IDE

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Background

Insulin degrading enzyme (IDE), a 110 kDa Zn requiring metalloproteinase, is responsible for insulin degradation. The ability of IDE to degrade the insulin B chain was discovered over 60 years ago. IDE is located in the cytoplasm, cell membrane, certain cell organelles (peroxisomes, mitochondria, etc.), and secreted into the extracellular space. IDE is ubiquitously expressed in both insulin-sensitive and non-insulin-sensitive cells, and is present in most organisms from E. coli to mammals.

IDE-mediated insulin degradation mainly occurs in the liver and kidneys. The liver will remove approximately 75% during the first portal passage. In addition, insulin degradation also occurs in fibroblasts, monocytes, adipocytes, lymphocytes and many other tissues. Insulin is the preferred substrate for IDE, but the enzyme can also cleave many other short polypeptides, such as glucagon, beta-amyloid peptide (Aβ), atrial natriuretic peptide, and insulin-like growth factor 1 and 2, many of which are amyloidogenic. The N and C terminal units of IDE form two parts of the proteolytic chamber containing the zinc-binding active site. In the open conformation, the substrate can enter and leave. Only when the protease is in the closed conformation, the bipartite catalytic site is fully formed and active. Therefore, IDE can cleave peptides containing up to 70 amino acids which fit inside the chamber, it is powerless against large proteins, and does not show strong cleavage site specificity. Interestingly, the targeted mutation that disrupted the contact between IDE-N and IDE-C caused a 40-fold increase in the catalytic activity of the enzyme. In addition to degradation activity, IDE can also play a regulatory role in some cells, including regulation of androgen and glucocorticoid receptors, antigen presentation, peroxisomal fatty acid oxidation, and cell growth and differentiation, etc.

IDE and type 2 diabetes

T2DM is a metabolic disorder characterized by insulin resistance, and may also be accompanied by a relative decrease in insulin secretion. From the study of genome wide and candidate gene methods, it was found that the genetic polymorphism in the IDE locus on chromosome 10 is closely related to the increased risk of T2DM. Since then, many studies have reported the relationship between IDE polymorphism and various aspects of impaired insulin metabolism, including insulin sensitivity, decreased insulin secretion, and liver insulin degradation. In addition to other typical features of T2DM, IDE mutations in the Goto-Kakizaki rat model can cause changes in cellular insulin degradation. On the other hand, IDE overexpression will increase the rate of insulin degradation and effectively reduce the efficiency of insulin stimulation in the insulin signaling pathway. These studies have shown that the level and activity of IDE may contribute to the pathogenesis of T2DM.

I. Arthur Mirsky, who discovered IDE, predicted that IDE inhibitors would provide an ideal anti-diabetic treatment strategy. In the past decade, a series of new and potent IDE inhibitors have been developed. Among them, Maianti et al. proposed the use of IDE inhibitor 6bK as a new strategy for T2DM. This conclusion is based on the decrease in postprandial glucose concentration after oral glucose administration in lean and obese mice after acute 6bK treatment. However, whether long-term inhibition of IDE activity is also effective as a human anti-diabetic strategy remains to be determined, and additional studies on the regulation of IDE in diabetic patients are needed. It is worth mentioning that IDE inhibition may cause chronic hyperinsulinemia, increase insulin resistance and impair insulin secretion.  

Figure 1. Possible side effects of pharmacological IDE inhibition (Pivovarova, O.; et al. 2016)

IDE and Alzheimer’s disease

Alzheimer's disease is a neurodegenerative disease characterized by neuroinflammation, Aβ agglomeration, and cognitive dysfunction. Due to the many similar pathological mechanisms of T2DM and late-onset AD, AD is generally considered a form of diabetes and is called "type 3 diabetes". T2DM, hyperinsulinemia, and systemic insulin resistance will all increase the risk of AD and vice versa. At the same time, some studies have reported the association of polymorphisms within IDE locus with AD risk and plasma Aβ levels. A large number of human studies have found that the decreased Aβ-degrading IDE activity and expression in the brain of AD subjects and AD high-risk subjects, although some researchers have not observed changes in IDE activity. Interestingly, Kim et al. found that IDE activity was reduced in chromosome 10-linked late-onset AD, but its expression did not decrease, indicating that there is a possibility of systemic defects in IDE activity. Therefore, in some cases, AD may be caused by IDE's failure to degrade Aβ.  

Figure 2. IDE as a pathological link between type 2 diabetes and Alzheimer’s disease (Pivovarova, O.; et al. 2016)