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

Sara L. Jepsen; Kaare V. Grunddal; Nicolai J Wewer Albrechtsen; Maja S Engelstoft; Maria B N Gabe; Elisa P Jensen; Cathrine Ørskov; Steen S Poulsen; Mette M Rosenkilde; Jens Pedersen; Fiona M Gribble; Frank Reimann; Carolyn F Deacon; Thue W Schwartz; Andreas D Christ; Rainer E Martin; Jens J Holst

doi:10.1152/ajpendo.00239.2019

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

Sara L. Jepsen, Kaare V. Grunddal, Nicolai J Wewer Albrechtsen, Maja S Engelstoft, Maria B N Gabe, Elisa P Jensen, Cathrine Ørskov, Steen S Poulsen, Mette M Rosenkilde, Jens Pedersen, Fiona M Gribble, Frank Reimann, Carolyn F Deacon, Thue W Schwartz, Andreas D Christ, Rainer E Martin, Jens J Holst

12 Citations (Scopus)

Abstract

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.

Original language	English
Journal	A J P: Endocrinology and Metabolism (Online)
ISSN	1522-1555
DOIs	https://doi.org/10.1152/ajpendo.00239.2019
Publication status	Published - Dec 2019

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Jepsen, S. L., Grunddal, K. V., Wewer Albrechtsen, N. J., Engelstoft, M. S., Gabe, M. B. N., Jensen, E. P., Ørskov, C., Poulsen, S. S., Rosenkilde, M. M., Pedersen, J., Gribble, F. M., Reimann, F., Deacon, C. F., Schwartz, T. W., Christ, A. D., Martin, R. E., & Holst, J. J. (2019). Paracrine Crosstalk between Intestinal L- and D-cells Controls Secretion of Glucagon-Like Peptide-1 in mice. A J P: Endocrinology and Metabolism (Online). https://doi.org/10.1152/ajpendo.00239.2019

Jepsen, SL , Grunddal, KV , Wewer Albrechtsen, NJ, Engelstoft, MS, Gabe, MBN, Jensen, EP, Ørskov, C , Poulsen, SS, Rosenkilde, MM, Pedersen, J, Gribble, FM, Reimann, F, Deacon, CF , Schwartz, TW, Christ, AD, Martin, RE & Holst, JJ 2019, 'Paracrine Crosstalk between Intestinal L- and D-cells Controls Secretion of Glucagon-Like Peptide-1 in mice', A J P: Endocrinology and Metabolism (Online). https://doi.org/10.1152/ajpendo.00239.2019

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

abstract = "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.",

author = "Jepsen, {Sara L.} and Grunddal, {Kaare V.} and {Wewer Albrechtsen}, {Nicolai J} and Engelstoft, {Maja S} and Gabe, {Maria B N} and Jensen, {Elisa P} and Cathrine {\O}rskov and Poulsen, {Steen S} and Rosenkilde, {Mette M} and Jens Pedersen and Gribble, {Fiona M} and Frank Reimann and Deacon, {Carolyn F} and Schwartz, {Thue W} and Christ, {Andreas D} and Martin, {Rainer E} and Holst, {Jens J}",

year = "2019",

month = dec,

doi = "10.1152/ajpendo.00239.2019",

language = "English",

journal = "A J P: Endocrinology and Metabolism (Online)",

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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 -

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

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