Stratifying Diabetes: Desperately Seeking Specificity

In 1836 William Barret Travis drew his sword and marked a line in the sand. Those willing to stay and defend the Alamo fort were invited to cross the line; in doing so, like Davy Crockett they became immortal, whereas those remaining on the other side of that line were broadly lost to history. Travis was a “splitter.” Physicians, also, tend to be “splitters,” designating individuals with or without disease and subdividing those with disease into groups according to key features (1). Diseases gain identity through clinical phenotype. Only in recent years have we incorporated genetic and nongenetic laboratory-based features into that identity. In doing so, we seek to encapsulate each disease as a categorical entity.

But diabetes has confounded categorization, in part because its key elements are not exclusive to the disease (1–4). Even raised blood glucose is only a proxy for loss of the homeostatic relationship between insulin secretion and insulin sensitivity—a relationship whose tipping point is designated “diabetes” when the risk of retinopathy increases. Initially characterized by the striking clinical phenotype of juvenile-onset diabetes, that classification evolved historically according to therapy (insulin-dependent diabetes) and then immunogenetic features (type 1 diabetes, T1D). The remaining cohort without these characteristic features were designated adult-onset diabetes, non–insulin-dependent diabetes, or, nowadays, type 2 diabetes (T2D). A proportion …