Insulin-degrading enzyme

Insulin-degrading enzyme (IDE) is a 1019-amino acid metalloproteinase that degrades insulin, glucagon, and amyloid-β peptides derived from the amyloid precursor protein (APP), along with various other bioactive peptides including natriuretic peptides and bradykinin (UniProt: P14735). This broad peptide-degrading activity positions IDE as a critical regulator of peptide hormone signaling and blood glucose homeostasis. The enzyme also plays a role in antigen processing and serves as an entry receptor for varicella-zoster virus.

IDE is expressed across multiple tissues and functions at the intersection of metabolic regulation, neuropeptide clearance, and innate immunity. Its capacity to degrade amyloid-β is particularly relevant to neurodegeneration, as impaired clearance of APP-derived peptides is implicated in Alzheimer's disease pathology. IDE variants have been investigated as potential genetic risk factors in AD and diabetes.

In Alzheimer's disease, IDE is significantly upregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2 fold-change: 0.83; Chaparral AD proteomics), suggesting a possible compensatory response to elevated amyloid-β burden. This upregulation may reflect an attempted but ultimately insufficient mechanism to clear pathogenic peptide accumulation in the AD brain.