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

<p dir="ltr"><i>Objective</i><i> </i>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).</p><p dir="ltr"><i>Research and methods</i><i> </i>Next generation targeted sequencing technology was used to genotype eight <i>HLA class II</i> genes (<i>DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, </i>and <i>DPB1)</i> 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 .</p><p dir="ltr"><i>Results</i><i> </i>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 <i>HLA DR4-DQ8</i> (OR=1.63, p=6.37*10^-6) haplotype and negatively associated with the <i>HLA DR7</i>-containing <i>DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 </i>(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).</p><p dir="ltr"><i>Conclusions</i> 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.</p>