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Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner

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  • Sara L Jepsen
  • Nicolai J Wewer Albrechtsen
  • Johanne Agerlin Windeløv
  • Katrine D Galsgaard
  • Jenna Elizabeth Hunt
  • Thomas B Farb
  • Hannelouise Kissow
  • Jens Pedersen
  • Carolyn F Deacon
  • Rainer E Martin
  • Jens J Holst
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Somatostatin (SS) inhibits glucagon-like peptide-1 (GLP-1) secretion in a paracrine manner. We hypothesized that blocking somatostatin subtype receptor 2 (SSTR2) and 5 (SSTR5) would improve glycemia by enhancing GLP-1 secretion. In the perfused mouse small intestine, the selective SSTR5 antagonist (SSTR5a) stimulated glucose-induced GLP-1 secretion to a larger degree than the SSTR2 antagonist (SSTR2a). In parallel, mice lacking the SSTR5R showed increased glucose-induced GLP-1 secretion. Both antagonists improved glycemia in vivo in a GLP-1 receptor-dependent (GLP-1R-dependent) manner, as the glycemic improvements were absent in mice with impaired GLP-1R signaling and in mice treated with a GLP-1R-specific antagonist. SSTR5a had no direct effect on insulin secretion in the perfused pancreas, whereas SSTR2a increased insulin secretion in a GLP-1R-independent manner. Adding a dipeptidyl peptidase 4 inhibitor (DPP-4i) in vivo resulted in additive effects on glycemia. However, when glucose was administered intraperitoneally, the antagonist was incapable of lowering blood glucose. Oral administration of SSTR5a, but not SSTR2a, lowered blood glucose in diet-induced obese mice. In summary, we demonstrate that selective SSTR antagonists can improve glucose control primarily through the intestinal GLP-1 system in mice.

OriginalsprogEngelsk
Artikelnummere143228
TidsskriftJCI Insight
Vol/bind6
Udgave nummer4
ISSN2379-3708
DOI
StatusUdgivet - 22 feb. 2021

Bibliografisk note

Funding Information:
Mouse perfusion studies were supported by an unrestricted grant to JJH from the Novo Nordisk Center for Basic Metabolic Research (Novo Nordisk Foundation, Denmark, NNF10CC1016515) and by a grant to JJH from the European Research Council (grant 695069). In vivo studies were supported by grants to SLJ from the AP Moller Foundation and the Augustinus Foundation. SLJ was supported by a postdoctoral grant from the European Research Council (grant 695069).

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