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
diabetes2,3 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.
