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

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

doi:10.1172/jci.insight.143228

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

Sara L. Jepsen,¹ Nicolai J. Wewer Albrechtsen,¹ Johanne Agerlin Windeløv,¹ Katrine D. Galsgaard,¹ Jenna Elizabeth Hunt,¹ Thomas B. Farb,² Hannelouise Kissow,³ Jens Pedersen,⁴ Carolyn F. Deacon,¹ Rainer E. Martin,⁵ and Jens J. Holst⁶

Published January 12, 2021 - More info

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Abstract

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 glycaemia 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 glycaemia in vivo in a GLP-1 receptor (GLP-1R) dependent manner, as the glycaemic improvements were absent in mice with impaired GLP-1R signalling 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 glycaemia, however, when glucose was administered intraperitoneally the antagonists 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.

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

Sara L. Jepsen,¹ Nicolai J. Wewer Albrechtsen,¹ Johanne Agerlin Windeløv,¹ Katrine D. Galsgaard,¹ Jenna Elizabeth Hunt,¹ Thomas B. Farb,² Hannelouise Kissow,³ Jens Pedersen,⁴ Carolyn F. Deacon,¹ Rainer E. Martin,⁵ and Jens J. Holst⁶

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

Sara L. Jepsen,1 Nicolai J. Wewer Albrechtsen,1 Johanne Agerlin Windeløv,1 Katrine D. Galsgaard,1 Jenna Elizabeth Hunt,1 Thomas B. Farb,2 Hannelouise Kissow,3 Jens Pedersen,4 Carolyn F. Deacon,1 Rainer E. Martin,5 and Jens J. Holst6

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Sara L. Jepsen,¹ Nicolai J. Wewer Albrechtsen,¹ Johanne Agerlin Windeløv,¹ Katrine D. Galsgaard,¹ Jenna Elizabeth Hunt,¹ Thomas B. Farb,² Hannelouise Kissow,³ Jens Pedersen,⁴ Carolyn F. Deacon,¹ Rainer E. Martin,⁵ and Jens J. Holst⁶