Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 105, Issue 11, Pages -Publisher
ENDOCRINE SOC
DOI: 10.1210/clinem/dgaa435
Keywords
beta cell function; insulin secretion; non-alcoholic fatty pancreas disease; pancreatic steatosis; prediabetes; type 2 diabetes
Categories
Funding
- Federal Ministry of Education and Research (BMBF) [01GI0925]
- European Union [155005, 115881]
- EFPIA
- Swiss State Secretariat for Education, Research and Innovation (SERI) [16.0097]
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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: A total of 360 nondiabetic 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 oral glucose tolerance test (TUEF) and fasting blood collection before surgery (PB). A genome-wide polygenic score for T2D was computed from 484,788 genotyped variants. The interaction of magnetic resonance imaging-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, whereas 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.
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