Increased Genetic Risk for β-Cell Failure Is Associated With β-Cell Function Decline in People With Prediabetes.

Area of Science:

• Genetics
• Metabolic Diseases
• Diabetes Research

Background:

• Partitioned polygenic scores (pPS) offer insights into the genetic architecture of complex diseases like type 2 diabetes (T2D).
• Understanding the genetic contribution to specific pathophysiologic processes in T2D is crucial for targeted prevention and treatment strategies.

Purpose of the Study:

• To investigate the association of T2D-related pPS with diabetes-specific traits and T2D incidence within the context of the Diabetes Prevention Program (DPP).
• To determine if genetic predisposition influences response to lifestyle or metformin interventions for T2D prevention.

Main Methods:

• Five T2D pPS (beta-cell, proinsulin, liver/lipid, obesity, lipodystrophy) were generated for 2,647 DPP participants. Associations with diabetes-related traits and T2D incidence were analyzed using general linear models and Cox regression.
• Analyses were adjusted for age, sex, principal components, and in sensitivity analyses, for body mass index (BMI).

Main Results:

• Higher beta-cell pPS was significantly associated with poorer beta-cell function (lower insulinogenic index and corrected insulin response) at 1-year follow-up, even after baseline adjustments.
• Beta-cell pPS showed a nominal association with increased T2D incidence when adjusted for BMI (HR 1.10 per SD, P = 0.035).
• Liver/lipid pPS was associated with reduced triglyceride levels at 1-year follow-up (effect per SD -4.37, P = 0.001). No significant interactions were found between pPS and DPP intervention groups.

Conclusions:

• Despite diabetes prevention interventions, individuals with a high genetic predisposition for beta-cell dysfunction (high beta-cell pPS) exhibited impaired beta-cell function.
• These findings highlight the persistent influence of genetic factors on T2D pathophysiology, irrespective of lifestyle or pharmacological interventions.