2488-PUB: The Role of GLP-1 in Metabolic Responses during Sepsis

Sepsis is characterized by a dysregulated immune response that can result in end organ damage and is the number one cause of death in the ICU. Among the hormones that are altered by sepsis, there is an increase in the gut peptide glucagon-like peptide-1 (GLP-1). Traditionally, GLP-1 is important for regulating glucose homeostasis and has previously been linked to appetite inhibition. However, its function during sepsis remains unknown. GLP-1 is coded by the preproglucagon gene (Gcg) and is expressed not only by intestinal endocrine cells but also in pancreatic α-cells. Previously, we have shown increases in plasma GLP-1 in response to LPS are contributed to by both pancreatic and intestinal sources and that either pancreatic or intestinal sources of GLP-1 are sufficient to maintain glucose responses to LPS. Because T2DM patients have an increased susceptibility to sepsis, the goal of this study was to determine if high-fat diet and impaired glucose tolerance change the metabolic or appetitive inhibition response during sepsis. To model sepsis, we administered lipopolysaccharide (LPS) to C57BL/6 mice who had been on high-fat diet (HFD) or chow for 12 weeks. We observed that compared to vehicle treatment, LPS significantly increased plasma levels of GLP-1 in both HFD and chow-fed mice, but plasma GLP-1 was significantly higher in HFD mice compared to chow-fed. HFD mice also had a greater decrease in glucose in response to LPS. Furthermore, we observed that HFD mice had increased and prolonged appetite inhibition in response to LPS. Future directions will explore tissue-specific changes in GLP-1 response, source, and effectiveness during sepsis under the conditions of high-fat diet and impaired glucose control. Disclosure E.M. Davis: None. C. Hutch: None. K. Kim: None. B. Maerz: None. M. Lehrke: Consultant; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S, Zafgen, Inc.