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Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity
Insulin replacement therapy is a widely adopted treatment for all patients with type 1 diabetes and some with type 2 diabetes. However, injection of insulin has suffered from problems such as tissue irritation, abscesses, discomfort, and inconvenience. The use of orally bioactive insulin mimetics th...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964510/ https://www.ncbi.nlm.nih.gov/pubmed/24651808 http://dx.doi.org/10.2337/db13-0334 |
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author | Qiang, Guifen Xue, Shenghui Yang, Jenny J. Du, Guanhua Pang, Xiaobin Li, Xiaoting Goswami, Devrishi Griffin, Patrick R. Ortlund, Eric A. Chan, Chi Bun Ye, Keqiang |
author_facet | Qiang, Guifen Xue, Shenghui Yang, Jenny J. Du, Guanhua Pang, Xiaobin Li, Xiaoting Goswami, Devrishi Griffin, Patrick R. Ortlund, Eric A. Chan, Chi Bun Ye, Keqiang |
author_sort | Qiang, Guifen |
collection | PubMed |
description | Insulin replacement therapy is a widely adopted treatment for all patients with type 1 diabetes and some with type 2 diabetes. However, injection of insulin has suffered from problems such as tissue irritation, abscesses, discomfort, and inconvenience. The use of orally bioactive insulin mimetics thus represents an ideal treatment alternative. Here we show that a chaetochromin derivative (4548-G05) acts as a new nonpeptidyl insulin mimetic. 4548-G05 selectively activates an insulin receptor (IR) but not insulin-like growth factor receptor-I or other receptor tyrosine kinases. Through binding to the extracellular domain of the IR, 4548-G05 induces activation of the receptor and initiates the downstream Akt and extracellular signal–related kinase pathways to trigger glucose uptake in C2C12 myotubes. Moreover, it displays a potent blood glucose-lowering effect when administrated orally in normal, type 1 diabetic, and type 2 diabetic mice models. Therefore, 4548-G05 may represent a novel pharmacological agent for antidiabetes drug development. |
format | Online Article Text |
id | pubmed-3964510 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-39645102015-04-01 Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity Qiang, Guifen Xue, Shenghui Yang, Jenny J. Du, Guanhua Pang, Xiaobin Li, Xiaoting Goswami, Devrishi Griffin, Patrick R. Ortlund, Eric A. Chan, Chi Bun Ye, Keqiang Diabetes Pharmacology and Therapeutics Insulin replacement therapy is a widely adopted treatment for all patients with type 1 diabetes and some with type 2 diabetes. However, injection of insulin has suffered from problems such as tissue irritation, abscesses, discomfort, and inconvenience. The use of orally bioactive insulin mimetics thus represents an ideal treatment alternative. Here we show that a chaetochromin derivative (4548-G05) acts as a new nonpeptidyl insulin mimetic. 4548-G05 selectively activates an insulin receptor (IR) but not insulin-like growth factor receptor-I or other receptor tyrosine kinases. Through binding to the extracellular domain of the IR, 4548-G05 induces activation of the receptor and initiates the downstream Akt and extracellular signal–related kinase pathways to trigger glucose uptake in C2C12 myotubes. Moreover, it displays a potent blood glucose-lowering effect when administrated orally in normal, type 1 diabetic, and type 2 diabetic mice models. Therefore, 4548-G05 may represent a novel pharmacological agent for antidiabetes drug development. American Diabetes Association 2014-04 2014-03-13 /pmc/articles/PMC3964510/ /pubmed/24651808 http://dx.doi.org/10.2337/db13-0334 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Pharmacology and Therapeutics Qiang, Guifen Xue, Shenghui Yang, Jenny J. Du, Guanhua Pang, Xiaobin Li, Xiaoting Goswami, Devrishi Griffin, Patrick R. Ortlund, Eric A. Chan, Chi Bun Ye, Keqiang Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity |
title | Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity |
title_full | Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity |
title_fullStr | Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity |
title_full_unstemmed | Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity |
title_short | Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity |
title_sort | identification of a small molecular insulin receptor agonist with potent antidiabetes activity |
topic | Pharmacology and Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964510/ https://www.ncbi.nlm.nih.gov/pubmed/24651808 http://dx.doi.org/10.2337/db13-0334 |
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