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

Islets
Nathalie EsserSakeneh Zraika

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 s...Continue Reading

References

Jul 7, 2009·Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme·L SimonsenC F Deacon
Nov 3, 2010·International Journal of Obesity : Journal of the International Association for the Study of Obesity·K F StandevenP J Grant
Apr 20, 2016·Trends in Endocrinology and Metabolism : TEM·Giulia CantiniMichaela Luconi
Mar 23, 2017·Cell Metabolism·Adam P ChambersDarleen A Sandoval
Jun 25, 2017·The Lancet. Diabetes & Endocrinology·Nicolas VodovarDamien Logeart

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Citations

May 16, 2019·Diabetologia·Nathalie Esser, Sakeneh Zraika
May 11, 2019·The Journal of Clinical Endocrinology and Metabolism·Nicolai J Wewer AlbrechtsenPeter Plomgaard
Feb 6, 2020·International Journal of Molecular Sciences·Elisa WeißUrsula Hiden
Aug 3, 2021·Journal of the Endocrine Society·Sasha A S KjeldsenNicolai J Wewer Albrechtsen
Feb 8, 2022·American Journal of Physiology. Endocrinology and Metabolism·Nathalie EsserSakeneh Zraika

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Methods Mentioned

BETA
ELISA

Related Concepts

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Cardiovascular Biology of GLP-1

Glucagon-like peptide 1 (GLP-1) plays a role in glucose metabolism, energy homeostasis, and inflammation suppression. GLP-1 receptor signaling has been shown to impact cardiovascular function. This feed focuses on the role of GLP-1 and GLP-1 receptor agonists on cardiovascular biology.

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