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

Abstract

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes 1 . However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is it 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 immanent 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 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..

Phenotyping the Prediabetic Population—A Closer Look at Intermediate Glucose Status and Cardiovascular Disease

“…Both also had a risk of nephropathy, but only sub-phenotype 5 had a high mortality risk. Another interesting finding was that there was a category of patients who had an increased risk of developing renal disease and all-cause mortality independent of the development of T2DM [31,36].…”

“…It is well established that T2DM is a heterogeneous disease revolving around beta-cell failure. Several studies concluded that pathophysiological heterogeneity exists before the diagnosis of diabetes, although this fact is not yet reflected in the current definition of prediabetes [31]. While isolated IGT is mostly associated with obesity and IR, the primary abnormality in isolated IFG is β-cell dysfunction with impaired insulin secretion [1].…”

“…To this end, a very recent study uses measurements linked to the glucose metabolism as well as variables of diabetes pathogenesis in order to sub-classify prediabetes. These variables are HDL, IR, insulin secretion, IFG, a genetic risk score for T2DM risk, and MRI measurements of fat compartments and liver fat content [31]. In order to simplify and to perform phenotyping where the data above were not available for another cohort, they used theoretically similar variables such as glycemia during glucose challenge, insulin sensitivity, insulin secretion, fasting insulin, fasting triglycerides, waist circumference, hip circumference, BMI, and HDL cholesterol.…”

“…Figure 2.A stratified screening process for prediabetes. ASCVD, atherosclerotic cardiovascular disease; cluster 3, high-risk prediabetic phenotype with low insulin secretion and high genetic risk; cluster 5, high-risk prediabetic phenotype, high liver fat content, and high IR[31]; CVD, cardiovascular disease; DM, diabetes mellitus; PDM, prediabetes.…”

SYmptom-Based STratification of DiabEtes Mellitus by Renal Function Decline (SYSTEM): A Retrospective Cohort Study and Modeling Assessment

“…Patient reported outcomes and symptom-based diagnosis are increasingly used in all levels of healthcare ( 6 ) including evaluation of clinical interventions ( 10 – 12 ), disease diagnosis, surveillance ( 13 ), and stratification ( 7 , 14 – 17 ). Clustering of symptom is associated with specific cluster of etiology and pathogenesis ( Figure 1 ) ( 7 , 15 , 16 , 18 ). Different diseases of similar symptomatology share genetic associations and protein-protein interactions ( 9 ).…”