Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism
| Autor: | Peter D Mark, Katrine D. Galsgaard, Jens J. Holst, Steve M. Mongovin, Hannelouise Kissow, Carolyn F. Deacon, Lasse H Hansen, Ellen E. Blaak, Frederik Ceutz, Gijs H. Goossens, Mette M. Rosenkilde, Marie Winther-Sørensen, Dijana Terzic, Nicolai J. Wewer Albrechtsen, Sakeneh Zraika, Peter Plomgaard, Sasha A.S. Kjeldsen, Jens P. Goetze, Jenna Hunt, Nathalie Esser |
|---|---|
| Přispěvatelé: | Humane Biologie, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty endocrine system Endocrinology Diabetes and Metabolism Entresto (sacubitril/valsartan) GAS-CHROMATOGRAPHY 030209 endocrinology & metabolism Glucagon Sacubitril Entresto GLUCOSE 03 medical and health sciences 0302 clinical medicine NEUTRAL ENDOPEPTIDASE Internal medicine ALPHA-CELL HYPERPLASIA medicine Neprilysin Clinical Research Articles ATRIAL-NATRIURETIC-PEPTIDE RECEPTOR PLASMA Chemistry Catabolism digestive oral and skin physiology fungi SANDWICH ELISA Angiotensin II INSULIN 030104 developmental biology Endocrinology (sacubitril/valsartan) Valsartan proglucagon-derived peptides HEART-FAILURE Glucagon receptor metabolism Sacubitril Valsartan AcademicSubjects/MED00250 hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | 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, vol. 5, no. 9, bvab084 . https://doi.org/10.1210/jendso/bvab084 Journal of the Endocrine Society Journal of the endocrine society, 5(9):bvab084. Oxford University Press |
| ISSN: | 2472-1972 |
| DOI: | 10.1210/jendso/bvab084 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|