The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.

中文翻译：

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引入内型概念以应对1型糖尿病中疾病异质性的挑战。

多年来，新发1型糖尿病的临床诊断一直被认为相对简单。然而，近来，人们越来越意识到，在这种单一的临床表型中，存在着相当大的异质性：疾病的发作跨越了整个年龄范围；遗传易感性很复杂；进展速度显着不同，胰岛素分泌能力也存在显着差异；并发症发生率，血糖控制和治疗干预效果差异很大。机械学和免疫病理学研究通常显示受试者之间相当大的斑驳，破坏了有关疾病途径的结论。在没有更好的理解的情况下，1型糖尿病的异质性代表着主要的障碍，既阻碍了发病机理的破译，也阻碍了设计，进行，并解释疾病改良剂的临床试验。这种认识发生在临床医学发生前所未有的变化的时期，并且越来越强调更大的个性化和更高的精确度。对于诸如1型糖尿病的复杂疾病，维持“单一疾病”方法的选择似乎是站不住脚的，个体化每个患者的护理的观念也是如此，这使我们不得不从表型（可观察到的特征）和概念上减少1型糖尿病的概念。在疾病内型方面（潜在的生物学机制）更多。在这里，我们提供一种分析1型糖尿病异质性的方法的观点。借鉴其他疾病的经验教训和迄今为止收集的数据，我们旨在描绘一个路线图，通过该路线图，该领域可以将内型概念纳入实验室和临床实践。我们预计，这样的努力将加速精密医学的实施，并可能对我们的转化研究，试验设计和临床管理方法产生影响。