Abstract
Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic β-cells. Investigation of mice with tissue-specific genetic deletion of Ide in the liver and pancreatic β-cells (L-IDE-KO and B-IDE-KO mice, respectively) has revealed additional roles for IDE in the regulation of hepatic insulin action and sensitivity. In this review, we discuss current knowledge about IDE’s function as a regulator of insulin secretion and hepatic insulin sensitivity, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions. Insulin proteostasis and insulin sensitivity have both been highlighted as targets controlling blood sugar levels in type 2 diabetes, so a clearer understanding the physiological functions of IDE in pancreas and liver could led to the development of novel therapeutics for the treatment of this disease.
Highlights
Insulin-degrading enzyme (IDE; EC 3.4.24.56; a.k.a. insulin protease, insulinase, insulysin, insulin-glucagon protease, neutral thiol protease, metalloendoprotease, amyloiddegrading protease or peroxisomal protease) is a neutral Zn2+ metallo-endopeptidase that is ubiquitously expressed in insulin-responsive and non-responsive cells [1,2]
As shown by Parmentier and colleagues, MAGE-A3, a cytosolic human tumor protein, is degraded by IDE, leading to different sets of antigenic peptides presented by major histocompatibility complex (MHC) class I molecules to cytotoxic T lymphocytes (CTLs) [105]
Assessment of β-cell function, and histomorphological analyses of pancreas (β-cell mass, β-cell area, number of islets, and mean islets size) revealed that β-cell function and mass in L-IDE-KO mice were similar to wildtype controls [86]. These findings indicate that hepatic Ide ablation causes insulin resistance independently of any effect on circulating insulin levels, suggesting that the hyperinsulinemia observed in IDE-KO mice emerged as a secondary compensatory response to systemic insulin resistance
Summary
Insulin-degrading enzyme (IDE; EC 3.4.24.56; a.k.a. insulin protease, insulinase, insulysin, insulin-glucagon protease, neutral thiol protease, metalloendoprotease, amyloiddegrading protease or peroxisomal protease) is a neutral Zn2+ metallo-endopeptidase that is ubiquitously expressed in insulin-responsive and non-responsive cells [1,2]. Human IDE shares significant sequence similarity with orthologs in bacteria and yeast, for example, including the HxxEH zinc-binding motif. IDE homologues Axl1p and Ste are incapable of degrading insulin despite possessing the conserved zinc-binding motif [12]. Nardilysin has several other roles unrelated to hepatic or pancreatic function, such as modulation of thermoregulation [17] It mediates cell migration by acting as a specific receptor for heparin-binding epidermal growth factor-like growth [18]. This protein provides a good example of how paralogs (rather than orthologs) can evolve to develop diverse functions
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