Longitudinal Metabolic Trajectories in Diabetes Prevention Program Participants Reveal Subgroups With Varying Micro-...

Area of Science:

• Metabolic health and disease progression
• Longitudinal studies in diabetes research
• Clinical phenotyping and risk stratification

Background:

• Type 2 diabetes (T2D) and its complications develop over decades, with limited understanding of early progression from prediabetes.
• Heterogeneity in disease development necessitates identifying distinct patient subgroups for targeted interventions.

Purpose of the Study:

• To investigate if long-term metabolic trajectories starting in prediabetes can identify subgroups with different risks of T2D complications.
• To analyze how metabolic patterns influence the development of microvascular and macrovascular events.

Main Methods:

• Analysis of clinical data from 1,732 participants in the Diabetes Prevention Program/Outcomes Study over 19 years.
• Utilized tensor decomposition to identify longitudinal patterns and Gaussian mixture modeling for cluster definition.
• Quantified cluster-specific complication risks using Cox and logistic regression.

Main Results:

• Four distinct metabolic clusters were identified.
• Two clusters (73%) showed stable metabolic profiles with low complication rates despite T2D development.
• One cluster (12%) exhibited rapid insulin resistance and hyperglycemia, leading to high rates of retinopathy and neuropathy.
• A fourth cluster (15%) presented with early microalbuminuria and progressive kidney function decline, doubling cardiovascular event risk.

Conclusions:

• Most individuals with prediabetes (two-thirds) follow metabolically resilient paths.
• Distinct trajectories of insulin resistance or renal dysfunction precede micro- or macrovascular complications.
• Intervention for individuals with prediabetes and microalbuminuria should occur before T2D onset to optimize macrovascular event prevention.