Autoantibodies in diabetes mellitus

The determination of autoantibodies plays a central role in the differentiation of diabetes mellitus, especially in the differentiation between type 1 and type 2 diabetes and between LADA and type 1/2 diabetes.

The most important antibodies in type 1 diabetes are:

• Cytoplasmic islet cell antibodies (ICA)
• Insulin autoantibodies (IAA)
• Antibodies against glutamate decarboxylase (anti-GAD65)
• Antibodies against the tyrosine kinase IA-2 (anti-IA-2A)
• Antibodies against the zinc transporter-8 (Anti ZnT8).

The heterogeneously composed family of cytoplasmic islet cell antibodies (ICA) are often the first to be detected in the manifestation phase of type 1 diabetes in adolescents (prevalence 60-90%). However, their value is now increasingly underestimated compared to other beta-cell antibodies. For LADA, the occurrence of antibodies against GAD65 is diagnostically most meaningful. These also occur in older patients with a high prevalence (approx. 80%) and remain detectable in the course of diabetes for longer than any other beta cell antibody. Therefore they can confirm autoimmune diabetes even years after the onset of the disease.

GAD65 autoantibodies have the greatest importance for the screening and differential diagnosis of LADA and type 2 diabetes. Positive findings prove the presence of an autoimmune process, negative GADA findings exclude an autoimmunological etiology with a high probability. In case of negative findings, other antibodies against islet cells or insulin can be determined additionally to improve sensitivity. Their occurrence is partly age-dependent. IA-2 antibodies against tyrosine phosphatase in the islet cell membrane are more likely to be found in young patients. Insulin antibodies are used to assess the risk of developing diabetes in young children. Their determination under insulin therapy is not very useful, as it is then not possible to differentiate between antibodies against exogenous or endogenous insulin.

ZnT8-Ak show a good (negative) correlation with the mass and residual function of beta cells and can be detected without another diabetes-specific autoantibody reacting positively (25-30% of cases). The additional determination of ZnT8-Ak increases the overall sensitivity of antibody diagnostics in type 1 diabetes to > 90%.

The occurrence of diabetes-specific autoantibodies can be detected already during the symptom-free development phase of autoimmune diabetes. A general screening, e.g. of school children, does not make sense, since no effective measures can be taken to prevent the disease.

1. Achenbach P et al (2009) Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk. Diabetologia 52: 1881-1888.
2. Böhm BO et al (2011) S3-guideline therapy of type 1 diabetes. Version 1.0 German Diabetes Society 2011
3. Chmiel R et al (2013) Diabetes type 1: Islet autoantibodies as diagnostic markers. Dtsch Arztebl International 110: 16.
4. Couper JJ et al (2014) Phases of type 1 diabetes in children and adolescents. Pediatric diabetes 15: 18-25.
5. Craig ME et al. (2006) ISPAD Clinical Practice Consensus Guidelines 2006-2007: Definition, epidemiology and classification. Pediatric diabetes 7: 343-351.
6. Leslie RDG et al (2008) Diabetes classification: grey zones, sound and smoke: Action LADA 1st Diabetes Metab Res Rev 24: 511-519
7. Pham MN et al (2011) Pro- and anti-inflammatory cytokines in latent autoimmune diabetes in adults, type 1 and type 2 diabetes patients: Action LADA 4 Diabetologia 54: 1630-1638.
8. Schlosser M et al (2010) Diabetes Antibody Standardization Program: evaluation of assays for insulin autoantibodies. Diabetologia 53: 2611-2620
9. Wenzlau JM et al (2007) The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. PNAS 104: 17040-17045.
10. Zhang L et al (2011) Prediction and prevention of type 1 diabetes mellitus. J Diabetes 3: 48-57