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

Area of Science:

• Endocrinology
• Metabolic Disease Research
• Personalized Medicine

Background:

• Intermediate hyperglycemia, or prediabetes, signifies increased type 2 diabetes risk.
• Current prediabetes definitions lack predictive power for disease progression and underlying pathophysiology.
• Heterogeneity in prediabetes may influence future metabolic health and complication risks.

Purpose of the Study:

• To identify distinct pathophysiological subphenotypes of prediabetes.
• To determine if these subphenotypes predict differential risks for type 2 diabetes and other complications.
• To validate findings in an independent cohort.

Main Methods:

• Utilized partitioning on variables from oral glucose tolerance tests, MRI-assessed body fat distribution, liver fat content, and genetic risk.
• Analyzed an extensively phenotyped cohort at increased risk for type 2 diabetes.
• Replicated findings in an independent cohort using anthropometric and glycemic data.

Main Results:

• Identified six distinct prediabetes subphenotypes (clusters).
• Clusters 3 and 5 showed imminent type 2 diabetes risk.
• Cluster 6 exhibited moderate type 2 diabetes risk but elevated risks for kidney disease and all-cause mortality.
• Findings were replicated in an independent cohort.

Conclusions:

• Significant pathophysiological heterogeneity exists within prediabetes.
• Subphenotyping prediabetes can identify individuals at high risk for complications beyond type 2 diabetes.
• This approach enables more precise risk stratification and personalized management strategies for individuals with intermediate hyperglycemia.