Global and Partitioned Polygenic Risk Scores: Associations With Pathophysiology and Incidence of Type 2 Diabetes in...

Type 2 diabetes partitioned polygenic risk scores (pPRS) are related to their physiological impact on insulin secretion and sensitivity. We investigated associations of two pPRS sets obtained from multiancestry cohorts with the relationship between insulin secretion and sensitivity and diabetes incidence in the Diabetes Prevention Program (DPP). We generated 12 and 8 pPRS from soft- and hard-clustering approaches, respectively, in 2,052 DPP participants randomized to intensive lifestyle intervention, metformin, or placebo. Baseline insulin secretion demand and compensation were estimated through the relationship between secretion and sensitivity. Most expected associations of pPRS with insulin secretion and sensitivity were replicated. Some pPRS associated with lower secretion compensation. Global PRS associations with diabetes incidence were stronger than those of any pPRS in both sets. When insulin secretion compensation and demand modified pPRS associations with diabetes incidence, modification occurred only for demand: higher compensation associated with decreased diabetes incidence regardless of pPRS level. A β-cell dysfunction pPRS interacted with DPP treatments in a way that suggested that these treatments may be less effective in those genetically predisposed to diabetes due to insulin deficiency. Regardless of genetic risk as measured by pPRS, inadequate compensatory insulin secretion contributes to progression to diabetes in people with prediabetes.

The extent to which partitioned polygenic risk scores (pPRS) for type 2 diabetes influence the relationship between insulin secretion and sensitivity has not been examined in people with prediabetes. We investigated whether insulin secretion compensation and demand, estimated through the relationship between insulin secretion and sensitivity, mediated or modified the associations of two sets of pPRS with diabetes incidence in Diabetes Prevention Program participants. Several pPRS modified the effects of insulin demand on diabetes incidence, but none modified the effect of compensation. In people with prediabetes, inadequate compensatory insulin secretion contributes to progression to diabetes regardless of genetic risk as measured by pPRS.