miR-30d-5p promotes beta cell recovery and immunomodulation in type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing beta cells, leading to hyperglycemia. A transient partial remission (PR) phase, marked by improved glycemic control and suppressed autoimmunity, often occurs shortly after diagnosis. We hypothesized that miR-30d-5p, which is highly upregulated during the PR phase in children, may contribute to immune regulation and beta cell recovery.

We investigated the role of miR-30d-5p using human pancreatic slices (HPSs), non-obese diabetic (NOD) mice and human peripheral blood samples. HPSs were transfected with miR-30d-5p oligonucleotides to examine post-transcriptional regulation mechanisms. RNA sequencing was conducted in HPSs to identify differentially expressed genes. Functional assays included insulin secretion, and lineage tracing of beta cells. Additionally, non-obese diabetic (NOD) mice were treated with miR-30d-5p to evaluate effects on diabetes onset and incidence. T cell phenotyping and cytokine secretion were assessed in human T cells from patients with T1D.

HPS transfection was successfully achieved, providing a model to investigate the effects of the miRNA in insulin-expressing cells. Functional studies suggested that miR-30d-5p contributes to insulin secretion, and lineage tracing was consistent with the emergence of insulin-producing cells. RNA sequencing identified transcriptional changes associated with pathways related to beta cell function and cellular differentiation. In NOD mice, miR-30d-5p treatment was associated with delayed diabetes onset, suggesting potential immunomodulatory and beta cell-protective effects. In human T lymphocytes, miR-30d-5p was associated with increased expression of inhibitory molecules (PD-1, CTLA-4, CD200, TIM-3, LAG-3) and modulated interferon-gamma secretion.

Our findings suggest that miR-30d-5p may participate in in immune cell regulation and processes associated with beta cell recovery in T1D. This study highlights the complex interaction between immune and epigenetic mechanisms during the PR phase and supports further investigation of miR-30d-5p as a potential therapeutic target for preserving beta cell function.