Harmine Plus Exendin-4 Enhances Remission of Recent-Onset Type 1 Diabetes Following Anti-CD3 Therapy

Abstract

Type 1 diabetes (T1D) results from autoimmune destruction of pancreatic {beta}-cells. While anti-CD3 therapy can delay disease progression and preserve residual {beta}-cell function, disease reversal will likely require both immune modulation and {beta}-cell regeneration. We found that the combination of harmine and exendin-4 (H+E) reduced inflammation-induced human {beta}-cell apoptosis, suppressed cytokine signaling and immunogenicity pathways, and improved {beta}-cell function. Although H+E alone did not reverse diabetes in NOD mice, low-dose anti-CD3 followed by H+E normalized blood glucose, increased insulin levels, improved glucose tolerance, expanded {beta}-cell mass, and enhanced diabetes remission. These effects were associated with reduced pro-inflammatory T-cell responses, increased regulatory T cells, and greater expression of exhaustion-related T-cell markers, without broad lymphocyte depletion. Similar immunomodulatory effects were observed in activated human PBMCs. Transcriptomic analyses identified the lncRNA SNHG6 as a key mediator of H+E action; SNHG6 protected {beta}-cells from cytokine-induced stress, apoptosis, and immunogenicity. Together, these findings demonstrate that H+E promotes {beta}-cell recovery and resilience while reducing {beta}-cell immunogenicity, enabling remission of recent-onset T1D when combined with anti-CD3 therapy. SNHG6 emerges as a novel regulator of {beta}-cell protection during inflammation.