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. 2026 Feb 1;49(2):344-351.
doi: 10.2337/dc25-2006.

Genetic Predictors of Response to Oral Insulin for Type 1 Diabetes Prevention

Lu You  1 , Hemang M Parikh  1 , Taylor M Triolo  2 , Lauric A Ferrat  3   4 , Erin L Templeman  3 , Richard A Oram  3 , Peter A Gottlieb  2 , Stephen S Rich  5 , Suna Onengut-Gumuscu  5 , Andrea K Steck  2 , Jeffrey Krischer  1 , Maria J Redondo  6
Affiliations

Genetic Predictors of Response to Oral Insulin for Type 1 Diabetes Prevention

Lu You et al. Diabetes Care. .

Abstract

Objective: The TrialNet Oral Insulin Prevention Trial TN07 tested oral insulin to prevent stage 3 type 1 diabetes (T1D) in 560 relatives with stage 1 T1D of individuals with T1D. Of the three predefined risk strata, participants in secondary stratum 1 (SS1) (n = 55), characterized by low first-phase insulin release, responded significantly better to oral insulin. We aimed to identify genetic factors associated with treatment response.

Research design and methods: The TEDDY-T1DExomeChip was used to genotype 552 participants with available DNA. Cox models examined associations between response to oral insulin and HLA haplotypes, 33 preselected T1D-associated single nucleotide polymorphisms, T1D genetic risk score 2 (GRS2), and type 2 diabetes (T2D)-associated polygenic scores. For primary analyses, P values were Benjamini-Hochberg (BH) corrected for multiple comparisons; results not passing correction were considered nominal.

Results: GLIS3 rs7020673 was significantly associated with response to oral insulin in SS1 (BH-corrected P = 0.031 without and P = 0.022 with covariate adjustment). Additional nominal associations included better response with HLA-DRB1*04:01-DQA1*03:01-DQB1*03:02 (hazard ratio [HR] 0.22 vs. 1.09; unadjusted P = 0.031; adjusted P = 0.045) in SS1 and worse responses with TNFAIP3 and CTLA4 in at least one stratum. In exploratory analyses, participants with T1D-GRS2 >12.5 responded better to oral insulin (HR 0.68) than those with T1D-GRS2 ≤12.5 (HR 2.10; unadjusted P = 0.003; adjusted P = 0.006) in the overall cohort, and lower proinsulin- and obesity-partitioned T2D polygenic scores were associated with greater treatment benefit in SS1 and in another secondary stratum, respectively.

Conclusions: Genetic differences distinguish responders from nonresponders to oral insulin for T1D prevention. Genetics may enable precision medicine by identifying individuals likely to benefit from T1D-modifying therapies.

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Conflict of interest statement

Duality of Interest. R.A.O. has a grant to study GRSs for autoimmune diseases from Randox outside the submitted work. The University of Exeter has a licensing and royalty agreement with Randox for a 10-SNP T1D-GRS outside the submitted work. No other potential conflicts of interest relevant to this article were reported.

Figures

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Graphical abstract
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References

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