Faculty Opinions recommendation of Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.

Author(s):  
Paul Savage
2001 ◽  
Vol 226 (4) ◽  
pp. 334-341 ◽  
Author(s):  
M.C. Camberos ◽  
A.A. Pérez ◽  
D.P. Udrisar ◽  
M.I. Wanderley ◽  
J.C. Cresto

We studied the ability of ATP to inhibit in vitro the degrading activity of insulin-degrading enzyme. The enzyme was purified from rat skeletal muscle by successive chromatographic steps. The last purification step showed two bands at 110 and 60 kDa in polyacrylamide gel. The enzyme was characterized by its insulin degradation activity, the substrate competition of unlabeled to labeled insulin, the profile of enzyme inhibitors, and the recognition by a specific antibody. One to 5 mM ATP induced a dose-dependent inhibition of insulin degradation (determined by trichloroacetic acid precipitation and insulin antibody binding). Inhibition by 3 mM adenosine 5′-diphosphate, adenosine 5′-monophosphate, guanosine 5′-triphosphate, pyrophosphate, β-γ-methyleneadenosine 5′-triphosphate, adenosine 5′-O-(3 thiotriphosphate), and dibutiryl cyclic adenosine 5′-monophosphate was 74%, 4%, 38%, 46%, 65%, 36%, and 0%, respectively, of that produced by 3 mM ATP. Kinetic analysis of ATP inhibition suggested an allosteric effect as the plot of 1/v (insulin degradation) versus ATP concentration was not linear and the Hill coefficient was more than 1 (1.51 and 2.44). The binding constant for allosteric inhibition was K1T = 1.5 × 10–7 M showing a decrease of enzyme affinity induced by ATP. We conclude that ATP has an inhibitory effect on the insulin degradation activity of the enzyme.


Nature ◽  
2014 ◽  
Vol 511 (7507) ◽  
pp. 94-98 ◽  
Author(s):  
Juan Pablo Maianti ◽  
Amanda McFedries ◽  
Zachariah H. Foda ◽  
Ralph E. Kleiner ◽  
Xiu Quan Du ◽  
...  

2018 ◽  
Vol 15 (7) ◽  
pp. 610-617 ◽  
Author(s):  
Huifeng Zhang ◽  
Dan Liu ◽  
Huanhuan Huang ◽  
Yujia Zhao ◽  
Hui Zhou

Background: β-amyloid (Aβ) accumulates abnormally to senile plaque which is the initiator of Alzheimer's disease (AD). As one of the Aβ-degrading enzymes, Insulin-degrading enzyme (IDE) remains controversial for its protein level and activity in Alzheimer's brain. Methods: The electronic databases PubMed, EMBASE, The Cochrane Library, OVID and Sinomed were systemically searched up to Sep. 20th, 2017. And the published case-control or cohort studies were retrieved to perform the meta-analysis. Results: Seven studies for IDE protein level (AD cases = 293; controls = 126), three for mRNA level (AD cases = 138; controls = 81), and three for enzyme activity (AD cases = 123; controls = 75) were pooling together. The IDE protein level was significantly lower in AD cases than in controls (SMD = - 0.47, 95% CI [-0.69, -0.24], p < 0.001), but IDE mRNA and enzyme activity had no significant difference (SMD = 0.02, 95% CI [-0.40, 0.43] and SMD = 0.06, 95% CI [-0.41, 0.53] respectively). Subgroup analyses found that IDE protein level was decreased in both cortex and hippocampus of AD cases (SMD = -0.43, 95% CI [-0.71, -0.16], p = 0.002 and SMD = -0.53, 95% CI [-0.91, -0.15], p = 0.006 respectively). However, IDE mRNA was higher in cortex of AD cases (SMD = 0.71, 95% CI [0.14, 1.29], p = 0.01), not in hippocampus (SMD = -0.26, 95% CI [-0.58, 0.06]). Conclusions: Our results indicate that AD patients may have lower IDE protease level. Further relevant studies are still needed to verify whether IDE is one of the factors affecting Aβ abnormal accumulation and throw new insights for AD detection or therapy.


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