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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
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.
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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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