title: GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering.
abstract: Hypoglycemia and hyperglycemia are both predictors for adverse outcome in critically ill patients. Hyperinsulinemia is induced by inflammatory stimuli as a relevant mechanism for glucose lowering in the critically ill. The incretine hormone GLP-1 was currently found to be induced by endotoxin, leading to insulin secretion and glucose lowering under inflammatory conditions in mice. Here, we describe GLP-1 secretion to be increased by a variety of inflammatory stimuli, including endotoxin, interleukin-1β (IL-1β), and IL-6. Although abrogation of IL-1 signaling proved insufficient to prevent endotoxin-dependent GLP-1 induction, this was abolished in the absence of IL-6 in respective knockout animals. Hence, we found endotoxin-dependent GLP-1 secretion to be mediated by an inflammatory cascade, with IL-6 being necessary and sufficient for GLP-1 induction. Functionally, augmentation of the GLP-1 system by pharmacological inhibition of DPP-4 caused hyperinsulinemia, suppression of glucagon release, and glucose lowering under endotoxic conditions, whereas inhibition of the GLP-1 receptor led to the opposite effect. Furthermore, total GLP-1 plasma levels were profoundly increased in 155 critically ill patients presenting to the intensive care unit (ICU) in comparison with 134 healthy control subjects. In the ICU cohort, GLP-1 plasma levels correlated with markers of inflammation and disease severity. Consequently, GLP-1 provides a novel link between the immune system and the gut with strong relevance for metabolic regulation in context of inflammation.
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Kahles
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Möllmann
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Diebold
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Hannes M
authors.initials: HM
authors.lastname: Findeisen
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Lebherz
authors.affiliation: Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Internal Medicine III, University Hospital Aachen, Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Marx
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany mlehrke@ukaachen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Lehrke
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000378:metabolism; D055815:Young Adult
chemical_list: D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1