Oral Insulin Delay of Stage 3 Type 1 Diabetes Revisited in HLA DR4-DQ8 Participants in the TrialNet Oral Insulin Prevention Trial (TN07)
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OBJECTIVE: To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among patients with stage 1/2 who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2As). RESEARCH AND METHODS: Next-generation targeted sequencing technology was used to genotype eight HLA class II genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, and DPB1) in 546 participants in the TrialNet oral insulin preventative trial (TN07). Baseline levels of autoantibodies against insulin (IAA), GAD65 (GADA), and IA-2A were determined prior to treatment assignment. Available clinical and demographic covariables from TN07 were used in this post hoc analysis with the Cox regression model to quantify the preventive efficacy of oral insulin. RESULTS: Oral insulin reduced the frequency of T1D onset among participants with elevated IA-2A levels (HR 0.62; P = 0.012) but had no preventive effect among those with low IA-2A levels (HR 1.03; P = 0.91). High IA-2A levels were positively associated with the HLA DR4-DQ8 haplotype (OR 1.63; P = 6.37 × 10−6) and negatively associated with the HLA DR7–containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 extended haplotype (OR 0.49; P = 0.037). Among DR4-DQ8 carriers, oral insulin delayed the progression toward stage 3 T1D onset (HR 0.59; P = 0.027), especially if participants also had high IA-2A level (HR 0.50; P = 0.028). CONCLUSIONS: These results suggest the presence of a T1D endotype characterized by HLA DR4-DQ8 and/or elevated IA-2A levels; for those patients with stage 1/2 disease with such an endotype, oral insulin delays the clinical T1D onset.
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Two phase 2 trials of daily oral administration of 7.5 mg insulin in children with multiple autoantibodies showed no significant effect in delaying the onset of clinical diabetes; however, subgroup analyses showed a delay in disease progression in individuals with impaired insulin secretion, with the HLA DR4-DQ8 haplotype, or with high concentrations of insulin or IA2 autoantibodies.
“Two phase 2 trials evaluated daily oral administration of 7•5 mg insulin in children with multiple autoantibodies.40,41 Neither trial showed a significant effect in delaying the onset of clinical diabetes; however, subgroup analyses showed a delay in disease progression in individuals with impaired insulin secretion, with the HLA DR4DQ8 haplotype, or with high concentrations of insulin or IA2 auto”
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- Authors
- Zhao, L. P., Papadopoulos, G. K., Skyler, J. S., Parikh, H. M., Kwok, W. W., Bondinas, G. P., Moustakas, A. K., Wang, R., Pyo, C.-W., Nelson, W. C., Geraghty, D. E., & Lernmark, Å.
- Affiliations
- University of Washington (US)
- Technological Educational Institute of Epirus (GR)
- University of Miami (US)
- University of South Florida (US)
- Benaroya Research Institute (US)
- Ionian University (GR)
- Fred Hutch Cancer Center (US)
- Lund University (SE)
- Corresponding author
- Zhao, Lue Ping
- Lernmark, Åke
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2024-07-01
- Volume
- 47
- Issue
- 9
- Pages
- 1608-1616
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC11362107
- OpenAlex
- W4400195161
- Cited by
- 20
- References
- 38
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 1
- FWCI
- 5.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Division of Diabetes, Endocrinology, and Metabolic Diseases (RO1 DK132406)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- oral insulin, type 1 diabetes prevention, HLA-DR4-DQ8, IA-2 autoantibodies, HLA class II haplotypes, insulin autoantibodies, GAD65 antibodies, disease endotypes
- MeSH terms
- Administration, Oral, Adolescent, Adult, Autoantibodies, Child, Diabetes Mellitus, Type 1, Female, HLA-DQ Antigens, Humans, Insulin, Male, HLA-DR4 Antigen
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