Association of Pancreas Fat with Impaired Insulin Secretion Depends on Liver Fat and Circulating Fatty Acids

Objective: Beta cell failure is a crucial factor in the pathogenesis of type 2 diabetes. Fat accumulation within the pancreas is associated with impaired insulin secretion only in the context of prediabetes. In vitro evidence suggests an underlying mechanism that depends on the crosstalk between fatty liver and pancreatic fat via circulating factors, including free fatty acids. We now addressed the existence of such an inter-organ crosstalk in humans. We therefore tested for interaction between pancreatic fat content, liver fat, and circulating free fatty acids on insulin secretion. Methods: We metabolically characterized 296 individuals (93 males/203 females) at increased risk of type 2 diabetes by an 75g oral glucose tolerance test. Insulin sensitivity, insulin secretion, and free fatty acid levels were assessed. Pancreatic fat accumulation was measured by MR-imaging, liver fat was determined by MR-spectroscopy. Results: There was a significant interaction between pancreatic fat content, liver fat, and free fatty acids on insulin secretion (e.g., p Conclusion: Pancreatic fat accumulation appears to be harmful for human beta cell function only when additional factors, i.e., fatty liver and elevated levels of circulating free fatty acids are present. These results can explain why the impact of pancreas fat on insulin secretion is only detectable in a prediabetic context and point towards liver fat and circulating factors as possible targets to indirectly improve beta cell function. Disclosure B. Jaghutriz: None. R. Wagner: None. J. Machann: None. N. Stefan: Consultant; Self; Merck Sharp u0026 Dohme Corp.. Speaker9s Bureau; Self; Novo Nordisk A/S. Research Support; Self; AstraZeneca. Speaker9s Bureau; Self; AstraZeneca, OmniaMed Ltd.. A. Peter: None. D.I. Siegel-Axel: None. F. Gerst: None. S. Ullrich: None. A. Fritsche: Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH, Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH. H. Haering: None. M. Heni: Research Support; Self; Boehringer Ingelheim GmbH. Speaker9s Bureau; Self; Boehringer Ingelheim GmbH, Merck Sharp u0026 Dohme Corp., Novo Nordisk Inc..