Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action
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...
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| Published in: | Cell metabolism Vol. 32; no. 3; pp. 353 - 365.e8 |
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| Main Authors: | , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
Elsevier Inc
01-09-2020
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | 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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•The small molecule SRI-37330 inhibits TXNIP expression in mouse and human islets•SRI-37330 decreases glucagon secretion and action and blocks hepatic glucose output•Oral SRI-37330 reverses obesity- and STZ-induced diabetes and hepatic steatosis in mice•Its antidiabetic effects and safety profile make SRI-37330 an attractive drug candidate
Here, Thielen et al. show that a newly designed, orally available small molecule inhibited pancreatic islet TXNIP expression, glucagon secretion, hepatic glucagon action, glucose production, and steatosis, and exhibited strong anti-diabetic effects in mouse models of type 1 and type 2 diabetes, promising a distinct and innovative diabetes treatment approach. |
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| Bibliography: | AUTHOR CONTRIBUTIONS L.A.T. conducted most of the experiments, analyzed the data, prepared the figures and drafted the manuscript. J.C. helped with all the in vivo mouse studies and was responsible for the islet isolations. G.J. developed and established the screening assay and conducted some of the molecular biology experiments, O.M.C. optimized and synthesized the small molecule compounds, G.X. conducted the hormone analyses, S.H.J. performed the alpha cell and primary hepatocyte experiments, T.B.G and B.L. helped with the in vitro and in vivo experiments, P.L. provided statistical advice, C.E.A. and M.J.S. oversaw the high-throughput screening and chemistry work, M.K. and P.S. were responsible for the analysis of the RNAseq data, J.K.K. was responsible for design, execution and analysis of the clamp studies, A.S. conceived the project, designed the studies helped analyze the results and revised the manuscript. All authors reviewed and approved the manuscript. |
| ISSN: | 1550-4131 1932-7420 |
| DOI: | 10.1016/j.cmet.2020.07.002 |