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

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Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner. / Jepsen, Sara L; Albrechtsen, Nicolai J. Wewer ; Windeløv, Johanne Agerlin; Galsgaard, Katrine D; Hunt, Jenna Elizabeth; Farb, Thomas B.; Kissow, Hannelouise; Pedersen, Jens; Deacon, Carolyn F.; Martin, Rainer E.; Holst, Jens J.

In: JCI insight, 12.01.2021.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Jepsen, SL, Albrechtsen, NJW, Windeløv, JA, Galsgaard, KD, Hunt, JE, Farb, TB, Kissow, H, Pedersen, J, Deacon, CF, Martin, RE & Holst, JJ 2021, 'Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner', JCI insight. https://doi.org/10.1172/jci.insight.143228

APA

Jepsen, S. L., Albrechtsen, N. J. W., Windeløv, J. A., Galsgaard, K. D., Hunt, J. E., Farb, T. B., Kissow, H., Pedersen, J., Deacon, C. F., Martin, R. E., & Holst, J. J. (2021). Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner. JCI insight. https://doi.org/10.1172/jci.insight.143228

Vancouver

Jepsen SL, Albrechtsen NJW, Windeløv JA, Galsgaard KD, Hunt JE, Farb TB et al. Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner. JCI insight. 2021 Jan 12. https://doi.org/10.1172/jci.insight.143228

Author

Jepsen, Sara L ; Albrechtsen, Nicolai J. Wewer ; Windeløv, Johanne Agerlin ; Galsgaard, Katrine D ; Hunt, Jenna Elizabeth ; Farb, Thomas B. ; Kissow, Hannelouise ; Pedersen, Jens ; Deacon, Carolyn F. ; Martin, Rainer E. ; Holst, Jens J. / Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner. In: JCI insight. 2021.

Bibtex

@article{5324f6361763466e95ba40d410d37ae0,
title = "Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner",
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.",
author = "Jepsen, {Sara L} and Albrechtsen, {Nicolai J. Wewer} and Windel{\o}v, {Johanne Agerlin} and Galsgaard, {Katrine D} and Hunt, {Jenna Elizabeth} and Farb, {Thomas B.} and Hannelouise Kissow and Jens Pedersen and Deacon, {Carolyn F.} and Martin, {Rainer E.} and Holst, {Jens J}",
year = "2021",
month = jan,
day = "12",
doi = "10.1172/jci.insight.143228",
language = "English",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "American Society for Clinical Investigation",

}

RIS

TY - JOUR

T1 - Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R-dependent manner

AU - Jepsen, Sara L

AU - Albrechtsen, Nicolai J. Wewer

AU - Windeløv, Johanne Agerlin

AU - Galsgaard, Katrine D

AU - Hunt, Jenna Elizabeth

AU - Farb, Thomas B.

AU - Kissow, Hannelouise

AU - Pedersen, Jens

AU - Deacon, Carolyn F.

AU - Martin, Rainer E.

AU - Holst, Jens J

PY - 2021/1/12

Y1 - 2021/1/12

N2 - 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.

AB - 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.

U2 - 10.1172/jci.insight.143228

DO - 10.1172/jci.insight.143228

M3 - Journal article

C2 - 33434183

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

ER -

ID: 255397429