Partitioned Polygenic Risk Scores (pPRS) Associate with Insulin Dynamics and Type 2 Diabetes Incidence in Prediabetes
Background
The progression from prediabetes to Type 2 Diabetes (T2D) is characterized by declining insulin secretion and insulin sensitivity. While traditional risk factors are well-established, genetic predisposition, quantified by polygenic risk scores (PRS), offers a deeper understanding of individual risk. Specifically, partitioned PRS (pPRS) aim to dissect genetic risk into distinct pathophysiological pathways, such as those affecting β-cell function or insulin resistance. However, how these pPRS influence the intricate relationship between insulin secretion and sensitivity, and ultimately T2D incidence, in individuals with prediabetes remains a critical gap in personalized prevention strategies.
Study Design
Researchers investigated associations of two sets of partitioned polygenic risk scores (pPRS) with insulin dynamics and diabetes incidence within the Diabetes Prevention Program (DPP) cohort. The study included 2,052 DPP participants who were randomized to either intensive lifestyle intervention, metformin, or placebo. They generated 12 pPRS from a soft-clustering approach and 8 pPRS from a hard-clustering approach. Baseline insulin secretion demand and compensation were estimated by analyzing the relationship between insulin secretion and sensitivity. The primary endpoint was diabetes incidence over the study period, assessing how pPRS mediated or modified these associations.
Results
The study replicated most expected associations of pPRS with insulin secretion and insulin sensitivity, confirming their physiological relevance. Notably, some pPRS were specifically linked to lower secretion compensation. While individual pPRS showed relevant associations, global PRS demonstrated stronger associations with diabetes incidence compared to any single pPRS in both sets. The modifying effect of insulin secretion compensation and demand on pPRS associations with diabetes incidence was observed only for demand. Crucially, higher compensation consistently associated with decreased diabetes incidence, irrespective of the pPRS level. A specific β-cell dysfunction pPRS exhibited an interaction with DPP treatments, suggesting: > These treatments may be less effective in those genetically predisposed to diabetes due to insulin deficiency. This highlights a potential genetic influence on treatment response, where inadequate compensatory insulin secretion remains a key driver of progression to diabetes.
Key Findings
- Most expected associations of pPRS with insulin secretion and sensitivity were replicated.
- Global PRS associations with diabetes incidence were stronger than those of any individual pPRS.
- Higher insulin secretion compensation consistently associated with decreased diabetes incidence, irrespective of pPRS level.
- A
β-cell dysfunctionpPRS suggested reduced effectiveness of DPP treatments for individuals genetically predisposed to insulin deficiency.
Why It Matters
This research refines our understanding of how genetic predisposition, specifically through partitioned polygenic risk scores (pPRS), influences the progression from prediabetes to Type 2 Diabetes. For clinicians and individuals, it underscores that while genetic risk is a factor, compensatory insulin secretion is a critical, potentially modifiable mechanism that can mitigate diabetes progression, regardless of genetic background. The finding that a β-cell dysfunction pPRS may predict reduced efficacy of standard DPP interventions (lifestyle, metformin) suggests a future for genetically-informed personalized prevention strategies. This could lead to tailored interventions, where individuals with specific genetic predispositions might benefit from alternative or intensified approaches to preserve β-cell function.
polygenic risk score
type 2 diabetes
prediabetes
insulin secretion
insulin sensitivity
dpp