Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism

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Standard

Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism. / Kjeldsen, Sasha A.S.; Hansen, Lasse H; Esser, Nathalie; Mongovin, Steve; Winther-Sørensen, Marie; Galsgaard, Katrine D; Hunt, Jenna E; Kissow, Hannelouise; Ceutz, Frederik R.; Terzic, Dijana; Mark, Peter D; Plomgaard, Peter; Goetze, Jens P; Goossens, Gijs H.; Blaak, Ellen E.; Deacon, Carolyn F.; Rosenkilde, Mette M; Zraika, Sakeneh; Holst, Jens J; Wewer Albrechtsen, Nicolai J.

I: Endocrine Research, Bind 5, Nr. 9, bvab084, 2021.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

Harvard

Kjeldsen, SAS, Hansen, LH, Esser, N, Mongovin, S, Winther-Sørensen, M, Galsgaard, KD, Hunt, JE, Kissow, H, Ceutz, FR, Terzic, D, Mark, PD, Plomgaard, P, Goetze, JP, Goossens, GH, Blaak, EE, Deacon, CF, Rosenkilde, MM, Zraika, S, Holst, JJ & Wewer Albrechtsen, NJ 2021, 'Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism', Endocrine Research, bind 5, nr. 9, bvab084. https://doi.org/10.1210/jendso/bvab084

APA

Kjeldsen, S. A. S., Hansen, L. H., Esser, N., Mongovin, S., Winther-Sørensen, M., Galsgaard, K. D., Hunt, J. E., Kissow, H., Ceutz, F. R., Terzic, D., Mark, P. D., Plomgaard, P., Goetze, J. P., Goossens, G. H., Blaak, E. E., Deacon, C. F., Rosenkilde, M. M., Zraika, S., Holst, J. J., & Wewer Albrechtsen, N. J. (2021). Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism. Endocrine Research, 5(9), [bvab084]. https://doi.org/10.1210/jendso/bvab084

Vancouver

Kjeldsen SAS, Hansen LH, Esser N, Mongovin S, Winther-Sørensen M, Galsgaard KD o.a. Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism. Endocrine Research. 2021;5(9). bvab084. https://doi.org/10.1210/jendso/bvab084

Author

Kjeldsen, Sasha A.S. ; Hansen, Lasse H ; Esser, Nathalie ; Mongovin, Steve ; Winther-Sørensen, Marie ; Galsgaard, Katrine D ; Hunt, Jenna E ; Kissow, Hannelouise ; Ceutz, Frederik R. ; Terzic, Dijana ; Mark, Peter D ; Plomgaard, Peter ; Goetze, Jens P ; Goossens, Gijs H. ; Blaak, Ellen E. ; Deacon, Carolyn F. ; Rosenkilde, Mette M ; Zraika, Sakeneh ; Holst, Jens J ; Wewer Albrechtsen, Nicolai J. / Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism. I: Endocrine Research. 2021 ; Bind 5, Nr. 9.

Bibtex

@article{cc406c0a22674afea56b4a1552a615e4,
title = "Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism",
abstract = "Context: Inhibitors of the protease neprilysin (NEP) are used for treating heart failure, but are also linked to improvements in metabolism. NEP may cleave proglucagon-derived peptides, including the glucose and amino acid (AA)-regulating hormone glucagon. Studies investigating NEP inhibition on glucagon metabolism are warranted.Objective: This work aims to investigate whether NEP inhibition increases glucagon levels.Methods: Plasma concentrations of glucagon and AAs were measured in eight healthy men during a mixed meal with and without a single dose of the NEP inhibitor/angiotensin II type 1 receptor antagonist, sacubitril/valsartan (194 mg/206 mg). Long-term effects of sacubitril/valsartan (8 weeks) were investigated in individuals with obesity (n = 7). Mass spectrometry was used to investigate NEP-induced glucagon degradation, and the derived glucagon fragments were tested pharmacologically in cells transfected with the glucagon receptor (GCGR). Genetic deletion or pharmacological inhibition of NEP with or without concomitant GCGR antagonism was tested in mice to evaluate effects on AA metabolism.Results: In healthy men, a single dose of sacubitril/valsartan significantly increased postprandial concentrations of glucagon by 228%, concomitantly lowering concentrations of AAs including glucagonotropic AAs. Eight-week sacubitril/valsartan treatment increased fasting glucagon concentrations in individuals with obesity. NEP cleaved glucagon into 5 inactive fragments (in vitro). Pharmacological NEP inhibition protected both exogenous and endogenous glucagon in mice after an AA challenge, while NEP-deficient mice showed elevated fasting and AA-stimulated plasma concentrations of glucagon and urea compared to controls.Conclusion: NEP cleaves glucagon, and inhibitors of NEP result in hyperglucagonemia and may increase postprandial AA catabolism without affecting glycemia.",
author = "Kjeldsen, {Sasha A.S.} and Hansen, {Lasse H} and Nathalie Esser and Steve Mongovin and Marie Winther-S{\o}rensen and Galsgaard, {Katrine D} and Hunt, {Jenna E} and Hannelouise Kissow and Ceutz, {Frederik R.} and Dijana Terzic and Mark, {Peter D} and Peter Plomgaard and Goetze, {Jens P} and Goossens, {Gijs H.} and Blaak, {Ellen E.} and Deacon, {Carolyn F.} and Rosenkilde, {Mette M} and Sakeneh Zraika and Holst, {Jens J} and {Wewer Albrechtsen}, {Nicolai J}",
note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.",
year = "2021",
doi = "10.1210/jendso/bvab084",
language = "English",
volume = "5",
journal = "Endocrine Research",
issn = "0743-5800",
publisher = "Taylor & Francis",
number = "9",

}

RIS

TY - JOUR

T1 - Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism

AU - Kjeldsen, Sasha A.S.

