Diabetes Type 1 Autoantibody Panel
Diabetes Type 1 Autoantibody Panel
This panel is used to diagnose type 1 diabetes (T1D) in symptomatic children and adults, differentially diagnose type 1 vs type 2 diabetes, assess risk for development of T1D in presymptomatic individuals, and determine teplizumab therapy or clinical trial eligibility.
Test Summary
Diabetes Type 1 Autoantibody Panel
Test code: 13621
Clinical use
- Diagnose type 1 diabetes (T1D) in symptomatic children and adults
- Differentially diagnose T1D vs type 2 diabetes (T2D)
- Screen and assess risk for development of T1D in presymptomatic individuals
- Determine eligibility for teplizumab therapy or clinical trials for new therapies that delay onset of clinical diabetes
Clinical background
T1D is characterized by autoimmune destruction of insulin-producing pancreatic β cells, progression to hyperglycemia, ketoacidosis, and a need for exogenous insulin (stage 3). About 5% to 10% of all diabetes cases1 are type 1, and the incidence of T1D in the United States is increasing: about 2% annually overall or higher (≥4%) for some minority and racial groups.2
Disease onset can happen at any age; incidence peaks at 10 to 14 years of age but more diagnoses may occur in adults than in children.3 Slowly progressing autoimmune diabetes with an adult onset has been termed latent autoimmune diabetes in adults (LADA), although there is debate on whether this is simply another form of T1D.1
Clinical presentation of T1D may vary with age and differ from T2D. Children often present with polyuria/polydipsia and 25% to 50% present with diabetic ketoacidosis, which is less frequent in adult-onset T1D.1 Adult-onset T1D is usually distinguished from T2D by leaner body mass, family history of diabetes, more rapid progression to insulin dependence, and comorbidities (eg, cancer treatment with immune checkpoint inhibitors or a triggering infection, such as COVID-19).1 In addition, proinsulin-derived C-peptide levels are usually decreased in T1D (due to destruction of insulin-producing β cells) vs elevated in T2D (due to insulin resistance and insulin overproduction).
A hallmark of T1D is its association with autoantibodies (also called islet autoantibodies or IAbs) targeting insulin, tyrosine phosphatase-related islet antigen 2 (IA-2), zinc transporter 8 (ZnT8), and glutamic acid decarboxylase-65 (GAD). Using these 4 antibodies together (Table 1),4-7 T1D can be diagnosed in 93% to 98% of symptomatic patients.8-10 On this basis, the American Diabetes Association recommends screening for T1D using these markers, especially among patients who are at risk (eg, family history of autoimmune diabetes).1
Table 1. Clinical Performance of Diabetes Type 1 Autoantibody Panel (test code 13621) Components
| Autoantibody panel componenta | Test code |
Method |
Sensitivity, % |
Specificity,b % |
Glutamic Acid Decarboxylase-65 Antibody |
34878 |
ELISA |
83 |
99 |
Insulin Autoantibody |
36178 |
RIA |
50 |
99c |
IA-2 Antibody |
37933 |
ELISA |
58 |
97 |
Zinc Transporter 8 (ZnT8) Antibody |
93022 |
ELISA |
68 |
98 |
| ELISA, enzyme-linked immunosorbent assay; RIA, radioimmunoassay. | |
| a | Panel components can be ordered separately. |
| b | Comparison cohorts for all markers included healthy individuals and patients with other autoimmune diseases.4-7 For GAD, the comparison cohort also included patients with type 2 diabetes (T2D).4 For IA-2, it also included patients with metabolic syndrome, urinary tract infection, or kidney disease.6 For ZnT8, it also included patients with T2D, metabolic syndrome, urinary tract infection, kidney disease, or testicular cancer.7 |
| c | This autoantibody cannot be distinguished from autoantibodies produced in response to exogenous insulin administration and is only useful for diagnosis before insulin therapy.1 |
In presymptomatic patients, progression to clinical disease is predicted by persistence of 2 or more T1D autoantibodies, the age at first detection, the target antigen(s), and autoantibody titers.1,11 Consensus guidance has been provided for diagnosing and monitoring individuals with pre-stage 3 diabetes and is based on the number of T1D autoantibodies and glycemic indices. At-home glucose monitoring and patient education are recommended as part of this process (for details, see Consensus Guidance for Monitoring Individuals With Islet Autoantibody–Positive Pre-Stage 3 Type 1 Diabetes | Diabetes Care | American Diabetes Association (diabetesjournals.org).
