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 A. Windeløv, Katrine D. Galsgaard, Jenna E. Hunt, Thomas B. Farb, Hannelouise Kissow, Jens Pedersen, Carolyn F. Deacon, Rainer E. Martin, Jens J. Holst
Sara L. Jepsen, Nicolai J. Wewer Albrechtsen, Johanne A. Windeløv, Katrine D. Galsgaard, Jenna E. Hunt, Thomas B. Farb, Hannelouise Kissow, Jens Pedersen, Carolyn F. Deacon, Rainer E. Martin, Jens J. Holst
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Research Article Endocrinology Metabolism

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 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.

Authors

Sara L. Jepsen, Nicolai J. Wewer Albrechtsen, Johanne A. Windeløv, Katrine D. Galsgaard, Jenna E. Hunt, Thomas B. Farb, Hannelouise Kissow, Jens Pedersen, Carolyn F. Deacon, Rainer E. Martin, Jens J. Holst

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Figure 3

The glucose-lowering effect of SSTR2a and SSTR5a is GLP-1R dependent.

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The glucose-lowering effect of SSTR2a and SSTR5a is GLP-1R dependent. (A...
(A) Blood glucose levels (mmol/L) in C57BL/6JRj mice receiving vehicle (black line), 4 mg/kg SSTR2a (red line), 4 mg/kg Ex9–39 (gray line), or SSTR2a + Ex9–39 (dashed red line) s.c. 15 minutes before an oral glucose load (n = 5–8). (B) The same as A but for 4 mg/kg SSTR5a (blue), 4 mg/kg SSTR5a + 4 mg/kg Ex9–39 (dashed blue line), n = 5–8. (C) Blood glucose levels (mmol/L) in Glp-1r–/– or Glp-1r+/+ mice after vehicle or 4 mg/kg SSTR2a. Glp-1r+/+ receiving vehicle (black line), Glp-1r–/– receiving vehicle (black dashed line), Glp-1r+/+ receiving 4 mg/kg SSTR2a (red line), Glp-1r–/– receiving 4 mg/kg SSTR2a (dashed red line), n = 8–13. (D) The same as in C but for 4 mg/kg SSTR5a indicated with blue. Glp-1r+/+ receiving 4 mg/kg SSTR5a (blue line), Glp-1r–/– receiving 4 mg/kg SSTR5a (dashed blue line), n = 10–13. (E) Blood glucose levels (mmol/L) in Sstr5–/– or Sstr5+/+ mice receiving vehicle or 4 mg/kg Ex9–39. Sstr5+/+ receiving vehicle (black line), Sstr5–/– receiving vehicle (black dashed line), Sstr5+/+ receiving 4 mg/kg Ex9–39 (gray line), Sstr5–/– receiving 4 mg/kg Ex9–39 (gray dashed line) (n = 4–5). (F) Blood glucose levels (mmol/L) after administration of vehicle (black line), 4 mg/kg SSTR2a (red line), 120 mg/kg DPP-4 (dashed black line), and a combination of SSTR2a and DPP-4i (red dashed line) (n = 8). (G) The same as in F but for 8 mg/kg SSTR5a (blue line) and SSTR5 + DPP-4i (blue dashed line) (n = 6–8). Data are shown as the mean ± SEM, and significance was evaluated based on iAUC by 1-way ANOVA followed by the Holm-Sidak post hoc analysis to correct for multiple testing.