Pancreatic steatosis associates with impaired insulin secretion in genetically predisposed individuals

CONTEXT Pancreatic steatosis leading to beta-cell failure might be involved in type 2 diabetes (T2D) pathogenesis. OBJECTIVE We hypothesized that the genetic background modulates the effect of pancreatic fat on beta-cell function and investigated genotype x pancreatic fat interactions on insulin secretion. DESIGN Two observational studies. SETTING University Hospital. PATIENTS OR PARTICIPANTS 360 non-diabetic individuals with elevated risk for T2D (Tuebingen Family Study, TUEF), and 64 patients undergoing pancreatectomy (Pancreas Biobank, PB, HbA1c<9%, no insulin therapy). MAIN OUTCOME MEASURES Insulin secretion calculated from 5-point OGTT (TUEF) and fasting blood collection prior to surgery (PB). A genome-wide polygenic score for T2D was computed from 484.788 genotyped variants. The interaction of MRI-measured and histologically quantified pancreatic fat with the polygenic score was investigated. Partitioned risk scores using genome-wide significant variants were also computed to gain insight into potential mechanisms. RESULTS Pancreatic steatosis interacted with genome-wide polygenic score on insulin secretion (p=0.003), which was similar in the replication cohort with histological measurements (p=0.03). There was a negative association between pancreatic fat and insulin secretion in participants with high genetic risk, while individuals with low genetic risk showed a positive correlation between pancreatic fat and insulin secretion. Consistent interactions were found with insulin-resistance-specific and a liver/lipid-specific polygenic scores. CONCLUSIONS The associations suggest that pancreatic steatosis only impairs beta-cell function in subjects at high genetic risk for diabetes. Genetically determined insulin resistance specifically renders pancreatic fat deleterious for insulin secretion.