Antagonizing somatostatin receptor subtype 2 and 5 reduces blood glucose in a gut- and GLP-1R–dependent manner
Sara L. Jepsen, … , Rainer E. Martin, Jens J. Holst
Sara L. Jepsen, … , Rainer E. Martin, Jens J. Holst
Published January 12, 2021
Citation Information: JCI Insight. 2021;6(4):e143228. https://doi.org/10.1172/jci.insight.143228.
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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 2

SSTR2a and SSTR5a lower blood glucose in vivo.

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SSTR2a and SSTR5a lower blood glucose in vivo. During hyperglycemia, in ...
During hyperglycemia, in the perfused pancreas, SSTR2a increases insulin whereas SSTR5a does not. (A–C) Plasma blood glucose (mmol/L), insulin levels (pmol/L), and GLP-1 levels (pmol/L) after male C57BL/6JRj mice received vehicle (black), 4 mg/kg SSTR2a (red), or SSTR5a (blue) by s.c. injection 15 minutes before an oral glucose load (n = 8). (D–J) Insulin, glucagon, and insulin levels after the pancreas was perfused with a perfusion buffer at low-glucose concentration (3.5 mM) from 0 to 40 minutes, after which the buffer was exchanged to a high-glucose-containing buffer (15 mM) for the rest of the experiment (D and F–J) or at a constant concentration of 15 mM (E). 1 μM SSTR2a, SSTR5a, or Ex9–39 was added to the arterial perfusate via a side-arm. 10 mM arginine was used as positive control at the end of each perfusion experiment (n = 6). (K and L) Male mice received s.c. injections of vehicle (PBS), 4 mg/kg SSTR2a, or SSTR5a at time –15 minutes, and at time 0 minutes they received the i.p. injection of glucose or PBS. (K) Blood glucose (mmol/L) levels after the following injections: PBS s.c. at –15 minutes and i.p. PBS at 0 minutes (black line), s.c. PBS at time –15 minutes and i.p. glucose at 0 minutes (black dashed line), s.c. SSTR2a at –15 minutes and i.p. PBS at 0 minutes (red line), or s.c. SSTR2a at –15 minutes and i.p. glucose at 0 minutes (red dashed line) (n = 8). (L) The same as in K, but with SSTR5a, represented in blue. SSTR5a s.c. at –15 minutes and i.p. PBS (blue line), i.p. glucose at 0 minutes and s.c. SSTR5a at –15 minutes (blue dashed line) (n = 8). Data are presented as the mean ± SEM. Statistical significance at specific time points was assessed by 2-way ANOVA followed by Tukey post hoc analysis to correct for multiple testing in vivo and by paired t test in the perfusion experiments. **P < 0.01, ***P < 0.001, ****P < 0.0001.