Human Insulin-Degrading Enzyme Working Mechanism

Amata, Orazio; Marino, Tiziana; Russo, Nino; Toscano, Marirosa

doi:10.1021/ja9037142

Cited by 48 publications

(73 citation statements)

References 49 publications

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“…Hepatic insulin removal and degradation is mainly controlled by a 130 kDa zinc-metalloproteinase known as IDE (Duckworth 1988, Duckworth et al 1998, Amata et al 2009, Fernández-Gamba et al 2009). …”

Section: Discussionmentioning

confidence: 99%

“…Although virtually every insulin-responsive cell expresses IDE, its main function in these organs is to oppose insulin signaling by uncoupling insulin from the insulin receptor (IR), either by simply removing or partially or completely degrading insulin (Duckworth 1988, Duckworth et al 1998, Amata et al 2009). Therefore, it is not surprising that hepatic IDE inhibition increased insulin sensitivity coupled with increased IR activity (Kuo et al 1991, Li et al 2002, Leissring et al 2010.…”

Section: Discussionmentioning

confidence: 99%

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Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Brandimarti¹,

Costa-Júnior²,

Ferreira³

et al. 2013

Journal of Endocrinology

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Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Brandimarti¹,

Costa-Júnior²,

Ferreira³

et al. 2013

Journal of Endocrinology

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“…Table 2 Catalytic parameters for the enzymatic processing of the peptide B (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) by IDE and the effect of the addition of 100 μM copper(II) or of 100 μM zinc(II) at pH 7.3 and 37°C. by a hydroxide bound to the zinc(II) ion [71] that can be stabilized by the T27 of the B20-30.…”

Section: B20-30 Peptide Fragmentsmentioning

confidence: 99%

Metal ions affect insulin-degrading enzyme activity

Grasso

Salomone

Tundo

et al. 2012

Journal of Inorganic Biochemistry

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Insulin degradation is a finely tuned process that plays a major role in controlling insulin action and most evidence supports IDE (insulin-degrading enzyme) as the primary degradative agent. However, the biomolecular mechanisms involved in the interaction between IDE and its substrates are often obscure, rendering the specific enzyme activity quite difficult to target. On the other hand, biometals, such as copper, aluminum and zinc, have an important role in pathological conditions such as Alzheimer's disease or diabetes mellitus. The metabolic disorders connected with the latter lead to some metallostasis alterations in the human body and many studies point at a high level of interdependence between diabetes and several cations. We have previously reported (Grasso et al., Chem. Eur. J. 17 (2011) 2752-2762) that IDE activity toward Aβ peptides can be modulated by metal ions. Here, we have investigated the effects of different metal ions on the IDE proteolytic activity toward insulin as well as a designed peptide comprising a portion of the insulin B chain (B20-30), which has a very low affinity for metal ions. The results obtained by different experimental techniques clearly show that IDE is irreversibly inhibited by copper(I) but is still able to process its substrates when it is bound to copper(II).

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“…Insulin clearance is fundamentally controlled by the liver and more than 50% of insulin secreted is removed by the liver after the second passage through the portal vein (Butterfield, 1970;Kotronen et al, 2008;Mittelman et al, 2000). Hepatic removal and degradation of insulin is mainly controlled by IDE (Amata et al, 2009;Duckworth et al, 1998). Every insulin-responsive cell expresses IDE mainly to oppose insulin signaling by uncoupling insulin from insulin receptor (IR) by removing or degrading insulin (Amata et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Hepatic removal and degradation of insulin is mainly controlled by IDE (Amata et al, 2009;Duckworth et al, 1998). Every insulin-responsive cell expresses IDE mainly to oppose insulin signaling by uncoupling insulin from insulin receptor (IR) by removing or degrading insulin (Amata et al, 2009). Accordingly, hepatic IDE inhibition increased insulin sensitivity coupled with increased IR activity (Li et al, 2002;Leissring et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Peptide hydroxamate derivatives as regulators for insulin receptor signaling and its degradation by zinc metalloprotease in diabetic rats

Elseweidy¹,

Amin²,

Atteia³

et al. 2016

Afr. J. Pharm. Pharmacol.

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Insulin-degrading enzyme (IDE) is the major zinc-metalloprotease involved in the cleavage of insulin, β-amyloid protein and mainly contributes to the pathophysiology of type 2 diabetes and Alzheimer's disease. Therefore, this enzyme is expressed as candidate target for drugs used in the management of diabetes and peptide hydroxamates have been reported recently as inhibitors for IDE. Novel synthesized peptide hydroxamic acid II containing tryptophan and a sulfonamide bond has been prepared in our laboratory. The aim of this study was to determine whether this drug could be of value in modulating diabetic states in rats. In this study, forty adult male Wistar albino rats received 20% fructose in drinking water (HFW) for six weeks to induce diabetes. Administration of the prepared compound at two dose level (5 and 10 mg/kg body weight, p.o) to diabetic rats significantly reduced IDE protein, glucagon levels, improved insulin receptor signaling (phosphorylation), insulin sensitivity and lipid profile. However, it induced certain up-regulation of IDE mRNA expression. These findings may confirm its role in the modulation of glucose homeostasis through IDE and insulin receptor signaling.

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Human Insulin-Degrading Enzyme Working Mechanism

Cited by 48 publications

References 49 publications

Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Metal ions affect insulin-degrading enzyme activity

Peptide hydroxamate derivatives as regulators for insulin receptor signaling and its degradation by zinc metalloprotease in diabetic rats

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