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Review
. 2023 May;15(5):397-408.
doi: 10.1111/1753-0407.13389. Epub 2023 Apr 19.

Effects of neprilysin and neprilysin inhibitors on glucose homeostasis: Controversial points and a promising arena

Faisal Holil AlAnazi  1 , Hayder M Al-Kuraishy  2 , Ali I Al-Gareeb  2 , Athanasios Alexiou  3   4 , Marios Papadakis  5 , Hanan A Ogaly  6 , Yousef Abud Alanazi  7 , Hebatallah M Saad  8 , Gaber El-Saber Batiha  9
Affiliations
Review

Effects of neprilysin and neprilysin inhibitors on glucose homeostasis: Controversial points and a promising arena

Faisal Holil AlAnazi et al. J Diabetes. 2023 May.

Abstract
in English, Chinese

Neprilysin (NEP) is a transmembrane zinc-dependent metalloproteinase that inactivates various peptide hormones including glucagon-like peptide 1 (GLP-1). NEP inhibitors may be effective in the management of type 2 diabetes mellitus (T2DM) by increasing the circulating level of GLP-1. However, acute-effect NEP inhibitors may lead to detrimental effects by increasing blood glucose independent of GLP-1. These findings suggest a controversial point regarding the potential role of NEP inhibitors on glucose homeostasis in T2DM patients. Therefore, this perspective aimed to clarify the controversial points concerning the role of NEP inhibitors on glucose homeostasis in T2DM. NEP inhibitors may lead to beneficial effects by inhibition of NEP, which is involved in the impairment of glucose homeostasis through modulation of insulin resistance. NEP increases dipeptidyl peptidase-4 (DPP4) activity and contributes to increasing active GLP-1 proteolysis so NEP inhibitors may improve glycemic control through increasing endogenous GLP-1 activity and reduction of DPP4 activity. Thus, NEP inhibitors could be effective alone or in combination with antidiabetic agents in treating T2DM patients. However, long-term and short-term effects of NEP inhibitors may lead to a detrimental effect on insulin sensitivity and glucose homeostasis through different mechanisms including augmentation of substrates and pancreatic amyloid deposition. These findings are confirmed in animal but not in humans. In conclusion, NEP inhibitors produce beneficial rather than detrimental effects on glucose homeostasis and insulin sensitivity in humans though most of the detrimental effects of NEP inhibitors are confirmed in animal studies.

脑啡肽酶(NEP)是一种跨膜锌依赖性金属蛋白酶，可使包括胰高血糖素样肽1 (GLP-1)在内的多种肽类激素失活。NEP抑制剂可能通过提高循环GLP-1水平来有效治疗2型糖尿病(T2DM)。然而，NEP抑制剂的急性效应可能会造成血糖升高，产生有害作用，且与GLP-1无关。这些发现提示NEP抑制剂对T2DM患者血糖稳态的作用尚存有争议。本视角旨在阐明NEP抑制剂对T2DM糖稳态作用的争议点。NEP通过调节胰岛素抵抗(IR)参与糖稳态受损，NEP抑制剂可能通过抑制NEP发挥有益作用。NEP增加二肽基肽酶-4 (DPP4)活性并有助于增加GLP-1蛋白水解活性，而NEP抑制剂可能通过增加内源性GLP-1活性和降低DPP4活性来改善血糖控制。因此，NEP抑制剂可单独或联合降糖药物治疗T2DM患者。然而，NEP抑制剂的长期和短期作用机制可能不同，包括增强底物和胰腺淀粉样蛋白沉积，导致对胰岛素敏感性和葡萄糖稳态的有害影响。这些发现在动物中得到证实，但在人类中未得到证实。综上所述，NEP抑制剂对人体葡萄糖稳态和胰岛素敏感性产生有益而非有害的影响，尽管大多数有害影响已在动物研究中得到证实。.

Keywords: 2型糖尿病; neprilysin; sacubitril; type 2 diabetes mellitus; 脑啡肽酶; 脑啡肽酶抑制剂.

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Figures

FIGURE 1
FIGURE 1
The physiological role of neprilysin (NEP) “Created with BioRender.com”.
FIGURE 2
FIGURE 2
Neprilysin (NEP) inhibitors in the management of heart failure “Created with BioRender.com”.
FIGURE 3
FIGURE 3
Human islet amyloid polypeptide (IAPP) and development of pancreatic β cell dysfunction “Created with BioRender.com”.
FIGURE 4
FIGURE 4
Role of neprilysin (NEP) and dipeptidyl peptidase‐4 (DPP4) in degrading of glucagon‐like peptide 1 (GLP‐1) “Created with BioRender.com”.
See this image and copyright information in PMC

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