Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 11; pp. 3518 - 3525
• Main Authors: Wagner, Róbert, Jaghutriz, Benjamin Assad, Gerst, Felicia, Barroso Oquendo, Morgana, Machann, Jürgen, Schick, Fritz, Löffler, Markus W, Nadalin, Silvio, Fend, Falko, Königsrainer, Alfred, Peter, Andreas, Siegel-Axel, Dorothea, Ullrich, Susanne, Häring, Hans-Ulrich, Fritsche, Andreas, Heni, Martin
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.11.2020; Copyright Oxford University Press
• Subjects: Adipose Tissue - diagnostic imaging; Aged; Beta cells; Blood banks; Blood Glucose; Body Mass Index; Clinical s; Dextrose; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes therapy; Female; Genetic aspects; Genetic Predisposition to Disease; Genomes; Genomics; Genotypes; Glucose; Glucose tolerance; Glucose Tolerance Test; Glucose tolerance tests; Glycosylated hemoglobin; Humans; Insulin; Insulin resistance; Insulin Resistance - genetics; Insulin secretion; Insulin Secretion - genetics; Magnetic resonance imaging; Male; Medical research; Medicine, Experimental; Middle Aged; Pancreas; Pancreas - diagnostic imaging; Pancreas - metabolism; Pancreatic Diseases - diagnostic imaging; Pancreatic Diseases - genetics; Pancreatic Diseases - metabolism; Patients; Prediabetic state; Secretion; Steatosis; Surgery; Type 2 diabetes; Germany; type 2 diabetes; insulin secretion; pancreatic steatosis; non-alcoholic fatty pancreas disease; prediabetes; beta cell function
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgaa435

Abstract 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.