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The following is a summary of “Modulation of Functional Activity of INS-VNTR Class I Haplotype Derived from Type 1 Diabetic Patients,” published in the April 2025 issue of Journal of Clinical Endocrinology & Metabolism by Chen et al. 

The INS-VNTR class I haplotype was understood to control INS expression in the thymus, potentially contributing to insulin tolerance induction.  

Researchers conducted a retrospective study to examine the functional roles of distinct tandem repeat units (TRUs) from insulin autoantibody–positive and –negative individuals with T1D.  

They amplified INS-VNTR class I haplotypes using DNA samples from 28 individuals with T1D matched by gender, age, and HLA, and subcloned the fragments into the pGL3-luciferase vector. The INS-VNTR locus was sequenced to assess the composition and quantity TRUs, evaluated promoter activity of the INS-VNTR region, and measured its binding affinity with AIRE and screened for small molecules that enhanced INS-VNTR-luc2 reporter activity.  

The results showed that the mean number of TRUs was higher in IAA^– individuals than in IAA⁺ individuals (39.8 vs 35.2). Longer TRUs enhanced INS-VNTR promoter activity more effectively in the presence of an AIRE, suggesting a stronger potential for insulin expression and tolerance induction. The ChIP and pull-down assays confirmed differential AIRE binding based on TRU length, indicating variable INS transcriptional activity in the thymus, the AIRE interaction with INS-VNTR induced endogenous insulin transcript expression in vitro. All-trans retinoic acid (ATRA; vitamin A) was shown to stimulate INS-VNTR promoter activity, supporting its potential as an early intervention strategy for pre-diabetes.  

Investigators concluded that longer TRUs of the class I INS-VNTR haplotype favored INS expression in the thymus and tolerance induction, suggesting that vitamin A supplementation could be beneficial for preventing insulin autoimmunity in the early stages of T1D onset. 

Source: academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaf243/8113930