Paracrine Crosstalk between Intestinal L- and D-cells Controls Secretion of Glucagon-Like Peptide-1 in mice

DPP-4 inhibitors, used for treatment of type 2 diabetes, act by increasing the concentrations of intact GLP-1 but at the same time they inhibit secretion of GLP-1, perhaps by a negative feed-back mechanism. We hypothesized that GLP-1 secretion is feed-back regulated by somatostatin from neighbouring D-cells, and blocking this feed-back circuit results in increased GLP-1 secretion. We used a wide range of experimental techniques including gene expression analysis, immunohistochemical approaches and the perfused mouse intestine to characterise the paracrine circuit controlling GLP-1 and somatostatin. We show that 1) antagonising the SSTr2 and SSTr5 led to increased GLP-1 and somatostatin secretion in the mouse, 2) that SS exhibits strong tonic inhibition of GLP-1 secretion preferentially through SSTr5 and 3) that the secretion of somatostatin was GLP-1 receptor dependent. We conclude that SS is a tonic inhibitor of GLP-1 secretion and interventions in the somatostain-GLP-1 paracrine loop leads to increased GLP-1 secretion.