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Identification of an Anti-diabetic, Orally Available Small Molecule that
Regulates TXNIP Expression and Glucagon Action.
Authors Thielen LA, Chen J, Jing G, Moukha-Chafiq O, Xu G, Jo S, Grayson TB, Lu B, Li P,
Augelli-Szafran CE, Suto MJ, Kanke M, Sethupathy P, Kim JK, Shalev A
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Cell Metabolism
Year 2020
Date Published 9/1/2020
Volume : Pages 32 : 353 - 365.e8
PubMed Reference 32726606
Abstract Diabetes is characterized by hyperglycemia, loss of functional islet beta cell
mass, deficiency of glucose-lowering insulin, and persistent alpha cell
secretion of gluconeogenic glucagon. Still, no therapies that target these
underlying processes are available. We therefore performed high-throughput
screening of 300,000 compounds and extensive medicinal chemistry optimization
and here report the discovery of SRI-37330, an orally bioavailable, non-toxic
small molecule, which effectively rescued mice from streptozotocin- and
obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and
human islets, SRI-37330 inhibited expression and signaling of
thioredoxin-interacting protein, which we have previously found to be elevated
in diabetes and to have detrimental effects on islet function. In addition,
SRI-37330 treatment inhibited glucagon secretion and function, reduced hepatic
glucose production, and reversed hepatic steatosis. Thus, these studies describe
a newly designed chemical compound that, compared to currently available
therapies, may provide a distinct and effective approach to treating diabetes.


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