AU - Hansen, Lasse H

AU - Esser, Nathalie

AU - Mongovin, Steve

AU - Winther-Sørensen, Marie

AU - Galsgaard, Katrine D

AU - Hunt, Jenna E

AU - Kissow, Hannelouise

AU - Ceutz, Frederik R.

AU - Terzic, Dijana

AU - Mark, Peter D

AU - Plomgaard, Peter

AU - Goetze, Jens P

AU - Goossens, Gijs H.

AU - Blaak, Ellen E.

AU - Deacon, Carolyn F.

AU - Rosenkilde, Mette M

AU - Zraika, Sakeneh

AU - Holst, Jens J

AU - Wewer Albrechtsen, Nicolai J

N1 - © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

PY - 2021

Y1 - 2021

N2 - Context: Inhibitors of the protease neprilysin (NEP) are used for treating heart failure, but are also linked to improvements in metabolism. NEP may cleave proglucagon-derived peptides, including the glucose and amino acid (AA)-regulating hormone glucagon. Studies investigating NEP inhibition on glucagon metabolism are warranted.Objective: This work aims to investigate whether NEP inhibition increases glucagon levels.Methods: Plasma concentrations of glucagon and AAs were measured in eight healthy men during a mixed meal with and without a single dose of the NEP inhibitor/angiotensin II type 1 receptor antagonist, sacubitril/valsartan (194 mg/206 mg). Long-term effects of sacubitril/valsartan (8 weeks) were investigated in individuals with obesity (n = 7). Mass spectrometry was used to investigate NEP-induced glucagon degradation, and the derived glucagon fragments were tested pharmacologically in cells transfected with the glucagon receptor (GCGR). Genetic deletion or pharmacological inhibition of NEP with or without concomitant GCGR antagonism was tested in mice to evaluate effects on AA metabolism.Results: In healthy men, a single dose of sacubitril/valsartan significantly increased postprandial concentrations of glucagon by 228%, concomitantly lowering concentrations of AAs including glucagonotropic AAs. Eight-week sacubitril/valsartan treatment increased fasting glucagon concentrations in individuals with obesity. NEP cleaved glucagon into 5 inactive fragments (in vitro). Pharmacological NEP inhibition protected both exogenous and endogenous glucagon in mice after an AA challenge, while NEP-deficient mice showed elevated fasting and AA-stimulated plasma concentrations of glucagon and urea compared to controls.Conclusion: NEP cleaves glucagon, and inhibitors of NEP result in hyperglucagonemia and may increase postprandial AA catabolism without affecting glycemia.

AB - Context: Inhibitors of the protease neprilysin (NEP) are used for treating heart failure, but are also linked to improvements in metabolism. NEP may cleave proglucagon-derived peptides, including the glucose and amino acid (AA)-regulating hormone glucagon. Studies investigating NEP inhibition on glucagon metabolism are warranted.Objective: This work aims to investigate whether NEP inhibition increases glucagon levels.Methods: Plasma concentrations of glucagon and AAs were measured in eight healthy men during a mixed meal with and without a single dose of the NEP inhibitor/angiotensin II type 1 receptor antagonist, sacubitril/valsartan (194 mg/206 mg). Long-term effects of sacubitril/valsartan (8 weeks) were investigated in individuals with obesity (n = 7). Mass spectrometry was used to investigate NEP-induced glucagon degradation, and the derived glucagon fragments were tested pharmacologically in cells transfected with the glucagon receptor (GCGR). Genetic deletion or pharmacological inhibition of NEP with or without concomitant GCGR antagonism was tested in mice to evaluate effects on AA metabolism.Results: In healthy men, a single dose of sacubitril/valsartan significantly increased postprandial concentrations of glucagon by 228%, concomitantly lowering concentrations of AAs including glucagonotropic AAs. Eight-week sacubitril/valsartan treatment increased fasting glucagon concentrations in individuals with obesity. NEP cleaved glucagon into 5 inactive fragments (in vitro). Pharmacological NEP inhibition protected both exogenous and endogenous glucagon in mice after an AA challenge, while NEP-deficient mice showed elevated fasting and AA-stimulated plasma concentrations of glucagon and urea compared to controls.Conclusion: NEP cleaves glucagon, and inhibitors of NEP result in hyperglucagonemia and may increase postprandial AA catabolism without affecting glycemia.

U2 - 10.1210/jendso/bvab084

DO - 10.1210/jendso/bvab084

M3 - Journal article

C2 - 34337276

VL - 5

JO - Endocrine Research

JF - Endocrine Research

SN - 0743-5800

IS - 9

M1 - bvab084

ER -

ID: 275829857