Interleukin-6 predicts inflammation-induced increase of Glucagon-like peptide-1 in humans in response to cardiac surgery with association to parameters of glucose metabolism

Abstract

ObjectiveGlucagon-like peptide-1 (GLP-1) is an incretin hormone, which gets secreted in response to nutritional stimuli from the gut mediating glucose-dependent insulin secretion. Interestingly, GLP-1 was recently found to be also increased in response to inflammatory stimuli in an interleukin 6 (IL-6) dependent manner in mice. The relevance of this finding to humans is unknown but has been suggested by the presence of high circulating GLP-1 levels in critically ill patients that correlated with markers of inflammation. This study was performed to elucidate, whether a direct link exists between inflammation and GLP-1 secretion in humans.Research design and methodsWe enrolled 22 non-diabetic patients scheduled for cardiac surgery as a reproducible inflammatory stimulus with repeated blood sampling before and after surgery.ResultsMean total circulating GLP-1 levels significantly increased in response to surgery from 25.5 ± 15.6 pM to 51.9 ± 42.7 pM which was not found in a control population. This was preceded by an early rise of IL6, which was significantly associated with GLP-1 under inflammatory but not basal conditions. Using repeated measure ANCOVA, IL6 best predicted the observed kinetics of GLP-1, followed by blood glucose concentrations and cortisol plasma levels. Furthermore, GLP-1 plasma concentrations significantly predicted endogenous insulin production as assessed by C-peptide concentrations over time, while an inverse association was found for insulin infusion rate.ConclusionWe found GLP-1 secretion to be increased in response to inflammatory stimuli in humans, which was associated to parameters of glucose metabolism and best predicted by IL6.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0330-8) contains supplementary material, which is available to authorized users.

Comparison of the Levels of C-Reactive Protein, GLP-1 and GLP-2 Among Individuals With Diabetes, Morbid Obesity and Healthy Controls: An Exploratory Study

“…Kahles et al (42) observed significantly higher levels of GLP-1 in critically ill individuals compared to healthy controls, and speculated on a possible mechanism mediated by interleukin-6 (IL-6). Lebherz et al (43) confirmed this finding, and observed that higher levels of GLP-1 among critically ill individuals were significantly correlated with IL-6 levels. Evidently, since these authors analyzed cohorts of individuals with acute high-grade inflammation, this phenomenon is not comparable to the inflammatory state associated with obesity and T2D.…”

“…In regard to the relationship between chronic inflammation and GLP-1, the evidence available to date tends to support that GLP-1 increases in response to inflammation (41)(42)(43)(44) . A pioneering study by Ellingsgaard et al (41) revealed that the administration of interleukin 6 (IL-6) or elevated IL-6 concentrations in response to exercise stimulates GLP-1 secretion from intestinal L-cells and pancreatic alpha cells, improving insulin secretion and blood glucose levels.…”

The Cardiovascular Biology of Glucagon-like Peptide-1

“…Inflammatory Signals Regulate GLP-1 Synthesis, Secretion, and Action Circulating levels of intestinal proglucagon-derived peptides (PGDPs), including GLP-1, were increased in rodents with experimental inflammation induced by injection of cytokines or lipopolysaccharide (LPS) (Ellingsgaard et al, 2011;Kahles et al, 2014;Nguyen et al, 2014). Levels of plasma GLP-1 were also markedly elevated $6.9-fold in 155 critically ill human subjects assessed on admission to an intensive care unit (Kahles et al, 2014), and a smaller but significant 2-fold increase in circulating total GLP-1 levels was observed in 22 non-diabetic human subjects studied within 24 hr of cardiac surgery and cardiopulmonary bypass (Lebherz et al, 2016). In both clinical studies, levels of interleukin-6 (IL-6) were elevated and correlated with plasma levels of total GLP-1.…”

Intra-islet glucagon-like peptide 1

“…Interestingly, recent studies have discovered that inflammatory stimuli such as endotoxin and IL-1β stimulate GLP-1 secretion in an IL-6-dependent manner in both mice and human (Kahles, et al 2014; Lebherz, et al 2016; Nguyen, et al 2014). In addition, glucose-dependent insulintropic peptide (GIP) appears to stimulate GLP-1 production in pancreatic islets via induction of IL-6 (Timper, et al 2016).…”