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Wagner, R. ; Jaghutriz, B.A. ; Gerst, F. ; Barroso Oquendo, M. ; Machann, J. ; Schick, F. ; Löffler, M.* ; Nadalin, S.* ; Fend, F.* ; Königsrainer, A.* ; Peter, A. ; Siegel-Axel, D. ; Ullrich, S. ; Häring, H.-U. ; Fritsche, A. ; Heni, M.

Pancreatic steatosis associates with impaired insulin secretion in genetically predisposed individuals.

J. Clin. Endocrinol. Metab. 105:dgaa435 (2020)

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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 × 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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Beta Cell Function ; Insulin Secretion ; Non-alcoholic Fatty Pancreas Disease ; Pancreatic Steatosis ; Prediabetes ; Type 2 Diabetes; Beta-cell Function; Fatty Pancreas; Glucose-tolerance; Accuracy; Risk

ISSN (print) / ISBN 0021-972X

e-ISSN 1945-7197

Journal Journal of Clinical Endocrinology & Metabolism, The

Quellenangaben Volume: 105, Issue: 11, Article Number: dgaa435

Publisher Endocrine Society

Publishing Place Bethesda, Md.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)

Grants Swiss State Secretariat for Education, Research and Innovation (SERI)
EFPIA
European Union
Federal Ministry of Education and Research (BMBF)