GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering

Diabetes. 2014 Oct;63(10):3221-9. doi: 10.2337/db14-0100. Epub 2014 Jun 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Blood Glucose / metabolism
  • Female
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Hyperinsulinism / metabolism*
  • Inflammation / metabolism*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice, Knockout
  • Middle Aged
  • Peptide Fragments / pharmacology
  • Receptors, Glucagon / metabolism
  • Young Adult


  • Blood Glucose
  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Interleukin-1beta
  • Interleukin-6
  • Lipopolysaccharides
  • Peptide Fragments
  • Receptors, Glucagon
  • exendin (9-39)
  • Glucagon-Like Peptide 1