GLP-1 Integrates the Innate Immune System to Glucose Homeostasis

Abstract

Glucagon-like peptide-1 (GLP-1) is a gut peptide that increases post prandially and functions to increase insulin secretion and improve glucose homeostasis. GLP-1 is coded by the preproglucagon gene (Gcg) and is expressed by intestinal and pancreatic cells. Interestingly, GLP-1 is also increased during sepsis, which is the most common cause of death in intensive care units (ICU). The goal of this study was to determine in a preclinical model of sepsis if the increase in GLP-1 was from intestinal or pancreatic cells. In order to model sepsis, we administered lipopolysaccharide (LPS) to Cre-control mice, to mice devoid of Gcg, and thus GLP-1 (Gcg null), to mice with Gcg expression reactivated only in the intestine (GcgRAδIntestine), and to mice with Gcg expression reactivated only in the pancreas (GcgRAδPancreas). LPS significantly increased GLP-1 in the control mice, as well as in the two reactivated genotypes compared to saline. However, the degree of the increase in both GcgRAδIntestine and GcgRAδPancreas mice was about 50% of control animals. LPS first increased, then significantly decreased blood glucose in control, pancreatic and intestinal reactivated mice but was significantly lower across all time points in Gcg null mice. These data suggest that both intestinal and pancreatic sources contribute to the increase in plasma GLP-1 seen in our model of sepsis. However, either pancreatic or intestinal sources of GLP-1 are sufficient to maintain glucose responses to LPS. Disclosure E.M. Davis: None. C. Hutch: None. K. Kim: None. B. Maerz: None. K.J. Roelofs: None. M. Lehrke: Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi, Amgen Inc., Bayer AG, MSD K.K. D.A. Sandoval: Research Support; Self; Novo Nordisk A/S, Zafgen, Ethicon US, LLC..