Antagonising the peptide hormone somatostatin (SS) is a novel promising approach to improve glycaemic control. SS inhibits secretion of glucagon-like peptide-1 (GLP-1), via binding to five SS receptors (SSTr1-5). Subtype specific SSTr antagonists can improve glycaemic control after an oral glucose tolerance test (OGTT) in mice, but the mechanism is still unclear. We hypothesized that the effect on glucose tolerance by antagonising SS may be intestinally derived involving GLP-1 rather than a direct effect on the pancreas. We investigated whether addition of a DPP-4 inhibitor would enhance the effect on glucose tolerance by subcutaneous (s.c.) injection of two SSTr antagonists specific for SSTr2 (SSTr2a) and SSTr5 (SSTr5a) in vivo in mice. Next, we used the same antagonists together with s.c. glucose to avoid release of endogenous incretins to estimate the intestinal contribution. Using SSTr5 knockout (KO) mice, which already have improved glycaemic control, we did an OGTT in combination with a GLP-1 receptor antagonist (exendin9-39) to see if the effect is mediated by the GLP-1 receptor. Both SSTr2a and SSTr5a lowered blood glucose levels (AUC) compared to the control group (PBS 34.06 (mmol/l)×min, SSTr2a 23,35 (mmol/l)×min, SSTr5a 26.59 (mmol/l)×min). The DPP-4 inhibitor in combination with SSTr2a markedly lowered glucose levels (AUC after SSTr2a+DPP-4 inhib: 9.8 (mmol/l)×min) whereas the combination with SSTr5a resulted in a minor additive effect (SSTr5a+DPP-4 inhib: 19.7 (mmol/l)×min). Interestingly the effect of the SSTr antagonists was completely lost when glucose was given s.c. and no lowering effect on glucose was observed. In SSTr5 KO mice, glucose tolerance was improved compared to wild type (WT) littermates (WT 30.6 (mmol/l)×min), SSTr5 KO 17.9 (mmol/l)×min), which was markedly impaired when given Exendin9-39. These studies strongly suggest that the effects of antagonising SS are mediated by a GLP-1 based mechanism derived from the intestine.

Disclosure

S.L. Jepsen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S.

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