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 4

In proximal perfused intestine of DIO and control mice, SSTR5a stimulates glucose-induced GLP-1 secretion more than SSTR2a, and SSTR5a improves glucose tolerance when applied orally in DIO mice.

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In proximal perfused intestine of DIO and control mice, SSTR5a stimulate...
(A–L) GLP-1 an SS output (fmol/min) or mean incremental output (fmol/20 min) in proximal intestinal perfusions of control and DIO mice. The intestine was stimulated with luminal glucose alone or in combination with simultaneous intra-arterial infusion of 1 μM SSTR2a or SSTR5a. (A) n = 7, (B) n = 5, (D) n = 7, (E) n = 6, (G) n = 7, (H) n = 5, (J) n = 7, and (K) n = 4. (M and N) In vivo studies in control and DIO mice undergoing an OGTT after oral administration of vehicle (black), 50 mg/kg SSTR2a (red), or SSTR5a (blue) 30 minutes before oral glucose. (M) Blood glucose levels (mmol/L) (n = 5–6, control mice). (N) Same as in M, but in DIO mice (n = 4). 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 (M) and by paired t test (C, F, I, and L), *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. The box plots show the median and 25th and 75th percentiles, and the whiskers represent the smallest and highest values.