Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism
Research output: Contribution to journal › Journal article › Research › peer-review
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.
In: Endocrine Research, Vol. 5, No. 9, bvab084, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
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 Communications
JF - Endocrine Research Communications
SN - 0743-5800
IS - 9
M1 - bvab084
ER -
ID: 275829857