Diabetes Research Institute, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Miami, Miller School of Medicine, Miami, FL, USA.
Diabet Med. 2013 Feb;30(2):135-46. doi: 10.1111/dme.12081.
It is widely accepted that Type 1 diabetes is a complex disease. Genetic predisposition and environmental factors favour the triggering of autoimmune responses against pancreatic β-cells, eventually leading to β-cell destruction. Over 40 susceptibility loci have been identified, many now mapped to known genes, largely supporting a dominant role for an immune-mediated pathogenesis. This role is also supported by the identification of several islet autoantigens and antigen-specific responses in patients with recent onset diabetes and subjects with pre-diabetes. Increasing evidence suggests certain viruses as a common environmental factor, together with diet and the gut microbiome. Inflammation and insulin resistance are emerging as additional cofactors, which might be interrelated with environmental factors. The heterogeneity of disease progression and clinical manifestations is likely a reflection of this multifactorial pathogenesis. So far, clinical trials have been mostly ineffective in delaying progression to overt diabetes in relatives at increased risk, or in reducing further loss of insulin secretion in patients with new-onset diabetes. This limited success may reflect, in part, our incomplete understanding of key pathogenic mechanisms, the lack of truly robust biomarkers of both disease activity and β-cell destruction, and the inability to assess the relative contributions of various pathogenic mechanisms at various time points during the course of the natural history of Type 1 diabetes. Emerging data and a re-evaluation of histopathological, immunological and metabolic findings suggest the hypothesis that unknown mechanisms of β-cell dysfunction may be present at diagnosis, and may contribute to the development of hyperglycaemia and clinical symptoms.
人们普遍认为 1 型糖尿病是一种复杂的疾病。遗传易感性和环境因素有利于触发针对胰岛β细胞的自身免疫反应，最终导致β细胞破坏。已经确定了 40 多个易感位点，其中许多现在已经映射到已知基因上，这在很大程度上支持了免疫介导的发病机制起主要作用。在近期发病的糖尿病患者和糖尿病前期患者中，发现了几种胰岛自身抗原和抗原特异性反应，也支持了这一作用。越来越多的证据表明某些病毒是一种常见的环境因素，与饮食和肠道微生物群一起。炎症和胰岛素抵抗是新出现的另外两个辅助因素，它们可能与环境因素相互关联。疾病进展和临床表现的异质性可能反映了这种多因素发病机制。到目前为止，临床试验在延迟高危亲属发生显性糖尿病的进展或减少新发糖尿病患者胰岛素分泌进一步丧失方面大多无效。这种有限的成功可能部分反映了我们对关键发病机制的理解不完整，缺乏真正稳健的疾病活动和β细胞破坏的生物标志物，以及无法评估各种发病机制在 1 型糖尿病自然史的各个时间点相对贡献的能力。新出现的数据和对组织病理学、免疫学和代谢发现的重新评估表明，β细胞功能障碍的未知机制可能在诊断时就存在，并可能导致高血糖和临床症状的发展。
