den Hollander Nicoline H M, Roep Bart O
Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.
Graduate School, Utrecht University, Utrecht, Netherlands.
Front Med (Lausanne). 2022 Jul 12;9:932086. doi: 10.3389/fmed.2022.932086. eCollection 2022.
Type 1 diabetes (T1D) remains a devastating disease that requires much effort to control. Life-long daily insulin injections or an insulin pump are required to avoid severe complications. With many factors contributing to disease onset, T1D is a complex disease to cure. In this review, the risk factors, pathophysiology and defect pathways are discussed. Results from (pre)clinical studies are highlighted that explore restoration of insulin production and reduction of autoimmunity. It has become clear that treatment responsiveness depends on certain pathophysiological or genetic characteristics that differ between patients. For instance, age at disease manifestation associated with efficacy of immune intervention therapies, such as depleting islet-specific effector T cells or memory B cells and increasing immune regulation. The new challenge is to determine in whom to apply which intervention strategy. Within patients with high rates of insulitis in early T1D onset, therapy depleting T cells or targeting B lymphocytes may have a benefit, whereas slow progressing T1D in adults may be better served with more sophisticated, precise and specific disease modifying therapies. Genetic barcoding and immune profiling may help determining from which new T1D endotypes patients suffer. Furthermore, progressed T1D needs replenishment of insulin production besides autoimmunity reversal, as too many beta cells are already lost or defect. Recurrent islet autoimmunity and allograft rejection or necrosis seem to be the most challenging obstacles. Since beta cells are highly immunogenic under stress, treatment might be more effective with stress reducing agents such as glucagon-like peptide 1 (GLP-1) analogs. Moreover, genetic editing by CRISPR-Cas9 allows to create hypoimmunogenic beta cells with modified human leukocyte antigen (HLA) expression that secrete immune regulating molecules. Given the differences in T1D between patients, stratification of endotypes in clinical trials seems essential for precision medicines and clinical decision making.
1型糖尿病（T1D）仍然是一种极具破坏性的疾病，需要付出很大努力来控制。需要终身每日注射胰岛素或使用胰岛素泵，以避免严重并发症。由于多种因素导致疾病发作，T1D是一种难以治愈的复杂疾病。在本综述中，将讨论风险因素、病理生理学和缺陷途径。重点介绍了（临床前）研究结果，这些研究探索了胰岛素分泌的恢复和自身免疫的降低。已经清楚的是，治疗反应性取决于患者之间不同的某些病理生理或遗传特征。例如，疾病表现时的年龄与免疫干预疗法的疗效相关，如消耗胰岛特异性效应T细胞或记忆B细胞以及增强免疫调节。新的挑战是确定对谁应用哪种干预策略。在T1D发病早期胰岛炎发生率高的患者中，消耗T细胞或靶向B淋巴细胞的治疗可能有益，而成年人进展缓慢的T1D可能更适合采用更复杂、精确和特异的疾病修饰疗法。基因条形码和免疫谱分析可能有助于确定患者患哪种新的T1D内型。此外，进展期T1D除了逆转自身免疫外，还需要补充胰岛素分泌，因为已经有太多的β细胞丢失或功能缺陷。复发性胰岛自身免疫和同种异体移植排斥或坏死似乎是最具挑战性的障碍。由于β细胞在应激状态下具有高度免疫原性，使用胰高血糖素样肽1（GLP-1）类似物等减轻应激的药物进行治疗可能更有效。此外，CRISPR-Cas9基因编辑可以创建具有修饰的人类白细胞抗原（HLA）表达的低免疫原性β细胞，这些细胞可分泌免疫调节分子。鉴于患者之间T1D的差异，在临床试验中对内型进行分层对于精准医学和临床决策似乎至关重要。
