Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice

Villa-Pérez, Pablo; Merino, Beatriz; Fernández-Díaz, Cristina M; Cidad, Pilar; Lobatón, Carmen D.; Moreno, A.; Muturi, Harrison T.; Ghadieh, Hilda E.; Najjar, Sonia M.; Leissring, Malcolm A.; Cózar‐Castellano, Irene; Perdomo, Germán

doi:10.1016/j.metabol.2018.08.001

Cited by 52 publications

(93 citation statements)

References 44 publications

(58 reference statements)

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“…However, this idea was not directly tested until recently. A recent study in liver-specific IDE knockout mice showed that IDE is not the ratelimiting factor controlling insulin clearance by the liver, since deleting it in liver caused no difference in the rate of exogenous insulin clearance [153]. This study highlights how critical it is to study the tissue-specific role of this protein, as it is an ubiquitous and multifunctional enzyme.…”

Section: Insulin Clearancementioning

confidence: 76%

“…These observations suggest a plausible explanation for the hyperinsulinemia reported in some studies of Total IDE-KO mice [192,193]. These studies hypothesized that hyperinsulinemia is due to decreased hepatic catabolism of insulin, however, subsequently L-IDE-KO mice showed normal insulin levels [153], leaving unexplained the hyperinsulinemia of these models.…”

Section: Differential Ide Expression In Pancreatic Islet Cellsmentioning

confidence: 85%

“…However, at 6 months of age, these mice showed severe glucose intolerance and insulin resistance [193]. Moreover, it must be taken into account that in these models, IDE is knocked out expression is driven exclusively in liver using the albumin promoter [153]. L-IDE-KO mice exhibited glucose intolerance and insulin resistance due to decreased insulin receptor levels in hepatocytes.…”

Section: Genetic Ablation Of Ide: a Complex Study Modelmentioning

confidence: 99%

“…There are numerous published studies about the effect of IDE inhibition in animal models [149,153,165,183,[186][187][188][189][190][191][192][193]. However, the ubiquity of this protein and its multifactorial role makes the analysis of these results a complicated task.…”

Section: Differential Ide Expression In Pancreatic Islet Cellsmentioning

confidence: 99%

“…Recently, Villa-Perez et al reported the first tissue-specific IDE knockout mouse, the liver specific IDE-KO mice (L-IDE-KO) [153]. These mice showed glucose intolerance and insulin resistance.…”

Section: Differential Ide Expression In Pancreatic Islet Cellsmentioning

confidence: 99%

See 4 more Smart Citations

Role of insulin-degrading enzyme (IDE) in pancreatic beta-cell function: relevance in health and diabetes mellitus

Díaz¹,

María²

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Section: Insulin Clearancementioning

confidence: 76%

Section: Differential Ide Expression In Pancreatic Islet Cellsmentioning

confidence: 85%

Section: Genetic Ablation Of Ide: a Complex Study Modelmentioning

confidence: 99%

Section: Differential Ide Expression In Pancreatic Islet Cellsmentioning

confidence: 99%

Section: Differential Ide Expression In Pancreatic Islet Cellsmentioning

confidence: 99%

See 3 more Smart Citations

Role of insulin-degrading enzyme (IDE) in pancreatic beta-cell function: relevance in health and diabetes mellitus

Díaz¹,

María²

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Long‐Term High‐Fat Diet Decreases Renal Insulin‐Degrading Enzyme Expression and Function by Inhibiting the PPARγ Pathway

Huang

Chen

et al. 2023

Molecular Nutrition Food Res

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Scope Long‐term high‐fat diet (HFD) causes insulin resistance, which is a primary etiological factor in the development of obesity and type 2 diabetes mellitus. Impaired insulin clearance is not only a consequence but also a cause of insulin resistance. The kidney is a major site of insulin clearance, where the insulin‐degrading enzyme (IDE) plays a vital role in the proximal tubule. Thus, the study investigates the role of renal IDE in the regulation of insulin resistance in HFD‐induced obese mice. Methods and results Twenty four‐weeks of HFD in C57BL/6 mice causes insulin resistance and impaires insulin clearance, accompanied by a decrease in renal IDE expression and activity. Palmitic acid decreases IDE mRNA and protein expressions in HK‐2 cells. RNA‐Seq analysis found that the PPAR pathway is involved. 24‐weeks of HFD decreases renal PPARγ, but not PPARα or PPARβ/δ mRNA expression. The inhibition of IDE expression by palmitic acid is prevented by the PPARγ agonist rosiglitazone. The amount of PPARγ bound to the promoters of IDE is decreased in palmitic acid‐treated cells. Rosiglitazone improves insulin clearance and insulin resistance and increases renal IDE expression in HFD fed‐mice. Conclusion Long‐term HFD decreases renal IDE expression and activity, and causes insulin resistance, which involves PPARγ.

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Insulin‐degrading enzyme: an ally against metabolic and neurodegenerative diseases

Sousa

Guarda

Meneses

et al. 2021

The Journal of Pathology

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Insulin-degrading enzyme (IDE) function goes far beyond its known proteolytic role as a regulator of insulin levels. IDE has a wide substrate promiscuity, degrading several proteins such as amyloid-β peptide, glucagon, islet amyloid polypeptide (IAPP), and insulin-like growth factors, which have diverse physiological and pathophysiological functions. Importantly, IDE plays other non-proteolytic functions such as: a chaperone/dead-end chaperone, an E1-ubiquitin activating enzyme, and a proteasome modulator. It also responds as a heat shock protein, regulating cellular proteostasis. Notably, amyloidogenic proteins such as IAPP, amyloid-β, and α-synuclein have been reported as substrates for IDE chaperone activity. This is of utmost importance as failure of IDE may result in increased protein aggregation, a key hallmark in the pathogenesis of beta cells in type 2 diabetes mellitus and of neurons in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this review, we focus on the biochemical and biophysical properties of IDE and the regulation of its physiological functions. We further raise the hypothesis that IDE plays a central role in the pathological context of dysmetabolic and neurodegenerative diseases and discuss its potential as a therapeutic target.

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Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice

Abstract: IDE is not a rate-limiting regulator of plasma insulin levels in vivo.

Cited by 52 publications

References 44 publications

Role of insulin-degrading enzyme (IDE) in pancreatic beta-cell function: relevance in health and diabetes mellitus

Role of insulin-degrading enzyme (IDE) in pancreatic beta-cell function: relevance in health and diabetes mellitus

Long‐Term High‐Fat Diet Decreases Renal Insulin‐Degrading Enzyme Expression and Function by Inhibiting the PPARγ Pathway

Insulin‐degrading enzyme: an ally against metabolic and neurodegenerative diseases

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