GLP-2 as an indicator and modulator of acute inflammation improves cardiac function and survival in sepsis

Abstract Purpose GLP-1 and GLP-2 (glucagon-like peptide-1/2) are gut hormones secreted in response to food. While GLP-1 controls glucose metabolism, GLP-2 is a local gut growth factor regulating intestinal nutrient absorption. GLP-2 has been found to be upregulated in patients with colitis. We hypothesize that beyond its local intestinal function GLP-2 might be involved in systemic immune responses. Methods and results To analyze whether GLP-2 secretion is modulated by the immune system, we measured circulating GLP-2 levels in 2 clinical cohorts. In the first cohort (n=34) GLP-2 levels increased over time following cardiac surgery as an inflammatory stimulus. In the second cohort 223 patients with sepsis had a 3.9 fold increase of GLP-2 plasma levels vs. 53 healthy controls (3.0 ng/mL vs. 11.4 ng/mL; p<0.001). High GLP-2 levels were associated with markers of inflammation (IL-6, PCT, CRP), septic cardiomyopathy (NT-proBNP) and independently predicted mortality in humans with sepsis. Induction of sepsis in mice by endotoxin or cecal ligation puncture strongly increased GLP-2 levels independent from food intake. By injecting various proinflammatory cytokines and inducing sepsis in IL1R−/− and IL6−/− mice we identified that inflammation upregulates GLP-2 secretion through IL-6. To identify the source of GLP-2 secretion under inflammation, we induced sepsis in Gcg−/− mice lacking endogenous GLP-2 production with a tissue-specific reactivation of Gcg in gut L-cells (GcgRAΔvilCre) or pancretic alpha cells (GcgRAΔPDX1-Cre). We observed sepsis-induced GLP-2 secretion to be derived from the pancreas and not from the gut. Additional in-vitro and ex-vivo approaches revealed that IL-6 directly activates GLP-2 secretion from pancreatic alpha cells. Gcg−/− mice lacking GLP-2 production and Glp2r−/− mice show aggravated sepsis indicating that endogenous upregulation of GLP-2 is protective. Finally, we analyzed whether inflammatory upregulation of GLP-2 has immunomodulatory relevance. We administered GLP-2 or saline as control per central jugular vein catheter mice who underwent CLP. GLP-2 treatment improved LV-contractility (dp/dtmax) in septic cardiomyopathy (control 7361 vs. GLP-2 9500 mmHg/s; p<0.01), inhibited sepsis-induced hypotension and reduced mortality (p=0.018). Mechanistically GLP-2 reduced myeloid immune cell infiltration into heart and liver tissue and decreased proinflammatory cytokine levels in various organs and the blood (TNF-α, IL-6 and IL-1β). After broad GLP-2 receptor profiling we found maximum mRNA expression in gut tissues with no expression on immune cells. By further mechanistic studies we found GLP-2 to protect against sepsis-induced gut barrier dysfunction. Conclusions Here we identified a counter-regulatory control system in which IL-6 derived upregulation of GLP-2 secretion limits excessive innate immune responses and protects against sepsis. These findings might open new avenues for the treatment of patients with inflammatory diseases. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): European Foundation for the Study of Diabetes, European Research Area Network on Cardiovascular Diseases (ERA-CVD and BMBF), Deutsche Forschungsgemeinschaft (DFG)