IDE

Official Full Name

insulin degrading enzyme

Organism

Homo sapiens

GeneID

3416

Background

This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein's function are associated with Alzheimer's disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.[provided by RefSeq, Sep 2009]

Synonyms

INSULYSIN;

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

Insulin-degrading enzyme (IDE) is found to be a zinc metalloprotease which major function in the degradation of insulin initially. However, in addition to insulin, recent studies also have reported that the targets of IDE range glucagon, atrial natriuretic peptide from beta amyloid peptide (Aβ). Therefore, it plays important roles in many diseases related to insulin such as Alzheimer’s disease and diabetes.

IDE mediated Aβ clearance

IDE Figure 1. Insulin degrading enzyme mediated Aβ degradation. (Jha N K, et al. 2015).

IDE is connected with Alzheimer disease (AD) for its ability of Aβ clearance in several reports. Indeed, IDE has been identified as the protease responsible for the clearance of Aβ deposition by acting on various components target to Aβ in the brain, which is shown in figure 1. Moreover, studies in AD patients have observed that AβPP intracellular domain (AICD) and insulin degraded, significantly reducing the levels of Aβ, when IED is overexpressed. Additionally, IDE-Met1, a long isoform of IED, has been found to affect the Aβ clearance process via mitochondrial biogenesis pathway without any toxic effect. It has also been found that the effect of IDE on extracellular Aβ clearance by cooperating with ApoE, which acts within microglia and in the extracellular space. Furthermore, a number of studies have demonstrated that IDE interrupts the accumulation of Aβ by binding to the receptor for the advanced glycation end products (RAGE), a transport protein of Aβ across the blood brain barrier (BBB) into the Central nervous system (CNS), contributing to maintain memory cognition and neuronal survival.

IDE and Alzheimer’s Disease

Based on the effect of IDE on Aβ clearance, further studies have found that IDE is the major protease responsible for Aβ clearance in human hippocampal lysates and for the degradation of Aβ in the cytoplasm and cerebrospinal fluid, suggesting its critical role in neuro related diseases including AD. A number of studies have delved into the actual mechanisms of action of the IDE on AD, finding that there is a positive association between the risk of late-onset AD and genetic variation in the IDE. For instance, studies with mice model have observed that overexpression of IDE blocks the formation of pathology-related amyloid plaque, and IDE gene variant related to increased expression of cerebral IDE, which decreases plasma Aβ levels and lower risk of the late-onset AD. Notably, the specific binding between IDE makes it the potential therapeutic target in neurodegenerative diseases.

IDE and type 2 diabetes

In addition to Aβ, insulin, which has pleiotropic biological functions in diabetes pathologic process, is also the major substrate of IDE. It has been shown that IDE cuts both A and B chains once in a processive manner to generate non-functional insulin fragments. However, IDE protects the insulin hexamer produced by pancreatic β cells from degradation, as it only cleaves monomeric insulin. Substantial studies have shown that IDE null mutants, gene knockout, and pharmacological inhibition in rodents all lead to increased blood insulin levels which may induce hyperinsulinemia. Additionally, IDE also has been found to decrease the activity of amylin and glucagon to regulate the blood glucose levels.

Summary

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

All the results mentioned above suggest that brain IDE is one of the pathological links between type 2 diabetes (T2D) and AD as illustrated in figure 2. It has been shown that glucose increased leads to the increase of reactive nitrogen species in neuronal, resulting in the aberrant S-nitrosylation of IDE and decreasing its activity. In addition, several studies have reported that the binding and degradation of IDE to Aβ can be interrupted by insulin, which makes IDE another potential link between AD and T2D. Thus, IDE might be the potential drugs target of both diseases.

References:

Haque R, et al. Insulin-degrading enzyme: a link between Alzheimer's and type 2 diAβetes mellitus. Cns & Neurological Disorders Drug Targets, 2014, 13(2):259.
Jha N K, et al. Impact of Insulin Degrading Enzyme and Neprilysin in Alzheimer's Disease Biology: Characterization of Putative Cognates for Therapeutic Applications. Journal of Alzheimers Disease Jad, 2015, 48(4):891.
Pivovarova O, et al. Insulin-degrading enzyme: new therapeutic target for diAβetes and Alzheimerâ’s disease? Annals of Medicine, 2016, 48(8):614-624.
Tang W J. Targeting insulin-degrading enzyme to treat type 2 diAβetes. Trends Endocrinol MetAβ, 2016, 27(1):24-34.
Tundo G R, et al. Multiple functions of insulin-degrading enzyme: a metAβolic crosslight? Critical Reviews in Biochemistry & Molecular Biology, 2017, 52(5):1.
Kurochkin I V, et al. Insulin-Degrading Enzyme in the Fight against Alzheimer's Disease. Trends in Pharmacological Sciences, 2017, 39(1).

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry