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Insulin-Degrading Enzyme in Health and Disease
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Insulin-Degrading Enzyme in Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 March 2022) | Viewed by 21923

Special Issue Editors

Prof. Dr. Irene Cozar-Castellano

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Guest Editor
Instituto de Biologia y Genetica Molecular (IBGM), University of Valladolid, Valladolid, Spain
Interests: diabetes mellitus; insulin resistance; endocrine pancreas; insulin-degrading enzyme
Dr. German Perdomo

E-Mail Website
Guest Editor
Spanish National Research Council (CSIC), Instituto de Biología y Genética Molecular (IBGM), 47003 Valladolid, Spain
Interests: obesity; diabetes; cardiovascular disease; metabolic syndrome; endocrinology; insulin resistance; insulin clearance; metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Insulin-degrading enzyme (IDE) is an endopeptidase that degrades insulin and amyloid β (Aβ). The Ide gene has been associated with type-2 diabetes mellitus (DM2), and it is a molecular link between DM2 and Alzheimer´s disease (AD). The physiological role(s) of IDE in glucose/insulin homeostasis is very controversial and its potential therapeutic benefit for DM2 and AD remains not completely understood. This Special Issue aims to gather expert articles on the structure, function, and regulation of IDE in physiological and pathophysiological conditions. I therefore invite you to submit original research articles or reviews.

Prof. Dr. Irene Cozar-Castellano
Dr. German Perdomo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • insulin-degrading enzyme
  • insulin degradation
  • insulin clearance
  • Abeta degradation
  • diabetes mellitus
  • Alzheimer's disease

Published Papers (7 papers)

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Research

Jump to: Review, Other

16 pages, 2772 KiB  
Article
New Insights on the Regulation of the Insulin-Degrading Enzyme: Role of microRNAs and RBPs
by Yolanda Martín-Martín, Ana Pérez-García, Marta Torrecilla-Parra, Mario Fernández-de Frutos, Virginia Pardo-Marqués, María José Casarejos, Rebeca Busto and Cristina M. Ramírez
Cells 2022, 11(16), 2538; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11162538 - 16 Aug 2022
Cited by 3 | Viewed by 2355
Abstract
The evident implication of the insulin-degrading enzyme (IDE) in Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM), among its capacity to degrade insulin and amyloid-β peptide (Aβ), suggests that IDE could be an essential link in the relation between hyperinsulinemia, insulin resistance [...] Read more.
The evident implication of the insulin-degrading enzyme (IDE) in Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM), among its capacity to degrade insulin and amyloid-β peptide (Aβ), suggests that IDE could be an essential link in the relation between hyperinsulinemia, insulin resistance and AD. However, little is known about the cellular and molecular regulation of IDE expression, and even less has been explored regarding the post-transcriptional regulation of IDE, although it represents a great molecular target of interest for therapeutic treatments. We recently described that miR-7, a novel candidate for linking AD and T2DM at the molecular level, regulates IDE and other key genes in both pathologies, including some key genes involved in the insulin signaling pathway. Here, we explored whether other miRNAs as well as other post-transcriptional regulators, such as RNA binding proteins (RBP), could potentially participate in the regulation of IDE expression in vitro. Our data showed that in addition to miR-7, miR-125, miR-490 and miR-199 regulate IDE expression at the post-transcriptional level. Moreover, we also found that IDE contains multiple potential binding sites for several RBPs, and a narrow-down prediction analysis led us to speculate on a novel regulation of IDE by RALY and HuD. Taken together, these results demonstrate the novel players controlling IDE expression that could represent potential therapeutical targets to treat several metabolic diseases with a high impact on human health, including AD and T2DM. Full article
(This article belongs to the Special Issue Insulin-Degrading Enzyme in Health and Disease)
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13 pages, 4048 KiB  
Article
Possible Role of Insulin-Degrading Enzyme in the Physiopathology of Retinitis Pigmentosa
by Alonso Sánchez-Cruz, María D. Hernández-Fuentes, Cayetana Murillo-Gómez, Enrique J. de la Rosa and Catalina Hernández-Sánchez
Cells 2022, 11(10), 1621; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101621 - 12 May 2022
Cited by 1 | Viewed by 1528
Abstract
Insulin-degrading enzyme (IDE) was named after its role as a proteolytic enzyme of insulin. However, recent findings suggest that IDE is a widely expressed, multitask protein, with both proteolytic and non-proteolytic functions. Here, we characterize the expression of IDE in the mammalian retina [...] Read more.
Insulin-degrading enzyme (IDE) was named after its role as a proteolytic enzyme of insulin. However, recent findings suggest that IDE is a widely expressed, multitask protein, with both proteolytic and non-proteolytic functions. Here, we characterize the expression of IDE in the mammalian retina in both physiological and pathological conditions. We found that IDE was enriched in cone inner segments. IDE levels were downregulated in the dystrophic retina of several mouse models of retinitis pigmentosa carrying distinct mutations. In rd10 mice, a commonly studied mouse model of retinitis pigmentosa, treatment with an IDE activator (a synthetic peptide analog of preimplantation factor) delayed loss of visual function and preserved photoreceptor cells. Together, these results point to potential novel roles for IDE in retinal physiology and disease, further extending the list of diverse functions attributed to this enzyme. Full article
(This article belongs to the Special Issue Insulin-Degrading Enzyme in Health and Disease)
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Figure 1