Laboratory testing plays an important role in both staging T1D (Figure, Table 2) and monitoring disease progression (Table 2),12 which can be delayed by treatment with teplizumab (TZIELD™). This drug is a CD3-directed antibody approved by the US Food and Drug Administration (FDA) for patients ≥8 years old with stage-2 T1D (Table 2).13
Table 2. Pre-Stage 3 T1D and Laboratory Monitoring Recommendations
Stage1,12 |
T1D Ab number |
Glycemic status |
Laboratory monitoring recommendations |
Pre-stage 1a |
1 |
Normoglycemic
|
Children <3 years
Children ≥3 years:
Adults
|
1 |
≥2 |
Normoglycemic |
Children <3 years
Children 3-9 years:
Children >9 years:
Adults
|
2b |
Usually ≥2 |
Dysglycemic (≥1 of the following):
|
Children
Adults
|
| FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; Ab, autoantibody; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; 2-h PG, 2-hour plasma glucose; NA, not applicable; OGTT, oral glucose tolerance test; T1D, type 1 diabetes. | |
| a | For patients exhibiting transient positivity (ie, reverting from seropositive to seronegative), there are no laboratory monitoring recommendations for children but adults should follow standard-of-care guidelines for T2D.12 |
| b | For teplizumab clinical trials, alternative stage 2 diagnostic criteria have been used: 30-, 60-, or 90-min PG ≥200 mg/dL on oral glucose tolerance test and confirmatory testing in patients aged ≥18 years.1 |
Quest Diagnostics offers the Diabetes Type 1 Autoantibody Panel (test code 13621) for diagnosis of type 1 diabetes, differentiation from type 2 diabetes, predicting progression to type 1 diabetes, and determining eligibility for teplizumab in conjunction with tests used for establishing glycemic status. See Laboratory Testing for Diabetes Diagnosis and Management for tests used to establish glycemic status.
Individuals suitable for testing
- Patients with diabetes of uncertain etiology
- Younger patients (<35 years) with atypical diabetes
- Patients with ketosis-prone diabetes that is not clearly type 1 diabetes
- Patients suspected of having maturity-onset diabetes of the young (MODY)
- Patients with gestational diabetes (help clarify risk of future diabetes)
- Obese patients with acute-onset diabetes with ketoacidosis
- Lean patients with nonketotic diabetes
- Presymptomatic patients who are at risk of T1D (eg, based on family history of autoimmune diabetes) or who have previously had a positive test result for ≥1 T1D autoantibody
- Patients ≥8 years old being considered for teplizumab therapy
Methods
- See Table 1
Interpretive information
For individuals with diagnosed diabetes, autoantibody results above the reference range indicate a T1D autoimmune etiology. The exception is insulin autoantibody, which may be elevated in patients who have been treated with exogenous insulin. A result below the reference range for all analytes does not completely rule out T1D; a minority of individuals with T1D may be seronegative (5% to 10% of adult-onset T1D) or have idiopathic T1D of unknown etiology.1 In advanced T1D, antibodies may or may not be present.1
For presymptomatic individuals, ≥2 autoantibody results above their reference ranges indicates increased 5-year risk for development of clinical (stage 3) T1D (44% for stage 1 and 75% for stage 2).11 According to So et al, elevated insulin autoantibody indicates high risk for progression to T1D when appearing in young children (<4 years); GAD and ZnT8 antibodies indicate high risk when appearing in older cohorts, and IA-2 autoantibody indicates high risk for all ages; high titers (with the exception of ZnT8 autoantibody) and autoantibody persistence (all 4 antibodies) are also associated with risk.11
References
- American Diabetes Association Professional Practice Committee. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2024. Diabetes Care. 2024;47(suppl 1):S20-S42. doi:10.2337/dc24-S002
- Divers J, Mayer-Davis EJ, Lawrence JM, et al. Trends in incidence of type 1 and type 2 diabetes among youth—selected counties and Indian reservations, United States, 2002-2015. MMWR Morb Mortal Wkly Rep. 2020;69(6):161-165. doi:10.15585/mmwr.mm6906a3
- 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(1):199. doi:10.1186/s12916-017-0958-6
- Glutamic Acid Decarboxylase (GAD) Autoantibody ELISA Kit. Package insert. KRONUS; December 2022.
