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

TY - JOUR

T1 - Paracrine Crosstalk between Intestinal L- and D-cells Controls Secretion of Glucagon-Like Peptide-1 in mice

AU - Jepsen, Sara L.

AU - Grunddal, Kaare V.

AU - Wewer Albrechtsen, Nicolai J

AU - Engelstoft, Maja S

AU - Gabe, Maria B N

AU - Jensen, Elisa P

AU - Ørskov, Cathrine

AU - Poulsen, Steen S

AU - Rosenkilde, Mette M

AU - Pedersen, Jens

AU - Gribble, Fiona M

AU - Reimann, Frank

AU - Deacon, Carolyn F

AU - Schwartz, Thue W

AU - Christ, Andreas D

AU - Martin, Rainer E

AU - Holst, Jens J

PY - 2019/12

Y1 - 2019/12

N2 - DPP-4 inhibitors, used for treatment of type 2 diabetes, act by increasing the concentrations of intact glucagon-like peptide-1 (GLP- 1), but at the same time, they inhibit secretion of GLP-1, perhaps by a negative feedback mechanism. We hypothesized that GLP-1 secretion is feedback regulated by somatostatin (SS) from neighboring D-cells, and blocking this feedback 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 characterize the paracrine circuit controlling GLP-1 and SS. We show that 1) antagonizing the SS receptor (SSTr) 2 and SSTr5 led to increased GLP-1 and SS secretion in the mouse, 2) SS exhibits strong tonic inhibition of GLP-1 secretion preferentially through SSTr5, and 3) the secretion of S 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 lead to increased GLP-1 secretion.

AB - DPP-4 inhibitors, used for treatment of type 2 diabetes, act by increasing the concentrations of intact glucagon-like peptide-1 (GLP- 1), but at the same time, they inhibit secretion of GLP-1, perhaps by a negative feedback mechanism. We hypothesized that GLP-1 secretion is feedback regulated by somatostatin (SS) from neighboring D-cells, and blocking this feedback 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 characterize the paracrine circuit controlling GLP-1 and SS. We show that 1) antagonizing the SS receptor (SSTr) 2 and SSTr5 led to increased GLP-1 and SS secretion in the mouse, 2) SS exhibits strong tonic inhibition of GLP-1 secretion preferentially through SSTr5, and 3) the secretion of S 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 lead to increased GLP-1 secretion.

U2 - 10.1152/ajpendo.00239.2019

DO - 10.1152/ajpendo.00239.2019

M3 - Journal article

C2 - 31503512

SN - 1522-1555

JO - A J P: Endocrinology and Metabolism (Online)

JF - A J P: Endocrinology and Metabolism (Online)

ER -