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Rigshospitalet - a part of Copenhagen University Hospital
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Paracrine Crosstalk between Intestinal L- and D-cells Controls Secretion of Glucagon-Like Peptide-1 in mice

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  • Sara L Jepsen
  • Kaare V Grunddal
  • Nicolai J Wewer Albrechtsen
  • Maja S Engelstoft
  • Maria B N Gabe
  • Elisa P Jensen
  • Cathrine Ørskov
  • Steen S Poulsen
  • Mette M Rosenkilde
  • Jens Pedersen
  • Fiona M Gribble
  • Frank Reimann
  • Carolyn F Deacon
  • Thue W Schwartz
  • Andreas D Christ
  • Rainer E Martin
  • Jens J Holst
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DPP-4 inhibitors, used for treatment of type 2 diabetes, act by increasing the concentrations of intact glucagon-like peptide-1 (GLP-1), but at the same time, they inhibit secretion of GLP-1, perhaps by a negative feedback mechanism. We hypothesized that GLP-1 secretion is feedback regulated by somatostatin (SS) from neighboring D-cells, and blocking this feedback circuit results in increased GLP-1 secretion. We used a wide range of experimental techniques, including gene expression analysis, immunohistochemical approaches, and the perfused mouse intestine to characterize the paracrine circuit controlling GLP-1 and SS. We show that 1) antagonizing the SS receptor (SSTr) 2 and SSTr5 led to increased GLP-1 and SS secretion in the mouse, 2) SS exhibits strong tonic inhibition of GLP-1 secretion preferentially through SSTr5, and 3) the secretion of S was GLP-1 receptor dependent. We conclude that SS is a tonic inhibitor of GLP-1 secretion, and interventions in the somatostain-GLP-1 paracrine loop lead to increased GLP-1 secretion.

Original languageEnglish
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Volume317
Issue number6
Pages (from-to)E1081-E1093
ISSN0193-1849
DOIs
Publication statusPublished - 2019

ID: 57969503