The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes¹. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes^2,3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs⁴. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.

中等高血糖状态表明患 2 型糖尿病的风险升高¹。然而，目前对前驱糖尿病的定义既不能反映 2 型糖尿病病理生理学的亚表型，也不能预测未来的代谢轨迹。我们对来自口服葡萄糖耐量测试、MRI 测量的体脂肪分布、肝脏脂肪含量和遗传风险的变量进行了划分，这些变量来自一组具有广泛表型且 2 型糖尿病风险增加的个体^2,3以确定六个不同的亚表型簇。三种已确定的亚表型血糖升高（第 3、5 和 6 组），但只​​有第 5 组和第 3 组中的个体具有迫在眉睫的糖尿病风险。相比之下，第 6 类人群患 2 型糖尿病的风险中等，但患肾病和全因死亡率的风险增加。^{使用简单的拟人化和血糖结构4}在独立队列中重复了研究结果。这项概念验证研究表明，在诊断出 2 型糖尿病之前就存在病理生理学异质性，并强调了一组在没有快速进展为明显 2 型糖尿病的情况下并发症风险增加的个体。