Autoimmune diabetes is often misunderstood, misdiagnosed, or detected later than it should be. The key to identifying it early lies in specific autoimmune markers, particularly anti-Glutamate Decarboxylase (GAD), anti-Protein Tyrosine Phosphatase-like Protein IA-2 (IA-2), anti-Zinc transporter 8 (ZnT8), and anti-insulin autoantibody (IAA). These lab tests help doctors determine whether high blood sugar is caused by immune destruction of pancreatic beta cells rather than insulin resistance alone.
What Is Autoimmune Diabetes?
Autoimmune diabetes occurs when the immune system mistakenly attacks insulin-producing beta cells in the pancreas. This process underlies:
- Type 1 diabetes
- LADA (Latent Autoimmune Diabetes in Adults), a slower, adult-onset form, often misdiagnosed as Type 2 Diabetes because, for a period, these patients still produce insulin but at an insufficient level.
Unlike Type 2 diabetes, the root issue is loss of insulin production, not just insulin resistance.
Autoimmune Diabetes is increasing and often misunderstood
Some statistics:
- Prevalence of Type 1 diabetes varies globally from 3.5:10,000 in Africa to 12.2:10,000 in the USA and is increasing at an estimated 3–4% per year in Europe.1
- The prevalence of LADA in a population of Type 2 Diabetes Mellitus patients is between 4% and 12%.2
Delayed diagnosis of Autoimmune Diabetes allows blood sugar levels to remain high, which can lead to severe, life-threatening complications, most notably Diabetic Ketoacidosis (DKA). A delayed LADA diagnosis often means the patient is wrongly treated for Type 2 diabetes, failing to receive essential insulin. Detecting this difference early changes treatment decisions and long-term outcomes.
As LADA can easily be confused with Type 2 Diabetes Mellitus, and it’s essential to diagnose autoimmune diabetes as early as possible, is there a case for increased testing of a panel of autoimmune markers?
Immunologic Targets Driving Assay Development
Anti-Glutamate Decarboxylase (GAD), anti-Protein Tyrosine Phosphatase-like Protein IA-2 (IA-2), anti-Zinc transporter 8 (ZnT8), and anti-insulin autoantibody (IAA) are all proteins produced as a result of immune dysregulation that target pancreatic beta cells. They have different modes of action and value as diagnostic markers.
Doctors should consider these tests when a diabetes diagnosis is unclear. These tests can help confirm Type 1 diabetes or LADA. A LADA diagnosis should be considered if a patient is not overweight, has a personal/family history of autoimmune diseases, and shows a rapid decline in glycaemic control despite following a type 2 diabetes management plan. They are often positive for GAD and ZnT8.
Glutamate Decarboxylase (GAD/ GAD65) Antibodies
This is the highest prevalence autoantibody in autoimmune diabetes. These antibodies target the glutamic acid decarboxylase enzyme, triggering an immune response that destroys insulin-producing pancreatic beta cells. Here are some features that make it an interesting marker:
- Dominant marker in adult-onset autoimmune diabetes (LADA).
- It can remain detectable for years making it ideal for retrospective and longitudinal studies.
- There is strong evidence of immune-mediated diabetes, essential for screening assays and multiplex panels.
IA-2 Autoantibodies
Associated with active beta-cell destruction by targeting a beta-cell protein involved in insulin secretion, this marker appears closer to disease onset and correlates with faster progression to insulin dependence.
- IA-2 autoantibodies would be crucial in a panel that was looking to predict the transition to insulin dependence.
Insulin Autoantibodies (IAA)
Often the first antibody detected, especially in paediatric cases, IAA binds to insulin, forming immune complexes that cause erratic blood sugar levels. It is a useful marker because:
- It helps identify early autoimmune diabetes, so is key for developing early-disease detection assays.
- Important in neonatal/early-onset cohorts.
It is important to note that post-exogenous insulin exposure confounds measurements, so it is most informative and best measured before insulin therapy starts.
Zinc transporter 8 (ZnT8 / a-zinc) Autoantibodies
ZnT8 autoantibodies target the ZnT8 protein located on the membrane of insulin secretory granules in beta cells. By destroying the beta cells, anti-ZnT8 causes a decline in insulin secretion.
- It improves detection when GAD/IA-2 are negative, increasing overall diagnostic sensitivity, making it useful for uncovering “seronegative” autoimmune cases that may otherwise be missed. When the ZnT8 antibody is tested along with the 3 other T1DM autoantibodies, autoimmunity detection rates were up to 98% in new-onset T1DM cases.3
Why Test Multiple Antibodies?
| Result | Meaning |
| 1 antibody positive | Autoimmune diabetes possible |
| 2+ antibodies positive | Strong evidence of autoimmune diabetes |
| Different antibody patterns | Help estimate stage & speed of progression |
As each marker appears at a different stage of disease, testing multiple markers and combining the data improves the accuracy of the diagnosis and provides doctors with valuable information to guide treatment decisions and insulin timing.
Important Companion Tests
| Marker | Application |
| C-peptide | Correlates autoantibody status with functional beta-cell loss, measuring how much insulin the body still makes. Low or declining C-peptide is indicative of beta-cell failure, therefore distinguishing Type 1 diabetes/ LADA from Type 2 diabetes. It can help decide when insulin is needed and track disease progression. |
| HbA1c & glucose | Confirm diabetes and severity. Used to monitor diabetes management and glycaemic status. |
| Islet Cell Antibodies (ICA) | An older, indirect test for autoimmune diabetes that is less specific than modern markers discussed earlier in the article. It is sometimes included for completeness. |
| Proinsulin | Elevated levels can indicate Beta-cell stress. Is typically used in research or speciality cases. |
Is It Time for Broader Access to Autoimmune Diabetes Testing?
Current tests for these more specialised autoimmune markers are often Research Use Only (RUO) and testing is typically performed in large reference labs using validated ELISA/ immunoassay methods.
Early detection has been shown to prevent hospitalisation and life-threatening conditions. Screening for Type 1 Diabetes will help people maximize their opportunities to delay Type 1 Diabetes onset while preparing for diabetes care.4 Understanding these markers transforms how diabetes is classified, monitored, and treated and is especially useful in adults who don’t fit neatly into “Type 1” or “Type 2” diagnostic buckets.
References
- M Popoviciu et al. Type 1 Diabetes Mellitus and Autoimmune Diseases: A Critical Review of the Association and the Application of Personalized Medicine. J. Pers. Med. 2023, 13(3), 422; https://doi.org/10.3390/jpm13030422
- V Rajkumar et al. Latent Autoimmune Diabetes. National Institute of Medicine. March 1, 2024. https://www.ncbi.nlm.nih.gov/books/NBK557897/
- Maniattu et al. Latent Autoimmune Diabetes of Adults Due to Positive Zinc Transporter 8 Antibody. Annals of Internal Medicine: Clinical Cases, 2025. Vol 4, Number 6. https://doi.org/10.7326/aimcc.2024.1092
- D Moore et al. Recommendations for Screening and Monitoring the Stages of Type 1 Diabetes in the Immune Therapy Era. Int J Gen Med. 2024 Jul 9;17:3003–3014. https://doi.org/10.2147/IJGM.S438009
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