GLP-1 Secretion Is Increased upon Blockade of the Somatostatin Receptor Subtype 2 and 5 Resulting in GLP-1 Receptor-Mediated Lowering of Blood Glucose in Mice

Abstract

Somatostatin (SS) is a hormone inhibiting the secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1) by binding to 5 SS receptors (SSTr). However, which SSTrs involved is still unclear. We hypothesized that antagonizing the SSTrs on enteroendocrine L-cells may increase secretion of GLP-1 and via GLP-1 receptor mediated mechanism lead to lowering of blood glucose. To investigate the level of the SSTrs we did expression analysis on L-cells isolated from throughout the murine intestine (n=3). We perfused the proximal small intestine from mice (n=6-7) to investigate the impact of SSTr2 and 5 on GLP-1 secretion using intra-arterial administration of specific antagonists. Lastly we performed oral glucose tolerance tests (OGTT) on mice (n=5-8) after giving 1mg/ml SSTr2 or 5 antagonist with and without the GLP-1 receptor antagonist exendin(9-39) to investigate the role of these receptors on the glucose profile and to elucidate if their effect was mediated via GLP-1. The expression levels of the SSTrs showed that SSTr2 and especially 5 had the highest expression on L-cells throughout the intestine. The SSTr2 antagonist resulted in a increase in GLP-1 secretion from the perfused intestine (100nM, 4.96pM±0.56; 1µM, 14.55pM±1.4; 10µM, 16.46pM±1.18pM; all p<0.0001). The same doses of SSTr5 antagonist gave a more potent GLP-1 secretion in this setup (100nM, 5.82pM±0.7 p=0.0004; 1µM, 19.79pM±1.2 p<0.0001; 10µM, 48pM±2.6 p<0.0001). Both SSTr2 and SSTr5 antagonists significantly reduced the blood glucose during an OGTT compared to the control (p=0.00and p=0.0072 respectively). This reduction in blood glucose was significantly increased when adding exendin(9-39) together with either the SSTr2 or 5 antagonist (p<0.0001 for SSTr2, p=0.0036 for SSTr5). Our results demonstrate that inhibiting the SSTr2 and SSTr5 increases GLP-1 secretion which in turn may cause the lowering in blood glucose during an OGTT. Disclosure S.L. Jepsen: None. N.J. Wewer Albrechtsen: Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Other Relationship; Self; Mercodia, Alpco. J. Pedersen: None. M.S. Engelstoft: None. C.F. Deacon: Other Relationship; Self; Merck & Co., Inc., Eli Lilly and Company. Employee; Spouse/Partner; Merck Sharp & Dohme Corp.. Stock/Shareholder; Spouse/Partner; Merck & Co., Inc. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics.