Multiple functions of insulin-degrading enzyme: a metabolic crosslight?

Abstract

Insulin-degrading enzyme (IDE) is a ubiquitous zinc peptidase of the inverzincin family, which has been initially discovered as the enzyme responsible for insulin catabolism; therefore, its involvement in the onset of diabetes has been largely investigated. However, further studies on IDE unraveled its ability to degrade several other polypeptides, such as β-amyloid, amylin, and glucagon, envisaging the possible implication of IDE dys-regulation in the "aggregopathies" and, in particular, in neurodegenerative diseases. Over the last decade, a novel scenario on IDE biology has emerged, pointing out a multi-functional role of this enzyme in several basic cellular processes. In particular, latest advances indicate that IDE behaves as a heat shock protein and modulates the ubiquitin-proteasome system, suggesting a major implication in proteins turnover and cell homeostasis. In addition, recent observations have highlighted that the regulation of glucose metabolism by IDE is not merely based on its largely proposed role in the degradation of insulin in vivo. There is increasing evidence that improper IDE function, regulation, or trafficking might contribute to the etiology of metabolic diseases. In addition, the enzymatic activity of IDE is affected by metals levels, thus suggesting a role also in the metal homeostasis (metallostasis), which is thought to be tightly linked to the malfunction of the "quality control" machinery of the cell. Focusing on the physiological role of IDE, we will address a comprehensive vision of the very complex scenario in which IDE takes part, outlining its crucial role in interconnecting several relevant cellular processes.

Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease

“…This suggests that a selfperpetuating cycle may become established, further exacerbating neurodegeneration [135]. Insulin-degrading enzyme (IDE), a major enzyme responsible for insulin degradation, can also degrade other targets such as glucagon, atrial natriuretic peptide, and the Aβ peptide and regulate proteasomal degradation and other cellular functions [136,137]. It has been demonstrated that IAPP can interact with Aβ and contribute to Aβ aggregation [138] and conformation [20,119,139].…”

Metformin Ameliorates Aβ Pathology by Insulin-Degrading Enzyme in a Transgenic Mouse Model of Alzheimer’s Disease

“…Early findings showed that IDE could regulate Aβ and insulin levels in vivo [37]. The major locations of IDE are the cytosol, mitochondria, and peroxisomes [38]. IDE is specific toward β-structure-forming substrates of toxic oligomers (Aβ) [39].…”

Ubiquitin binds the amyloid β peptide and interferes with its clearance pathways

“…These experiments are also paralleled by ESI-MS studies addressing Ab hydrolysis by the Insulin Degrading Enzyme (IDE), a protease which is known to be involved in the physiological amyloid clearance. 27 The effects of Ub on Ab amyloid aggregation and Ub chain growth reactions are nally investigated.…”