Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones

• Published in: Nature (London) 2014-07, Vol.511 (7507), p.94-98
• Main Authors: Maianti, Juan Pablo, McFedries, Amanda, Foda, Zachariah H., Kleiner, Ralph E., Du, Xiu Quan, Leissring, Malcolm A., Tang, Wei-Jen, Charron, Maureen J., Seeliger, Markus A., Saghatelian, Alan, Liu, David R.
• Format: Article
• Language: English
• Subjects: 13; 631/92; Animals; Binding Sites; Blood Glucose - metabolism; Care and treatment; Catalytic Domain; Crystal structure; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Diabetes therapy; Disease Models, Animal; Enzyme inhibitors; Enzymes; Experiments; Gastric Emptying - drug effects; Genetic aspects; Genetic Predisposition to Disease; Glucagon - metabolism; Glucose; Glucose Tolerance Test; Hormones; Humanities and Social Sciences; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin; Insulin - metabolism; Insulin resistance; Insulysin - antagonists & inhibitors; Insulysin - chemistry; Insulysin - genetics; Insulysin - metabolism; Islet Amyloid Polypeptide - metabolism; letter; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Macrocyclic Compounds - therapeutic use; Male; Mice; Mice, Inbred C57BL; Models, Molecular; multidisciplinary; Obesity - drug therapy; Obesity - metabolism; Peptides; Physiological aspects; Physiology; Rodents; Science; Signal Transduction - drug effects; Studies; Thinness - drug therapy; Thinness - metabolism; Type 2 diabetes
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13297

The discovery of a selective, physiologically active inhibitor of insulin-degrading enzyme (IDE) illuminates the therapeutic potential of IDE inhibitors for the treatment of diabetes and reveals that IDE regulates in vivo glucagon and amylin, in addition to insulin. An alternative approach to diabetes Established treatments for type-2 diabetes include drugs that increase insulin biosynthesis and secretion or improve insulin sensitivity. In theory, inhibition of endogenous insulin degradation could also be effective therapeutically, but despite the identification of the zinc metalloprotease insulin-degrading enzyme (IDE) as the product of a diabetes susceptibility gene, and decades of research, the relationship between IDE activity and glucose homeostasis has remained unclear. Here David Liu and colleagues report the first physiologically active IDE inhibitor, a 20-membered macrocycle that engages a binding pocket away from the enzyme's catalytic site. Treatment of lean and obese mice with this inhibitor shows that IDE not only regulates insulin abundance and signalling, but also that of glucagon and amylin. Acute IDE inhibition with the new inhibitor leads to substantially improved glucose tolerance. This work demonstrates the potential of IDE as a new target for anti-diabetes therapeutics. Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes 1 , 2 , and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene 3 , 4 , the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide –/– mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction 5 , 6 . IDE inhibitors that are active in vivo are therefore needed to elucidate IDE’s physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment in