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Autoantibodies and Type 1 Diabetes (T1D)

Test codes: 10584 (GAD65, IA-2, and Insulin Autoantibody), 93022 (ZnT8 Antibody), 34878 (GAD-65 Antibody), 37933 (IA-2 Antibody), 36178 (Insulin Autoantibody), 36741 (Islet Cell Antibody Screen with Reflex to Titer)

T1D results from the immune destruction of insulin-producing beta 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 effect of insulin. In the presence of insulin resistance, the pancreas makes extra insulin to maintain normal blood sugar. In due time, despite the extra amount of insulin, the body’s insulin resistance worsens until the pancreas cannot increase insulin production and the patient develops elevated blood glucose.

The incidence of T1D is rising worldwide, with annual increases of 2% to 5%.1-3 T1D most commonly affects pediatric patients and has a bimodal distribution within that population: peaks at ages 4 to 6 and ages 10 to 14.4  However, 25% to 50% of patients receive a diagnosis during adulthood.5 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.3  

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 polydipsia, polyuria, and weight loss,8 but up to 30% of all children with T1D present with diabetic ketoacidosis (DKA).9 DKA is a medical emergency that requires ICU hospitalization and predisposes to poorer health consequences, including higher lifetime A1C 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.10 The reason why such a high percentage of patients present with DKA is that 90% do not have a family history3; therefore, affected patients or family members do not recognize the gravity of the situation until late, when urgent hospitalization is necessary. 

Three stages of T1D are defined by autoantibodies and blood glucose level, as shown in Table 2.11 Over the past decades, work based on autoantibody screening helped identify individuals at high risk for T1D and understand that the immune system-mediated destruction of the beta cell begins long before the development of symptoms and abnormal blood sugar. Based on these observations, clinical guidelines have been established that provide pre-symptomatic and symptomatic staging of T1D. 

Table showing pre-symptomatic and symptomatic staging of T1D

T1D autoantibodies are markers of ongoing damage to insulin-producing beta cells. The first AAbs detected in T1D, called islet cell antibodies (ICAs), lacked specificity because they targeted many molecules and were too frequent in the general population. Thus, they have been replaced by 4 AAbs with better specificity: AAbs to insulin (IAA), a tyrosine phosphatase (IA2; previously ICA512), glutamic acid decarboxylase (GAD65), and zinc transporter 8 (ZnT8).12

Among these biomarkers, insulin is the only beta cell specific AAb identified. T1D AAbs often appear in a particular sequence, with insulin or GAD65 AAbs developing first, sometimes as early as 6 months of age, followed by IA2 and ZnT8 AAbs.

Discovery and validation of AAbs in different populations from multiple studies1,3 continue to refine risk prediction. Among individuals who test positive for a single AAb, approximately 14.5% progress to T1D within 10 years.13 Once multiple antibodies are detected, T1D almost inevitably follows. One study reported that of 585 children with more than 2 AAbs, nearly 70% developed T1D within ten years and 84% developed T1D within 15 years. An important aspect of this study was that some participants were recruited from the general population, and the findings were the same as for those recruited from T1D family members. This point indicates that the same sequence of events leads to clinical disease in both “sporadic” and familial cases of T1D. However, due to a higher disease awareness in affected families, familial T1DM is characterized by earlier disease manifestations, higher autoimmune comorbidity, and less metabolic decompensation at onset compared to sporadic cases.14

The American Diabetes Association (ADA) supports using autoantibody (Aab) testing to diagnose T1D.15  Clinical trials have consistently shown a reduction in diabetic ketoacidosis (DKA) rate and HbA1c levels in children screened for T1D with AAbs (Table 3). 

The recommendation is to use all 4 AAbs (ie, IA2, GAD65, IAA, and ZnT8) for T1D screening, diagnosis, and differential diagnosis from other types of diabetes mellitus. Testing all 4 AAbs at once provides the highest sensitivity for detecting the presence of at least 2 positive autoantibodies,23 which is associated with the eventual development of T1D.24  

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

Yes. Early identification and regular follow-up of individuals who test positive for beta-cell autoantibodies are associated with lower rates of diabetic ketoacidosis (DKA) rates (2%-3% vs 18%-29%).17,18 Early identification is also associated with lower longer-term HbA1c levels and risk of complications.25 These advances and the recent positive results of the TN10 prevention trial with teplizumab have opened opportunities to prevent T1D and its complications.26


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  3. Sims EK, Besser REJ, Dayan C, et al. Screening for Type 1 Diabetes in the General Population: A Status Report and Perspective. Diabetes. Apr 1 2022;71(4):610-623. doi:10.2337/dbi20-0054
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  7. Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G, Group ES. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. Jun 13 2009;373(9680):2027-33. doi:10.1016/S0140-6736(09)60568-7
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  10. 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. Aug 2020;63(8):1530-1541. doi:10.1007/s00125-020-05152-1
  11. 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. Oct 2018;19 Suppl 27:20-27. doi:10.1111/pedi.12734
  12. Torn C, Mueller PW, Schlosser M, Bonifacio E, Bingley PJ, Participating L. Diabetes Antibody Standardization Program: evaluation of assays for autoantibodies to glutamic acid decarboxylase and islet antigen-2. Diabetologia. May 2008;51(5):846-52. doi:10.1007/s00125-008-0967-2
  13. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. Jun 19 2013;309(23):2473-9. doi:10.1001/jama.2013.6285
  14. Karges B, Prinz N, Placzek K, et al. A Comparison of Familial and Sporadic Type 1 Diabetes Among Young Patients. Diabetes Care. May 2021;44(5):1116-1124. doi:10.2337/dc20-1829
  15. American Diabetes A. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2021. Diabetes Care. Jan 2021;44(Suppl 1):S15-S33. doi:10.2337/dc21-S002
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  18. 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. Nov 2014;15(7):494-501. doi:10.1111/pedi.12151
  19. 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. Nov 2011;34(11):2347-52. doi:10.2337/dc11-1026
  20. 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. Dec 2017;18(8):794-802. doi:10.1111/pedi.12485
  21. 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. Jun 2004;27(6):1399-404. doi:10.2337/diacare.27.6.1399
  22. Hekkala AM, Ilonen J, Toppari J, Knip M, Veijola R. Ketoacidosis at diagnosis of type 1 diabetes: Effect of prospective studies with newborn genetic screening and follow up of risk children. Pediatr Diabetes. Mar 2018;19(2):314-319. doi:10.1111/pedi.12541
  23. 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. Oct 23 2007;104(43):17040-5. doi:10.1073/pnas.0705894104
  24. Greenbaum CJ. A Key to T1D Prevention: Screening and Monitoring Relatives as Part of Clinical Care. Diabetes. May 2021;70(5):1029-1037. doi:10.2337/db20-1112
  25. Duca LM, Wang B, Rewers M, Rewers A. Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes Predicts Poor Long-term Glycemic Control. Diabetes Care. Sep 2017;40(9):1249-1255. doi:10.2337/dc17-0558
  26. 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. Aug 15 2019;381(7):603-613. doi:10.1056/NEJMoa1902226


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.


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