23 pages, 4201 KiB  
Article
Evolutionary Origin of Insulin-Degrading Enzyme and Its Subcellular Localization and Secretion Mechanism: A Study in Microglial Cells
by Miriam Corraliza-Gómez, Concepción Lillo, Irene Cózar-Castellano, Eduardo Arranz, Diego Sanchez and Maria D. Ganfornina
Cells 2022, 11(2), 227; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11020227 - 11 Jan 2022
Cited by 5 | Viewed by 2529
Abstract
The insulin-degrading enzyme (IDE) is a zinc-dependent metalloendopeptidase that belongs to the M16A metalloprotease family. IDE is markedly expressed in the brain, where it is particularly relevant due to its in vitro amyloid beta (Aβ)-degrading activity. The subcellular localization of IDE, a paramount [...] Read more.
The insulin-degrading enzyme (IDE) is a zinc-dependent metalloendopeptidase that belongs to the M16A metalloprotease family. IDE is markedly expressed in the brain, where it is particularly relevant due to its in vitro amyloid beta (Aβ)-degrading activity. The subcellular localization of IDE, a paramount aspect to understand how this enzyme can perform its proteolytic functions in vivo, remains highly controversial. In this work, we addressed IDE subcellular localization from an evolutionary perspective. Phylogenetic analyses based on protein sequence and gene and protein structure were performed. An in silico analysis of IDE signal peptide suggests an evolutionary shift in IDE exportation at the prokaryote/eukaryote divide. Subcellular localization experiments in microglia revealed that IDE is mostly cytosolic. Furthermore, IDE associates to membranes by their cytoplasmatic side and further partitions between raft and non-raft domains. When stimulated, microglia change into a secretory active state, produces numerous multivesicular bodies and IDE associates with their membranes. The subsequent inward budding of such membranes internalizes IDE in intraluminal vesicles, which later allows IDE to be exported outside the cells in small extracellular vesicles. We further demonstrate that such an IDE exportation mechanism is regulated by stimuli relevant for microglia in physiological conditions and upon aging and neurodegeneration. Full article
(This article belongs to the Special Issue Insulin-Degrading Enzyme in Health and Disease)
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16 pages, 1138 KiB  
Article
Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme
by Janine Mett, Anna A. Lauer, Daniel Janitschke, Lea V. Griebsch, Elena L. Theiss, Heike S. Grimm, Hennariikka Koivisto, Heikki Tanila, Tobias Hartmann and Marcus O. W. Grimm
Cells 2021, 10(11), 2941; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112941 - 29 Oct 2021
Cited by 12 | Viewed by 3511
Abstract
The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks of Alzheimer’s disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here, we demonstrate [...] Read more.
The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks of Alzheimer’s disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here, we demonstrate that saturated medium-chain fatty acids (MCFAs) increase total Aβ degradation whereas longer saturated fatty acids result in an inhibition of its degradation, an effect which could not be detected in IDE knock-down cells. Further analysis of the underlying molecular mechanism revealed that MCFAs result in an increased exosomal IDE secretion, leading to an elevated extracellular and a decreased intracellular IDE level whereas gene expression of IDE was unaffected in dependence of the chain length. Additionally, MCFAs directly elevated the enzyme activity of recombinant IDE, while longer-chain length fatty acids resulted in an inhibited IDE activity. The effect of MCFAs on IDE activity could be confirmed in mice fed with a MCFA-enriched diet, revealing an increased IDE activity in serum. Our data underline that not only polyunsaturated fatty acids such as docosahexaenoic acid (DHA), but also short-chain fatty acids, highly enriched, for example in coconut oil, might be beneficial in preventing or treating Alzheimer’s disease. Full article
(This article belongs to the Special Issue Insulin-Degrading Enzyme in Health and Disease)
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22 pages, 5275 KiB  
Article
Effects of Fasting and Feeding on Transcriptional and Posttranscriptional Regulation of Insulin-Degrading Enzyme in Mice
by Carlos M. González-Casimiro, Patricia Cámara-Torres, Beatriz Merino, Sergio Diez-Hermano, Tamara Postigo-Casado, Malcolm A. Leissring, Irene Cózar-Castellano and Germán Perdomo
Cells 2021, 10(9), 2446; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092446 - 16 Sep 2021
Cited by 9 | Viewed by 3236
Abstract
Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed Zn2+-metallopeptidase that regulates hepatic insulin sensitivity, albeit its regulation in response to the fasting-to-postprandial transition is poorly understood. In this work, we studied the regulation of IDE mRNA and protein levels [...] Read more.
Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed Zn2+-metallopeptidase that regulates hepatic insulin sensitivity, albeit its regulation in response to the fasting-to-postprandial transition is poorly understood. In this work, we studied the regulation of IDE mRNA and protein levels as well as its proteolytic activity in the liver, skeletal muscle, and kidneys under fasting (18 h) and refeeding (30 min and 3 h) conditions, in mice fed a standard (SD) or high-fat (HFD) diets. In the liver of mice fed an HFD, fasting reduced IDE protein levels (~30%); whereas refeeding increased its activity (~45%) in both mice fed an SD and HFD. Likewise, IDE protein levels were reduced in the skeletal muscle (~30%) of mice fed an HFD during the fasting state. Circulating lactate concentrations directly correlated with hepatic IDE activity and protein levels. Of note, L-lactate in liver lysates augmented IDE activity in a dose-dependent manner. Additionally, IDE protein levels in liver and muscle tissues, but not its activity, inversely correlated (R2 = 0.3734 and 0.2951, respectively; p < 0.01) with a surrogate marker of insulin resistance (HOMA index). Finally, a multivariate analysis suggests that circulating insulin, glucose, non-esterified fatty acids, and lactate levels might be important in regulating IDE in liver and muscle tissues. Our results highlight that the nutritional regulation of IDE in liver and skeletal muscle is more complex than previously expected in mice, and that fasting/refeeding does not strongly influence the regulation of renal IDE. Full article
(This article belongs to the Special Issue Insulin-Degrading Enzyme in Health and Disease)
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Review

