for changes in IAb status.    

The ADA recommendation is to use all 4 IAbs (ie, IA2A, GADA, IAA, and ZnT8A) for T1D screening, diagnosis, monitoring, and differential diagnosis from other types of diabetes mellitus. Individually, IA2A, GADA, IAA, and ZnT8A antibodies were detected in 72%, 68%, 55%, and 63%, respectively, of new-onset patients. Testing all 4 IAbs at once provides the highest sensitivity for the detection of autoimmunity and of ≥ 2 positive IAbs (Table 3).30

Table showing benefits associated with T1D detected by autoantibody screening (compared to no screening)

Yes, studies have shown that IAb number, younger age at seroconversion, IAb type, and order of IAb seroconversion are associated with increased risk of faster progression to stage 3 T1D. 

IAb number

Up to 50% of children who are positive for a single IAb revert to being negative for IAb,23 and children who are persistently positive for a single IAb have lower risk for progression than those who are positive for multiple IAbs. One study reported the 10-year risk of progression to T1D for children who are persistently positive for a single IAb is 14.5%, with most of that progression happening in the first 2 years after becoming positive. Among children who developed ≥2 autoantibodies, nearly 70% developed T1D within 10 years and 84% developed T1D within 15 years.22

Age of seroconversion

If seroconversion for a single IAb occurs at a younger age (<5 years), this represents a risk factor for progression to positivity for multiple IAbs, particularly during the initial 2 years.31,32

IAb type

A fast rate of progression to T1D is more common among children positive for IA2A (40.5%) than among those positive for GADA (12.9%) or IAA (13.1%).22  As children age, relative risks for progression can change depending on antibody subtype33: associated risk increases for GADA but decreases for IAA.34

Order of IAb seroconversion

The first autoantibody to appear differs significantly depending on age of seroconversion. For instance, in children 2 years old and younger, abnormal IAA titers most frequently develop first,35 and nearly all young children who progressed to T1D were IAA positive.36 In contrast, children ages 3 to 5 more frequently seroconvert to GADA positivity first.35

Yes. Early identification and regular follow-up of individuals who test positive for autoantibodies are associated with lower rates of diabetic ketoacidosis (DKA) (2%-3% vs 18%-29%).27,16 Early identification is also associated with lower long-term HbA1c levels and risk of complications.37 These advances and the positive results of the TN10 prevention trial with teplizumab have opened opportunities to prevent T1D and its complications.38

In 2024, the ADA and the European Association for the Study of Diabetes published consensus guidelines for monitoring individuals with IAb‑positive presymptomatic (ie, pre‑stage 3) T1D.21 In addition to discussing modalities to manage clinically IAb-positive patients, these guidelines emphasize providing these patients with educational and psychological support.  

References

 

