Background: Pancreatic fat (PF) related beta-cell failure might play a role in the pathophysiology of type 2 diabetes (T2D). We hypothesized that the effect of PF on beta-cell function can be modeled as a gene x environment interaction. To this end, we investigated the association of PF with insulin secretion in subjects with different genetic predisposition for T2D.

Methods: A genome-wide polygenic risk score (gwPRS) was computed combining summary statistics from a genome-wide association study with ∼900.000 participants and 480.000 genetic variants in our cohort. The interaction of MRI-measured PF with gwPRS was investigated in 376 nondiabetic participants.

Results: PF interacted with gwPRS on insulin secretion after adjustment for confounders (p=0.001). In participants with low gwPRS, PF associated positively with insulin secretion. In participants with high gwPRS, there was a negative association with insulin secretion.

Discussion: PF is a pathophysiologic factor potentially contributing to both primary insulin hypersecretion and impairment of insulin secretion, dependent on genetic predisposition.


B. Jaghutriz: None. M. Heni: Research Support; Self; Boehringer Ingelheim International GmbH, Sanofi. Speaker's Bureau; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Sanofi. J. Machann: None. F. Schick: None. S. Ullrich: Advisory Panel; Spouse/Partner; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp & Dohme Corp., Mylan, Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H. Haering: None. A. Fritsche: None. R. Wagner: Other Relationship; Self; Lilly Diabetes, Novo Nordisk A/S.


German Federal Ministry of Education and Research

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