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

Abstract

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.

Increased thyroid stimulating hormone (TSH) as a possible risk factor for atherosclerosis in subclinical hypothyroidism

“…Systemic expression of TSHRs suggests the role of TSH in different cardiometabolic processes and inflammatory reactions regardless of the thyroid gland. It has been reported that high TSH level is associated with an increased risk of cardiovascular diseases by reducing of insulin sensitivity and lipid metabolism [55,56]. A cross-sectional study conducted by Wang et al [57] showed that TSH affects lipid metabolism through THsdependent and THs-independent mechanisms causing hypercholesterolemia.…”

Cyclin‐dependent kinase 5 (CDK5) inhibitors in Parkinson disease

“… 85 It has been shown that overactivation of Cdk5 induces aberrant phosphorylation of neurofilaments; tau protein and amyloid precursor protein (APP) result in the formation of NFTs and associated mitochondrial dysfunction and neuronal apoptosis. 86 During neuronal stress both p39 and p35 are cleaved by calpain to p25 and p29; result in formation of Cdk5/p25 complex which has long and potent effect by 10‐fold than p35 in the activation of APP. 87 Therefore, Cdk5 and its activators are augmented and correlated with Aβ and NFTs in AD (Figure 3 ).…”

The possible role of nuclear factor erythroid‐2‐related factor 2 activators in the management of Covid‐19

“…In the context of insulin resistance, earlier investigations have shown a connection between the Renin‐Angiotensin‐Aldosterone system (RAAS) and ER stress. [ 187 ] Ang‐II increases the ER stress in adipose tissue. ACE2 improves mitochondrial and ER function to reduce intramuscular fat.…”