  1. Leslie RD, Williams R, Pozzilli P. Clinical review: Type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow. J Clin Endocrinol Metab. 2006;91:1654-1659.
  2. Lawrence JM, Imperatore G, Dabelea D, et al. Trends in incidence of type 1 diabetes among non-Hispanic white youth in the U.S., 2002-2009. Diabetes. 2014;63:3938-3945.
  3. Group SfDiYS, Liese AD, D'Agostino RB, Jr., et al. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118:1510-1518.
  4. Sims EK, Besser REJ, Dayan C, et al. Screening for type 1 diabetes in the general population: a status report and perspective. Diabetes. 2022;71:610-623.
  5. Felner EI, Klitz W, Ham M, et al. Genetic interaction among three genomic regions creates distinct contributions to early- and late-onset type 1 diabetes mellitus. Pediatr Diabetes. 2005;6:213-220.
  6. VanBuecken D, Lord S, Greenbaum CJ. Changing the Course of Disease in Type 1 Diabetes. In: Feingold KR, Anawalt B, Blackman MR, et al., eds. Endotext. South Dartmouth (MA)2000.
  7. Thunander M, Petersson C, Jonzon K, et al. Incidence of type 1 and type 2 diabetes in adults and children in Kronoberg, Sweden. Diabetes Res Clin Pract. 2008;82:247-255.
  8. Rogers MAM, Kim C, Banerjee T, et al. Fluctuations in the incidence of type 1 diabetes in the United States from 2001 to 2015: a longitudinal study. BMC Med. 2017;15:199.
  9. Nistico L, Iafusco D, Galderisi A, et al. Emerging effects of early environmental factors over genetic background for type 1 diabetes susceptibility: evidence from a Nationwide Italian Twin Study. J Clin Endocrinol Metab. 2012;97:E1483-1491.
  10. Patterson CC, Dahlquist GG, Gyurus E, et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. 2009;373:2027-2033.
  11. Roche EF, Menon A, Gill D, et al. Clinical presentation of type 1 diabetes. Pediatr Diabetes. 2005;6:75-78.
  12. Dabelea D, Rewers A, Stafford JM, et al. Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study. Pediatrics. 2014;133:e938-945.
  13. Cherubini V, Grimsmann JM, Akesson K, et al. Temporal trends in diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes between 2006 and 2016: results from 13 countries in three continents. Diabetologia. 2020;63:1530-1541.
  14. Ziegler AG, Kick K, Bonifacio E, et al. Yield of a public health screening of children for islet autoantibodies in Bavaria, Germany. JAMA. 2020;323:339-351.
  15. Elding Larsson H, Vehik K, Bell R, et al. Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up. Diabetes Care. 2011;34:2347-2352.
  16. Lundgren M, Sahlin A, Svensson C, et al. Reduced morbidity at diagnosis and improved glycemic control in children previously enrolled in DiPiS follow-up. Pediatr Diabetes. 2014;15:494-501.
  17. Wentworth JM, Oakey H, Craig ME, et al. Decreased occurrence of ketoacidosis and preservation of beta cell function in relatives screened and monitored for type 1 diabetes in Australia and New Zealand. Pediatr Diabetes. 2022;23:1594-1601.
  18. Barker JM, Goehrig SH, Barriga K, et al. Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. Diabetes Care. 2004;27:1399-1404.
  19. Jacobsen LM, Vehik K, Veijola R, et al. Heterogeneity of DKA incidence and age-specific clinical characteristics in children diagnosed with type 1 diabetes in the TEDDY study. Diabetes Care. 2022;45:624-633.
  20. Couper JJ, Haller MJ, Greenbaum CJ, et al. ISPAD Clinical Practice Consensus Guidelines 2018: stages of type 1 diabetes in children and adolescents. Pediatr Diabetes. 2018;19 Suppl 27:20-27.
  21. Phillip M, Achenbach P, Addala A, et al. Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes. Diabetes Care. 2024
  22. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309:2473-2479.
  23. Vehik K, Lynch KF, Schatz DA, et al. Reversion of beta-cell autoimmunity changes risk of type 1 diabetes: TEDDY Study. Diabetes Care. 2016;39:1535-1542.
  24. Torn C, Mueller PW, Schlosser M, et al. Diabetes Antibody Standardization Program: evaluation of assays for autoantibodies to glutamic acid decarboxylase and islet antigen-2. Diabetologia. 2008;51:846-852.
  25. American Diabetes A. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2021. Diabetes Care. 2021;44:S15-S33.
  26. Narendran P. Screening for type 1 diabetes: are we nearly there yet? Diabetologia. 2019;62:24-27.
  27. 27.  Winkler C, Schober E, Ziegler AG, et al. Markedly reduced rate of diabetic ketoacidosis at onset of type 1 diabetes in relatives screened for islet autoantibodies. Pediatr Diabetes. 2012;13:308-313.
  28. Steck AK, Larsson HE, Liu X, et al. Residual beta-cell function in diabetes children followed and diagnosed in the TEDDY study compared to community controls. Pediatr Diabetes. 2017;18:794-802.
  29. Hekkala AM, Ilonen J, Toppari J, et al. Ketoacidosis at diagnosis of type 1 diabetes: Effect of prospective studies with newborn genetic screening and follow up of risk children. Pediatr Diabetes. 2018;19:314-319.
  30. 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 U S A. 2007;104:17040-17045.
  31. Krischer JP, Liu X, Lernmark A, et al. Predictors of the initiation of islet autoimmunity and progression to multiple autoantibodies and clinical diabetes: the TEDDY study. Diabetes Care. 2022;45:2271-2281.
  32. Chmiel R, Giannopoulou EZ, Winkler C, et al. Progression from single to multiple islet autoantibodies often occurs soon after seroconversion: implications for early screening. Diabetologia. 2015;58:411-413.
  33. 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;102:2881-2886.
  34. So M, O'Rourke C, Ylescupidez A, et al. Characterising the age-dependent effects of risk factors on type 1 diabetes progression. Diabetologia. 2022;65:684-694.
  35. Ilonen J, Hammais A, Laine AP, et al. Patterns of beta-cell autoantibody appearance and genetic associations during the first years of life. Diabetes. 2013;62:3636-3640.
  36. Yu L, Dong F, Miao D, et al. Proinsulin/Insulin autoantibodies measured with electrochemiluminescent assay are the earliest indicator of prediabetic islet autoimmunity. Diabetes Care. 2013;36:2266-2270.
  37. Duca LM, Wang B, Rewers M, et al. Diabetic ketoacidosis at diagnosis of type 1 diabetes predicts poor long-term glycemic control. Diabetes Care. 2017;40:1249-1255.
  38. Herold KC, Bundy BN, Long SA, et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med. 2019;381:603-613. 

 

This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.

 

Document FAQS.297 Version: 1

Version 1 effective 09/30/2024 to present

Version 0 effective 06/30/2023 to 09/30/2024

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