近日，来自美国斯坦福大学医学院的研究人员在国际学术期刊JCI上发表了一项最新研究进展，他们发现在1型糖尿病发病前期胰腺内一种物质的累积对于该疾病的发展非常重要，而一种用于胆结石相关痉挛治疗的药物能够阻断小鼠模型体内这种物质的合成，延缓胰岛beta细胞受到的损伤，对于防止这种自身免疫性紊乱的发生具有一定作用。
最近的一些研究已经发现细胞外基质中的透明质酸发生大量沉积是1型糖尿病病人体内自身免疫性胰岛炎的一个显著特性，但这些透明质酸沉积与1型糖尿病之间的关系仍不清楚。
在这项研究中，研究人员发现透明质酸对于自身免疫性糖尿病的发病至关重要。研究人员利用一种1型糖尿病小鼠模型证明透明质酸的沉积在时间和解剖学上都与胰岛炎的发生相关。他们使用一种透明质酸合成抑制剂--4-MU对小鼠进行治疗，结果发现即使是在胰岛炎发生之后，药物治疗仍然可以延缓糖尿病进展，研究人员还在另外一种1型糖尿病小鼠模型--NOD小鼠上观察到了类似的效应。并且对这些小鼠进行1周的药物治疗足以防止糖尿病的发生。
研究人员证明4-MU能够减少HA的累积，限制效应T细胞的作用，并增加胰岛内FOXP3阳性Treg细胞的数目。与此现象一致的是，HA和抗CD44抗体能够抑制Treg细胞分化，而用4-MU进行治疗可以通过ERK1/2依赖性方式挽救Treg细胞的分化过程。
研究人员指出，目前仍然没有药物能够在人体内做到这一点，因此他们目前正在与FDA进行合作准备进行4-MU治疗1型糖尿病的临床试验，如果这种药物的效果能够得到临床验证，将会为1型糖尿病的治疗带来新的曙光。
Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis
Nadine Nagy1, Gernot Kaber1, Pamela Y. Johnson2, John A. Gebe2, Anton Preisinger2, Ben A. Falk2, Vivekananda G. Sunkari1, Michel D. Gooden2, Robert B. Vernon2, Marika Bogdani2, Hedwich F. Kuipers1, Anthony J. Day3, Daniel J. Campbell4, Thomas N. Wight2, and Paul L. Bollyky
We recently reported that abundant deposits of the extracellular matrix polysaccharide hyaluronan (HA) are characteristic of autoimmune insulitis in patients with type 1 diabetes (T1D), but the relevance of these deposits to disease was unclear. Here, we have demonstrated that HA is critical for the pathogenesis of autoimmune diabetes. Using the DO11.10RIPmOVA mouse model of T1D, we determined that HA deposits are temporally and anatomically associated with the development of insulitis. Moreover, treatment with an inhibitor of HA synthesis, 4-methylumbelliferone (4-MU), halted progression to diabetes even after the onset of insulitis. Similar effects were seen in the NOD mouse model, and in these mice, 1 week of treatment was sufficient to prevent subsequent diabetes. 4-MU reduced HA accumulation, constrained effector T cells to nondestructive insulitis, and increased numbers of intraislet FOXP3+ Tregs. Consistent with the observed effects of 4-MU treatment, Treg differentiation was inhibited by HA and anti-CD44 antibodies and rescued by 4-MU in an ERK1/2-dependent manner. These data may explain how peripheral immune tolerance is impaired in tissues under autoimmune attack, including islets in T1D. We propose that 4-MU, already an approved drug used to treat biliary spasm, could be repurposed to prevent, and possibly treat, T1D in at-risk individuals.