Patients who have diabetes mellitus (both type 1 and type 2) have increased susceptibility to sepsis. Among the hormones that are altered by sepsis, there is an increase in the glucoregulatory peptide glucagon-like peptide-1 (GLP-1), and in animal models there is a specific increase in pancreatic-produced GLP-1 vs. glucagon. While the function of GLP-1 during sepsis is unknown, GLP-1 agonists have recently been of interest as an anti-inflammatory agent. We hypothesized that GLP-1 increases are necessary for dampening pancreatic inflammatory responses to sepsis in lean and HFD-fed mice. To model sepsis, we administered 100ng/g lipopolysaccharide (LPS) to C57BL/6 mice who had been fed HFD or chow for 12 weeks. We found 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 and plasma glucose was significantly lower in HFD compared to chow-fed mice. To determine whether GLP-1 specifically regulated pancreatic inflammation, 24 hours after LPS we used flow cytometry to isolate pancreatic immune cells from chow-fed mice devoid of GLP-1 (GcgΔNull) and wild type (WT) mice. In chow-fed mice, we found approximately 20% more CD45+ cells in WT LPS treated mice compared to vehicle, and a similar percentage of CD45+ cells in LPS treated GcgΔNull mice compared to WT. In contrast, LPS administration to HFD-fed GcgΔNull mice, resulted in increased F4/80 positive cells compared to WT mice. Taken together, these data suggest that Gcg peptides are necessary to blunt LPS-induced inflammation in the pancreas and that GLP-1 physiologically regulates tissue inflammation. Future studies will determine whether the increased GLP-1 in HFD-fed mice is due to an increased inflammatory state or a decreased effectiveness of GLP-1.
E.M. Davis: None. C. Hutch: None. K. Kim: None. B. Maerz: None. M. Lehrke: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Other Relationship; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S.