- Insulin Autoantibody Radioimmunoassay Kit. Package insert. KRONUS; September 2009.
- IA-2 Autoantibody (IA-2Ab) ELISA Kit. Package insert. KRONUS; August 2021.
- Zinc Transporter 8 Autoantibody (ZnT8Ab) ELISA Assay. Package insert. KRONUS; August 2022.
- Andersson C, Vaziri-Sani F, Delli A, et al. Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes. Pediatr Diabetes. 2013;14(2):97-105. doi:10.1111/j.1399-5448.2012.00916.x
- Petruzelkova L, Ananieva-Jordanova R, Vcelakova J, et al. The dynamic changes of zinc transporter 8 autoantibodies in Czech children from the onset of type 1 diabetes mellitus. Diabet Med. 2014;31(2):165-171. doi:10.1111/dme.12308
- Wenzlau JM, Moua O, Sarkar SA, et al. SlC30A8 is a major target of humoral autoimmunity in type 1 diabetes and a predictive marker in prediabetes. Ann N Y Acad Sci. 2008;1150:256-259. doi:10.1196/annals.1447.029
- So M, Speake C, Steck AK, et al. Advances in type 1 diabetes prediction using islet autoantibodies: beyond a simple count. Endocr Rev. 2021;42(5):584-604. doi:10.1210/endrev/bnab013
- 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;47(8):1276-1298. doi:10.2337/dci24-0042
- TZIELD™ (teplizumab-mzwv) injection. Prescribing information. Provention Bio, Inc; November 2022.
Content reviewed 09/2024
This panel is used to diagnose type 1 diabetes (T1D) in symptomatic children and adults, differentially diagnose type 1 vs type 2 diabetes, assess risk for development of T1D in presymptomatic individuals, and determine teplizumab therapy or clinical trial eligibility.
Test Summary
Diabetes Type 1 Autoantibody Panel
Test code: 13621
Clinical use
- Diagnose type 1 diabetes (T1D) in symptomatic children and adults
- Differentially diagnose T1D vs type 2 diabetes (T2D)
- Screen and assess risk for development of T1D in presymptomatic individuals
- Determine eligibility for teplizumab therapy or clinical trials for new therapies that delay onset of clinical diabetes
Clinical background
T1D is characterized by autoimmune destruction of insulin-producing pancreatic β cells, progression to hyperglycemia, ketoacidosis, and a need for exogenous insulin (stage 3). About 5% to 10% of all diabetes cases1 are type 1, and the incidence of T1D in the United States is increasing: about 2% annually overall or higher (≥4%) for some minority and racial groups.2
Disease onset can happen at any age; incidence peaks at 10 to 14 years of age but more diagnoses may occur in adults than in children.3 Slowly progressing autoimmune diabetes with an adult onset has been termed latent autoimmune diabetes in adults (LADA), although there is debate on whether this is simply another form of T1D.1
Clinical presentation of T1D may vary with age and differ from T2D. Children often present with polyuria/polydipsia and 25% to 50% present with diabetic ketoacidosis, which is less frequent in adult-onset T1D.1 Adult-onset T1D is usually distinguished from T2D by leaner body mass, family history of diabetes, more rapid progression to insulin dependence, and comorbidities (eg, cancer treatment with immune checkpoint inhibitors or a triggering infection, such as COVID-19).1 In addition, proinsulin-derived C-peptide levels are usually decreased in T1D (due to destruction of insulin-producing β cells) vs elevated in T2D (due to insulin resistance and insulin overproduction).
