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Neprilysin inhibition in mouse islets enhances insulin secretion in a GLP-1 receptor dependent manner

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Bibliographic Details
Title: Neprilysin inhibition in mouse islets enhances insulin secretion in a GLP-1 receptor dependent manner
Authors: Nathalie Esser, Breanne M. Barrow, Edwina Choung, Nancy J. Shen, Sakeneh Zraika
Source: Islets. 10:175-180
Publisher Information: Informa UK Limited, 2018.
Publication Year: 2018
Subject Terms: Blood Glucose, insulin secretion, Dipeptidyl Peptidase 4, Diabetes Mellitus, Type 2/drug therapy/metabolism, Insulin Secretion/drug effects/physiology, Sciences de la santé humaine, Glucagon-Like Peptide-1 Receptor, neprilysin, Diabetes Mellitus, Experimental, Glucagon-Like Peptide-1 Receptor/metabolism, Islets of Langerhans, Mice, 03 medical and health sciences, 0302 clinical medicine, DPP-4, Endocrinology, metabolism & nutrition, Insulin Secretion, Animals, Human health sciences, Enzyme Inhibitors, Enzyme Inhibitors/pharmacology, Mice, Knockout, Dipeptidyl-Peptidase IV Inhibitors, Blood Glucose/metabolism, islet, Treatment Outcome, Diabetes Mellitus, Type 2, Dipeptidyl-Peptidase IV Inhibitors/pharmacology, Neprilysin/antagonists & inhibitors/metabolism, Neprilysin, Islets of Langerhans/metabolism, GLP-1, Dipeptidyl Peptidase 4/metabolism, Endocrinologie, métabolisme & nutrition
Description: Neprilysin, a widely expressed peptidase upregulated in type 2 diabetes, is capable of cleaving and inactivating the insulinotropic glucagon-like peptide-1 (GLP-1). Like dipeptidyl peptidase-4 (DPP-4), inhibition of neprilysin activity under diabetic conditions is associated with increased active GLP-1 levels and improved glycemic control. While neprilysin expression has been demonstrated in islets, its local contribution to GLP-1-mediated insulin secretion remains unknown. We investigated in vitro whether islet neprilysin inhibition enhances insulin secretion in response to glucose and/or exogenous GLP-1, and whether these effects are mediated by GLP-1 receptor (GLP-1R). Further, we compared the effect of neprilysin versus DPP-4 inhibition on insulin secretion. Isolated islets from wild-type (Glp1r+/+) and GLP-1 receptor knockout (Glp1r-/-) mice were incubated with or without the neprilysin inhibitor thiorphan and/or the DPP-4 inhibitor sitagliptin for 2.5 hours. During the last hour, insulin secretion was assessed in response to 2.8 mmol/l or 20 mmol/l glucose alone or plus exogenous active GLP-1. In Glp1r+/+ islets, neprilysin inhibition enhanced 2.8 mmol/l and 20 mmol/l glucose- and GLP-1-mediated insulin secretion to the same extent as DPP-4 inhibition. These effects were blunted in Glp1r-/- islets. In conclusion, inhibition of islet neprilysin in vitro increases glucose-mediated insulin secretion in a GLP-1R-dependent manner and enhances the insulinotropic effect of exogenous active GLP-1. Thus, neprilysin inhibitors may have therapeutic potential in type 2 diabetes by preserving islet-derived and circulating active GLP-1 levels.
Document Type: Article
Language: English
ISSN: 1938-2022
1938-2014
DOI: 10.1080/19382014.2018.1502521
Access URL: https://www.tandfonline.com/doi/pdf/10.1080/19382014.2018.1502521?needAccess=true
https://pubmed.ncbi.nlm.nih.gov/30142012
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284476
https://www.tandfonline.com/doi/full/10.1080/19382014.2018.1502521
https://europepmc.org/article/MED/30142012
https://pubmed.ncbi.nlm.nih.gov/30142012/
https://www.tandfonline.com/doi/pdf/10.1080/19382014.2018.1502521
https://hdl.handle.net/2268/267272
https://doi.org/10.1080/19382014.2018.1502521
Accession Number: edsair.doi.dedup.....b14ac8f6ade1c4242cda0c59ada1ce64
Database: OpenAIRE
Description
Abstract:Neprilysin, a widely expressed peptidase upregulated in type 2 diabetes, is capable of cleaving and inactivating the insulinotropic glucagon-like peptide-1 (GLP-1). Like dipeptidyl peptidase-4 (DPP-4), inhibition of neprilysin activity under diabetic conditions is associated with increased active GLP-1 levels and improved glycemic control. While neprilysin expression has been demonstrated in islets, its local contribution to GLP-1-mediated insulin secretion remains unknown. We investigated in vitro whether islet neprilysin inhibition enhances insulin secretion in response to glucose and/or exogenous GLP-1, and whether these effects are mediated by GLP-1 receptor (GLP-1R). Further, we compared the effect of neprilysin versus DPP-4 inhibition on insulin secretion. Isolated islets from wild-type (Glp1r+/+) and GLP-1 receptor knockout (Glp1r-/-) mice were incubated with or without the neprilysin inhibitor thiorphan and/or the DPP-4 inhibitor sitagliptin for 2.5 hours. During the last hour, insulin secretion was assessed in response to 2.8 mmol/l or 20 mmol/l glucose alone or plus exogenous active GLP-1. In Glp1r+/+ islets, neprilysin inhibition enhanced 2.8 mmol/l and 20 mmol/l glucose- and GLP-1-mediated insulin secretion to the same extent as DPP-4 inhibition. These effects were blunted in Glp1r-/- islets. In conclusion, inhibition of islet neprilysin in vitro increases glucose-mediated insulin secretion in a GLP-1R-dependent manner and enhances the insulinotropic effect of exogenous active GLP-1. Thus, neprilysin inhibitors may have therapeutic potential in type 2 diabetes by preserving islet-derived and circulating active GLP-1 levels.
ISSN:19382022
19382014
DOI:10.1080/19382014.2018.1502521