ArticleJournal of the Endocrine Society2021
Neprilysin Inhibition Increases Glucagon Levels in Humans and Mice With Potential Effects on Amino Acid Metabolism.
Article in Journal of the Endocrine Society, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes.Diabetes, obesity & metabolism · 2022Trial
- The effect of sacubitril/valsartan on urinary C-peptide excretion and endogenous insulin secretory capacity in a patient with type 2 diabetes: a case report.Journal of pharmaceutical health care and sciences · 2025Article
- Impact of angiotensin receptor neprilysin inhibitor on serum C-peptide levels in patients with type 2 diabetes.Diabetology international · 2025Article
- Secretion of glucagon, GLP-1 and GIP may be affected by circadian rhythm in healthy males.BMC endocrine disorders · 2024Article
- Underlying mechanisms of ketotherapy in heart failure: current evidence for clinical implementations.Frontiers in pharmacology · 2024Review
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- Glucagon and Its Receptors in the Mammalian Heart.International journal of molecular sciences · 2023Review
- 100 years of glucagon and 100 more.Diabetologia · 2023Review
- Effects of neprilysin and neprilysin inhibitors on glucose homeostasis: Controversial points and a promising arena.Journal of diabetes · 2023Review
- Acute Inhibition of Intestinal Neprilysin Enhances Insulin Secretion via GLP-1 Receptor Signaling in Male Mice.Endocrinology · 2023Article
- Opposing effects of chronic glucagon receptor agonism and antagonism on amino acids, hepatic gene expression, and alpha cells.iScience · 2022Article
- Neprilysin inhibition improves intravenous but not oral glucose-mediated insulin secretion via GLP-1R signaling in mice withAmerican journal of physiology. Endocrinology and metabolism · 2022Article
- Sacubitril/Valsartan contributes to improving the diabetic kidney disease and regulating the gut microbiota in mice.Frontiers in endocrinology · 2022Article
- Insulinotropic Effects of Neprilysin and/or Angiotensin Receptor Inhibition in Mice.Frontiers in endocrinology · 2022Article
- Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 3 countries.
Funding
Abstract
contextInhibitors 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.
objectiveThis work aims to investigate whether NEP inhibition increases glucagon levels.
methodsPlasma 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.
resultsIn 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.
conclusionNEP cleaves glucagon, and inhibitors of NEP result in hyperglucagonemia and may increase postprandial AA catabolism without affecting glycemia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.