Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells

• Published in: Nature medicine Vol. 17; no. 11; pp. 1481 - 1489
• Main Authors: Ellingsgaard, Helga, Hauselmann, Irina, Schuler, Beat, Habib, Abdella M, Baggio, Laurie L, Meier, Daniel T, Eppler, Elisabeth, Bouzakri, Karim, Wueest, Stephan, Muller, Yannick D, Hansen, Ann Maria Kruse, Reinecke, Manfred, Konrad, Daniel, Gassmann, Max, Reimann, Frank, Halban, Philippe A, Gromada, Jesper, Drucker, Daniel J, Gribble, Fiona M, Ehses, Jan A, Donath, Marc Y
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2011; Nature Publishing Group
• Subjects: 631/443/163; 692/698/1460; 692/699/2743/137/773; 692/699/2743/393; Animals; Biomedicine; Blood Glucose - metabolism; Cancer Research; Care and treatment; Cells, Cultured; Cellular biology; Diabetes; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diet, High-Fat; Disease Models, Animal; Endocrinology; Enteroendocrine Cells - drug effects; Enteroendocrine Cells - metabolism; Female; Genetic aspects; Glucagon-Like Peptide 1 - metabolism; Glucagon-Secreting Cells - drug effects; Glucagon-Secreting Cells - metabolism; Glucose Tolerance Test; Humans; Infectious Diseases; Insulin; Insulin - metabolism; Insulin Secretion; Interleukin-6; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukin-6 - pharmacology; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Medicine; Neurosciences; Neutralization; Obesity; Pancreas; Peptides; Pharmacology; Physical Conditioning, Animal; Physiological aspects; Signal Transduction - drug effects; Signal Transduction - physiology; Type 2 diabetes; Switzerland
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2513

Helga Ellingsgaard
et al
. show that secretion of interleukin-6 by muscle in response to exercise, or injection of recombinant protein, increases the expression of the incretin GLP-1 by both intestinal cells and by pancreatic alpha cells, thus potentiating insulin release and improving glycemic control. These results identify a new endocrine loop linking energy demands to homeostatic control while also suggesting further targets for type 2 diabetes therapy.
Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by
GCG
) and prohormone convertase 1/3 expression. In models of type 2 diabetes, the beneficial effects of IL-6 were maintained, and IL-6 neutralization resulted in further elevation of glycemia and reduced pancreatic GLP-1. Hence, IL-6 mediates crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. This previously unidentified endocrine loop implicates IL-6 in the regulation of insulin secretion and suggests that drugs modulating this loop may be useful in type 2 diabetes.