Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes.sup.1. 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.sup.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 constructs.sup.4. 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. Clustering of patients with prediabetes using simple clinical features reveals six distinct groups with differing risk of developing type 2 diabetes and its associated complications.
Author(s): Robert Wagner [sup.1] [sup.2] [sup.3] , Martin Heni [sup.1] [sup.2] [sup.3] [sup.4] , Adam G. Tabák [sup.5] [sup.6] [sup.7] , Jürgen Machann [sup.1] [sup.2] [sup.8] , Fritz Schick [sup.2] [...]