Park Yongsoo, Ko Kyung Soo, Rhee Byoung Doo
Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul 01757, Republic of Korea.
Int J Mol Sci. 2025 Mar 31;26(7):3249. doi: 10.3390/ijms26073249.
Type 1 diabetes (T1D) is generally viewed as an etiologic subtype of diabetes caused by the autoimmune destruction of the insulin-secreting β-cells. It has been known that autoreactive T cells unfortunately destroy healthy β-cells. However, there has been a notion of etiologic heterogeneity around the world implicating a varying incidence of a non-autoimmune subgroup of T1D related to insulin deficiency associated with decreased β cell mass, in which the β-cell is the key contributor to the disease. Beta cell dysfunction, reduced mass, and apoptosis may lead to insufficient insulin secretion and ultimately to the development of T1D. Interestingly, Korean as well as other ethnic genetic results have also suggested that genes related with insulin deficiency, let alone those of immune regulation, were associated with the risk of T1D in the young. Genes related with insulin secretion may influence the phenotype of diabetes differentially and different genes may be working on different steps of T1D development. Although we admit the consensus that islet autoimmunity is an essential component in the pathogenesis of T1D, however, dysfunction might occur not only in the immune system but also in the β-cells, the defect of which may induce further dysfunction of the immune system. These arguments stem from the fact that the β-cell might be the trigger of an autoimmune response. This emergent view has many parallels with the fact that by their nature and function, β-cells are prone to biosynthetic stress with limited measures for self-defense. Beta cell stress may induce an immune attack that has considerable negative effects on the production of a vital hormone, insulin. If then, both β-cell stress and islet autoimmunity can be harnessed as targets for intervention strategies. This also may explain why immunotherapy at best delays the progression of T1D and suggests the use of alternative therapies to expand β-cells, in combination with immune intervention strategies, to reverse the disease. Future research should extend to further investigate β-cell biology, in addition to studies of immunologic areas, to find appropriate biomarkers of T1D susceptibility. This will help to decipher β-cell characteristics and the factors regulating their function to develop novel therapeutic approaches.
1型糖尿病（T1D）通常被视为一种由胰岛素分泌β细胞的自身免疫性破坏引起的糖尿病病因亚型。已知自身反应性T细胞不幸地破坏健康的β细胞。然而，世界各地存在病因异质性的概念，这意味着与胰岛素缺乏相关的T1D非自身免疫亚组的发病率各不相同，胰岛素缺乏与β细胞数量减少有关，其中β细胞是该疾病的关键促成因素。β细胞功能障碍、数量减少和凋亡可能导致胰岛素分泌不足，并最终导致T1D的发生。有趣的是，韩国以及其他种族的基因研究结果也表明，与胰岛素缺乏相关的基因，更不用说免疫调节基因了，与年轻人患T1D的风险有关。与胰岛素分泌相关的基因可能对糖尿病的表型产生不同的影响，不同的基因可能在T1D发展的不同阶段起作用。尽管我们承认胰岛自身免疫是T1D发病机制中的一个重要组成部分，然而，功能障碍不仅可能发生在免疫系统中，也可能发生在β细胞中，β细胞的缺陷可能会导致免疫系统进一步功能障碍。这些观点源于β细胞可能是自身免疫反应触发因素这一事实。这种新出现的观点与以下事实有许多相似之处，即从其性质和功能来看，β细胞容易受到生物合成应激的影响，且自我防御措施有限。β细胞应激可能引发免疫攻击，这对重要激素胰岛素的产生有相当大的负面影响。如果是这样，那么β细胞应激和胰岛自身免疫都可以作为干预策略的靶点。这也可以解释为什么免疫疗法充其量只能延缓T1D的进展，并建议使用替代疗法来增加β细胞数量，结合免疫干预策略来逆转疾病。未来的研究除了免疫领域的研究外，还应进一步扩展到对β细胞生物学的研究，以找到T1D易感性的合适生物标志物。这将有助于解读β细胞的特征以及调节其功能的因素，从而开发新的治疗方法。