A hallmark of T1D is its association with autoantibodies (also called islet autoantibodies or IAbs) targeting insulin, tyrosine phosphatase-related islet antigen 2 (IA-2), zinc transporter 8 (ZnT8), and glutamic acid decarboxylase-65 (GAD). Using these 4 antibodies together (Table 1),4-7 T1D can be diagnosed in 93% to 98% of symptomatic patients.8-10 On this basis, the American Diabetes Association recommends screening for T1D using these markers, especially among patients who are at risk (eg, family history of autoimmune diabetes).1
Table 1. Clinical Performance of Diabetes Type 1 Autoantibody Panel (test code 13621) Components
| Autoantibody panel componenta | Test code |
Method |
Sensitivity, % |
Specificity,b % |
Glutamic Acid Decarboxylase-65 Antibody |
34878 |
ELISA |
83 |
99 |
Insulin Autoantibody |
36178 |
RIA |
50 |
99c |
IA-2 Antibody |
37933 |
ELISA |
58 |
97 |
Zinc Transporter 8 (ZnT8) Antibody |
93022 |
ELISA |
68 |
98 |
| ELISA, enzyme-linked immunosorbent assay; RIA, radioimmunoassay. | |
| a | Panel components can be ordered separately. |
| b | Comparison cohorts for all markers included healthy individuals and patients with other autoimmune diseases.4-7 For GAD, the comparison cohort also included patients with type 2 diabetes (T2D).4 For IA-2, it also included patients with metabolic syndrome, urinary tract infection, or kidney disease.6 For ZnT8, it also included patients with T2D, metabolic syndrome, urinary tract infection, kidney disease, or testicular cancer.7 |
| c | This autoantibody cannot be distinguished from autoantibodies produced in response to exogenous insulin administration and is only useful for diagnosis before insulin therapy.1 |
In presymptomatic patients, progression to clinical disease is predicted by persistence of 2 or more T1D autoantibodies, the age at first detection, the target antigen(s), and autoantibody titers.1,11 Consensus guidance has been provided for diagnosing and monitoring individuals with pre-stage 3 diabetes and is based on the number of T1D autoantibodies and glycemic indices. At-home glucose monitoring and patient education are recommended as part of this process (for details, see Consensus Guidance for Monitoring Individuals With Islet Autoantibody–Positive Pre-Stage 3 Type 1 Diabetes | Diabetes Care | American Diabetes Association (diabetesjournals.org).
Laboratory testing plays an important role in both staging T1D (Figure, Table 2) and monitoring disease progression (Table 2),12 which can be delayed by treatment with teplizumab (TZIELD™). This drug is a CD3-directed antibody approved by the US Food and Drug Administration (FDA) for patients ≥8 years old with stage-2 T1D (Table 2).13
Table 2. Pre-Stage 3 T1D and Laboratory Monitoring Recommendations
Stage1,12 |
T1D Ab number |
Glycemic status |
Laboratory monitoring recommendations |
Pre-stage 1a |
1 |
Normoglycemic
|
Children <3 years
Children ≥3 years:
Adults
|
1 |
≥2 |
Normoglycemic |
Children <3 years
Children 3-9 years:
Children >9 years:
Adults
|
2b |
Usually ≥2 |
Dysglycemic (≥1 of the following):
|
Children
Adults
|
| FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; Ab, autoantibody; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; 2-h PG, 2-hour plasma glucose; NA, not applicable; OGTT, oral glucose tolerance test; T1D, type 1 diabetes. | |
| a | For patients exhibiting transient positivity (ie, reverting from seropositive to seronegative), there are no laboratory monitoring recommendations for children but adults should follow standard-of-care guidelines for T2D.12 |
| b | For teplizumab clinical trials, alternative stage 2 diagnostic criteria have been used: 30-, 60-, or 90-min PG ≥200 mg/dL on oral glucose tolerance test and confirmatory testing in patients aged ≥18 years.1 |
Quest Diagnostics offers the Diabetes Type 1 Autoantibody Panel (test code 13621) for diagnosis of type 1 diabetes, differentiation from type 2 diabetes, predicting progression to type 1 diabetes, and determining eligibility for teplizumab in conjunction with tests used for establishing glycemic status. See Laboratory Testing for Diabetes Diagnosis and Management for tests used to establish glycemic status.
