New drug hope for diabetes mellitus
| Autor: | Peng Li, Junqin Chen, Anath Shalev, Jason K. Kim, Guanlan Xu, Lance A. Thielen, Omar Moukha-Chafiq, Praveen Sethupathy, Seong Ho Jo, Truman Grayson, Mark J. Suto, Gu Jing, Corinne E. Augelli-Szafran, Brian Lu, Matt Kanke |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Physiology Endocrinology Diabetes and Metabolism medicine.medical_treatment Administration Oral Pharmacology Alpha cell Mice Endocrinology 0302 clinical medicine Cells Cultured media_common geography.geographical_feature_category Chemistry Glucagon secretion Islet Beta cell TXNIP medicine.drug Drug medicine.medical_specialty media_common.quotation_subject MEDLINE Glucagon Streptozocin Article Diabetes Mellitus Experimental Small Molecule Libraries 03 medical and health sciences Internal medicine Diabetes mellitus medicine Animals Hypoglycemic Agents Humans Molecular Biology geography business.industry Insulin Cell Biology medicine.disease Streptozotocin Rats Mice Inbred C57BL 030104 developmental biology Diabetes Mellitus Type 1 Carrier protein business Carrier Proteins 030217 neurology & neurosurgery |
| Zdroj: | Cell Metab |
| ISSN: | 1759-5037 |
| Popis: | 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 mice) 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. |
| Databáze: | OpenAIRE |
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