Glucose-Dependent Insulinotropic Peptide Stimulates Glucagon-Like Peptide 1 Production by Pancreatic Islets via Interleukin 6, Produced by α Cells

BACKGROUND & AIMS: Glucose-dependent insulinotropic peptide (GIP) induces production of interleukin 6 (IL6) by adipocytes. IL6 increases production of glucagon-like peptide (GLP)-1 by L cells and alpha cells, leading to secretion of insulin from beta cells. We investigated whether GIP regulates GLP1 and glycemia via IL6. METHODS: We obtained samples of human pancreatic islets and isolated islets from mice; human alpha cells and beta cells were sorted by flow cytometry and incubated with GIP. Islets were analyzed by quantitative polymerase chain reaction and immunohistochemistry. BKS.Cg-Dock7m+/+ Leprdb/J db/db mice (diabetic mice) and db/+ mice, as well as C57BL/6J IL6-knockout mice (IL6-KO) and C57BL/6J mice with the full-length Il6 gene (controls), were fed a chow or a high-fat diet; some mice were given injections of recombinant GIP, IL6, GLP, a neutralizing antibody against IL6 (anti-IL6), lipopolysaccharide, and/or IL1B. Mice were given a glucose challenge and blood samples were collected and analyzed. RESULTS: Incubation of mouse and human pancreatic alpha cells with GIP induced their production of IL6, leading to production of GLP1 and insulin secretion from pancreatic islets. This did not occur in islets from IL6-KO mice or in islets incubated with anti-IL6. Incubation of islets with IL1B resulted in IL6 production but directly reduced GLP1 production. Incubation of mouse islets with the sodium glucose transporter 2 inhibitor dapagliflozin induced production of GLP1 and IL6. Injection of control mice with GIP increased plasma levels of GLP1, insulin, and glucose tolerance; these effects were amplified in mice given lipopolysaccharide but reduced in IL6-KO mice or in mice given anti-IL6. Islets from diabetic mice had increased levels of IL1B and IL6, compared with db/+ mice, but injection of GIP did not lead to production of GLP1 or reduce glycemia. CONCLUSIONS: In studies of pancreatic islets from human beings and mice, we found that GIP induces production of IL6 by alpha cells, leading to islet production of GLP1 and insulin. This process is regulated by inflammation, via IL1B, and by sodium glucose transporter 2. In diabetic mice, increased islet levels of IL6 and IL1B might increase or reduce the production of GLP1 and affect glycemia.