Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.
Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, 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. 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 insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Juan Pablo
JP
Maianti
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Amanda
A
McFedries
Department of Pharmacological Sciences, Stony Brook University, 1 Circle Road, Stony Brook, New York 11794, USA.
Zachariah H
ZH
Foda
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Ralph E
RE
Kleiner
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Xiu Quan
XQ
Du
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 3204 Biological Sciences III, Irvine, California 92697, USA.
Malcolm A
MA
Leissring
Ben-May Department for Cancer Research, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
Wei-Jen
WJ
Tang
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Maureen J
MJ
Charron
Department of Pharmacological Sciences, Stony Brook University, 1 Circle Road, Stony Brook, New York 11794, USA.
Markus A
MA
Seeliger
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Alan
A
Saghatelian
1] Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2] Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
David R
DR
Liu
D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism; D020134:Catalytic Domain; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics; D004195:Disease Models, Animal; D005746:Gastric Emptying / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D005934:Glucagon / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism*; D007339:Insulysin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013851:Thinness / Q000188:drug therapy / Q000378:metabolism
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D047028:Macrocyclic Compounds; D005934:Glucagon; D007339:Insulysin