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Oral insulin delay of Stage 3 type 1 diabetes revisited in HLA DR4-DQ8 participants in the TrialNet Oral Insulin Prevention Trial (TN-07)

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posted on 2024-07-01, 15:31 authored by Lue Ping Zhao, George K. Papadopoulos, Jay S. Skyler, Hemang M. Parikh, William W. Kwok, George P. Bondinas, Antonis K. Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark

Objective To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among stage 1/2 patients who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2A).

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 preventative efficacy of oral insulin .

Results 1) Oral insulin was found to reduce 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). 2) High IA-2A levels were found to be positively associated with the HLA DR4-DQ8 (OR=1.63, p=6.37*10-6) haplotype and negatively associated with the HLA DR7-containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 (OR=0.49, p=0.037) extended haplotype. 3) Among DR4-DQ8 carriers, oral insulin delayed the progression towards stage 3 T1D onset (HR=0.59, p=0.027), especially if participants also had high IA-2A levels (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, and, for those stage 1/2 patients with such an endotype, oral insulin is found to delaythe clinical T1D onset.

Funding

The study was supported by a grant (RO1 DK132406) from the National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

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