Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH PUBLISHING LLC
GLOBETECH PUBLISHING LLC
PZ HTL SA

Blocking Insulin-degrading Enzyme Reverses Diabetes Symptoms in Mouse Model

By BiotechDaily International staff writers
Posted on 15 Jun 2014
Image: Molecular model shows how the inhibitor binds to Insulin Degrading Enzyme (IDE). The inhibitor is depicted in orange and white spheres. IDE is depicted as the blue and green surface, and the gray ribbons (Photo courtesy of Dr. Markus Seeliger, Stony Brook University).
Image: Molecular model shows how the inhibitor binds to Insulin Degrading Enzyme (IDE). The inhibitor is depicted in orange and white spheres. IDE is depicted as the blue and green surface, and the gray ribbons (Photo courtesy of Dr. Markus Seeliger, Stony Brook University).
Determination of the structure of insulin-degrading enzyme (IDE) by X-ray crystallography paved the way for its successful inhibition and the easing of symptoms in a mouse model of type II diabetes.

The IDE gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates its activity, as well as participating in intercellular peptide signaling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein's function are associated with Alzheimer's disease and type II diabetes mellitus but mutations in this gene have not been shown to be causative for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion.

Investigators at Stony Brook University (NY, USA) and colleagues at Harvard University (Cambridge, MA, USA) and Brookhaven National Laboratory (Upton, NY, USA) reported in the May 21, 2014, online edition of the journal Nature that they had discovered a physiologically active IDE inhibitor from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE revealed that it engaged a binding pocket away from the catalytic site, which explained its remarkable selectivity.

Treatment of lean and obese mice with this inhibitor showed that IDE regulated the abundance and signaling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that increased insulin and amylin levels, such as oral glucose administration, acute IDE inhibition led to substantially improved glucose tolerance and slower gastric emptying.

"A strategy to protect the remaining amounts of insulin produced by diabetics in response to blood sugar levels is an attractive treatment alternative, particularly in the early stages of type II diabetes,” said contributing author Dr. Markus Seeliger, assistant professor of pharmacological sciences at Stony Brook University. “The research results give proof of concept that targeting this protein is extremely promising. The inhibitor we discovered successfully relieved the symptoms of type II diabetes in obese mice and not only elevated their insulin levels but promoted healthy insulin signaling within the blood.”

Related Links:

Stony Brook University
Harvard University
Brookhaven National Laboratory



comments powered by Disqus

Channels

Drug Discovery

view channel
Image: The nano-cocoon drug delivery system is biocompatible, specifically targets cancer cells, can carry a large drug load, and releases the drugs very quickly once inside the cancer cell. Ligands on the surface of the \"cocoon\" trick cancer cells into consuming it. Enzymes (the “worms\" in this image) inside the cocoon are unleashed once inside the cell, destroying the cocoon and releasing anticancer drugs into the cell (Photo courtesy of Dr. Zhen Gu, North Carolina State University).

Novel Anticancer Drug Delivery System Utilizes DNA-Based Nanocapsules

A novel DNA-based drug delivery system minimizes damage to normal tissues by utilizing the acidic microenvironment inside cancer cells to trigger the directed release of the anticancer drug doxorubicin (DOX).... Read more

Lab Technologies

view channel

Experimental Physicists Find Clues into How Radiotherapy Kills Cancer Cells

A new discovery in experimental physics has implications for a better determination of the process in which radiotherapy destroys cancer cells. Dr. Jason Greenwood from Queen’s University Belfast (Ireland) Center for Plasma Physics collaborated with scientists from Italy and Spain on the work on electrons, and published... Read more

Business

view channel

Interest in Commercial Applications for Proteomics Continues to Grow

Increasing interest in the field of proteomics has led to a series of agreements between private proteomic companies and academic institutions as well as deals between pharmaceutical companies and novel proteomics innovator biotech companies. Proteomics is the study of the structure and function of proteins.... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.