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

Nat Med. 2021 Jan;27(1):49-57. doi: 10.1038/s41591-020-1116-9. Epub 2021 Jan 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthropometry
  • Blood Glucose / metabolism
  • Body Composition
  • Cohort Studies
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Disease Progression
  • Disease Susceptibility
  • Female
  • Glucose Tolerance Test
  • Humans
  • Insulin / blood
  • Male
  • Middle Aged
  • Phenotype*

Substances

  • Blood Glucose
  • Insulin