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17 pages, 1053 KiB  
Review
Insulin-Degrading Enzyme, an Under-Estimated Potential Target to Treat Cancer?
by Laetitia Lesire, Florence Leroux, Rebecca Deprez-Poulain and Benoit Deprez
Cells 2022, 11(7), 1228; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11071228 - 05 Apr 2022
Cited by 3 | Viewed by 3918
Abstract
Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. [...] Read more.
Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. In recent years, several reports have underlined the overexpression of this enzyme in different cancers. Still, the exact role of IDE in the physiopathology of cancer remains to be elucidated. Known as the main enzyme responsible for the degradation of insulin, an essential growth factor for healthy cells and cancer cells, IDE has also been shown to behave like a chaperone and interact with the proteasome. The pharmacological modulation of IDE (siRNA, chemical compounds, etc.) has demonstrated interesting results in cancer models. All these results point towards IDE as a potential target in cancer. In this review, we will discuss evidence of links between IDE and cancer development or resistance, IDE’s functions, catalytic or non-catalytic, in the context of cell proliferation, cancer development and the impact of the pharmacomodulation of IDE via cancer therapeutics. Full article
(This article belongs to the Special Issue Insulin-Degrading Enzyme in Health and Disease)
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Other

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10 pages, 287 KiB  
Opinion
Insulin-Degrading Enzyme: Paradoxes and Possibilities
by Malcolm A. Leissring
Cells 2021, 10(9), 2445; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092445 - 16 Sep 2021
Cited by 13 | Viewed by 2923
Abstract
More than seven decades have passed since the discovery of a proteolytic activity within crude tissue extracts that would become known as insulin-degrading enzyme (IDE). Certainly much has been learned about this atypical zinc-metallopeptidase; at the same time, however, many quite fundamental gaps [...] Read more.
More than seven decades have passed since the discovery of a proteolytic activity within crude tissue extracts that would become known as insulin-degrading enzyme (IDE). Certainly much has been learned about this atypical zinc-metallopeptidase; at the same time, however, many quite fundamental gaps in our understanding remain. Herein, I outline what I consider to be among the most critical unresolved questions within the field, many presenting as intriguing paradoxes. For instance, where does IDE, a predominantly cytosolic protein with no signal peptide or clearly identified secretion mechanism, interact with insulin and other extracellular substrates? Where precisely is IDE localized within the cell, and what are its functional roles in these compartments? How does IDE, a bowl-shaped protein that completely encapsulates its substrates, manage to avoid getting “clogged” and thus rendered inactive virtually immediately? Although these paradoxes are by definition unresolved, I offer herein my personal insights and informed speculations based on two decades working on the biology and pharmacology of IDE and suggest specific experimental strategies for addressing these conundrums. I also offer what I believe to be especially fruitful avenues for investigation made possible by the development of new technologies and IDE-specific reagents. It is my hope that these thoughts will contribute to continued progress elucidating the physiology and pathophysiology of this important peptidase. Full article
(This article belongs to the Special Issue Insulin-Degrading Enzyme in Health and Disease)
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