Type 1 diabetes occurs as a consequence of progressive autoimmune destruction of beta cells. A potential treatment for this disease should address the immune attack on beta cells and their preservation/regeneration. The objective of this study was to elucidate whether the immunomodulatory synthetic oligonucleotide IMT504 was able to ameliorate diabetes in NOD mice and to provide further understanding of its mechanism of action. We found that IMT504 restores glucose homeostasis in a diabetes mouse model similar to human type 1 diabetes, by regulating expression of immune modulatory factors and improving beta cell function. IMT504 treatment markedly improved fasting glycemia, insulinemia, and homeostatic model assessment of beta cell function (HOMA-Beta cell) index. Moreover, this treatment increased islet number and decreased apoptosis, insulitis, and CD45⁺ pancreas-infiltrating leukocytes. In a long-term treatment, we observed improvement of glucose metabolism up to 9 days after IMT504 cessation and increased survival after 15 days of the last IMT504 injection. We postulate that interleukin (IL)-12B (p40), possibly acting as a homodimer, and Galectin-3 (Gal-3) may function as mediators of this immunomodulatory action. Overall, these results validate the therapeutic activity of IMT504 as a promising drug for type 1 diabetes and suggest possible downstream mediators of its immunomodulatory effect.

中文翻译：

---

寡核苷酸 IMT504 可改善雌性糖尿病 NOD 小鼠的葡萄糖代谢并控制免疫细胞介质

1 型糖尿病是 β 细胞进行性自身免疫性破坏的结果。这种疾病的潜在治疗方法应该解决对 β 细胞的免疫攻击及其保存/再生。本研究的目的是阐明免疫调节合成寡核苷酸 IMT504 是否能够改善 NOD 小鼠的糖尿病，并进一步了解其作用机制。我们发现 IMT504 通过调节免疫调节因子的表达和改善 β 细胞功能，在类似于人类 1 型糖尿病的糖尿病小鼠模型中恢复葡萄糖稳态。IMT504 治疗显着改善了空腹血糖、胰岛素血症和 β 细胞功能（HOMA-β 细胞）指数的稳态模型评估。此外，这种治疗增加了胰岛数量并减少了细胞凋亡、胰岛炎、⁺胰腺浸润白细胞。在长期治疗中，我们观察到在 IMT504 停止后长达 9 天的葡萄糖代谢改善，并在最后一次 IMT504 注射 15 天后增加存活率。我们假设白介素 (IL)-12B (p40) 可能充当同型二聚体，而 Galectin-3 (Gal-3) 可能充当这种免疫调节作用的介质。总体而言，这些结果验证了 IMT504 作为一种有前途的 1 型糖尿病药物的治疗活性，并表明其免疫调节作用的可能下游介质。