Individuals suitable for testing
- Patients with diabetes of uncertain etiology
- Younger patients (<35 years) with atypical diabetes
- Patients with ketosis-prone diabetes that is not clearly type 1 diabetes
- Patients suspected of having maturity-onset diabetes of the young (MODY)
- Patients with gestational diabetes (help clarify risk of future diabetes)
- Obese patients with acute-onset diabetes with ketoacidosis
- Lean patients with nonketotic diabetes
- Presymptomatic patients who are at risk of T1D (eg, based on family history of autoimmune diabetes) or who have previously had a positive test result for ≥1 T1D autoantibody
- Patients ≥8 years old being considered for teplizumab therapy
Methods
- See Table 1
Interpretive information
For individuals with diagnosed diabetes, autoantibody results above the reference range indicate a T1D autoimmune etiology. The exception is insulin autoantibody, which may be elevated in patients who have been treated with exogenous insulin. A result below the reference range for all analytes does not completely rule out T1D; a minority of individuals with T1D may be seronegative (5% to 10% of adult-onset T1D) or have idiopathic T1D of unknown etiology.1 In advanced T1D, antibodies may or may not be present.1
For presymptomatic individuals, ≥2 autoantibody results above their reference ranges indicates increased 5-year risk for development of clinical (stage 3) T1D (44% for stage 1 and 75% for stage 2).11 According to So et al, elevated insulin autoantibody indicates high risk for progression to T1D when appearing in young children (<4 years); GAD and ZnT8 antibodies indicate high risk when appearing in older cohorts, and IA-2 autoantibody indicates high risk for all ages; high titers (with the exception of ZnT8 autoantibody) and autoantibody persistence (all 4 antibodies) are also associated with risk.11
References
- American Diabetes Association Professional Practice Committee. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2024. Diabetes Care. 2024;47(suppl 1):S20-S42. doi:10.2337/dc24-S002
- Divers J, Mayer-Davis EJ, Lawrence JM, et al. Trends in incidence of type 1 and type 2 diabetes among youth—selected counties and Indian reservations, United States, 2002-2015. MMWR Morb Mortal Wkly Rep. 2020;69(6):161-165. doi:10.15585/mmwr.mm6906a3
- 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(1):199. doi:10.1186/s12916-017-0958-6
- Glutamic Acid Decarboxylase (GAD) Autoantibody ELISA Kit. Package insert. KRONUS; December 2022.
- Insulin Autoantibody Radioimmunoassay Kit. Package insert. KRONUS; September 2009.
- IA-2 Autoantibody (IA-2Ab) ELISA Kit. Package insert. KRONUS; August 2021.
- Zinc Transporter 8 Autoantibody (ZnT8Ab) ELISA Assay. Package insert. KRONUS; August 2022.
- Andersson C, Vaziri-Sani F, Delli A, et al. Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes. Pediatr Diabetes. 2013;14(2):97-105. doi:10.1111/j.1399-5448.2012.00916.x
- Petruzelkova L, Ananieva-Jordanova R, Vcelakova J, et al. The dynamic changes of zinc transporter 8 autoantibodies in Czech children from the onset of type 1 diabetes mellitus. Diabet Med. 2014;31(2):165-171. doi:10.1111/dme.12308
- Wenzlau JM, Moua O, Sarkar SA, et al. SlC30A8 is a major target of humoral autoimmunity in type 1 diabetes and a predictive marker in prediabetes. Ann N Y Acad Sci. 2008;1150:256-259. doi:10.1196/annals.1447.029
- So M, Speake C, Steck AK, et al. Advances in type 1 diabetes prediction using islet autoantibodies: beyond a simple count. Endocr Rev. 2021;42(5):584-604. doi:10.1210/endrev/bnab013
- 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;47(8):1276-1298. doi:10.2337/dci24-0042
- TZIELD™ (teplizumab-mzwv) injection. Prescribing information. Provention Bio, Inc; November 2022.
Content reviewed 09/2024