| Novel use of fluorescent glucose analogues to identify a new class of triazine-based insulin mimetics possessing useful secondary effects. | |
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MedLine Citation:
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PMID: 20927436 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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There is an urgent need to discover new compounds that effectively treat diabetes by mimicking the action of insulin (insulin mimetics). Traditional approaches to studying anti-diabetic agents in cells are inconvenient for screening chemical libraries to identify insulin mimetics. 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) and 6-NBDG are fluorescent analogues of glucose that could be employed in screening. However, there are no published data about the use of these analogues to identify new insulin mimetics. We have developed a screening system based on 6-NBDG using 3T3-L1 adipocytes in a 96-well culture plate format. 6-NBDG was found to produce a larger signal than 2-NBDG in this screening system. 6-NBDG uptake in 3T3-L1 adipocytes was sensitive to insulin, known insulin mimetics, inhibitors of glucose transport and insulin-sensitizing compounds. To validate our screening system, a chemical library of 576 tagged, triazine-based small molecules was screened. The screening results were identical to that obtained from a commercial enzyme-based glucose assay. Two inducers of glucose uptake were shown to be non-cytotoxic and confirmed as insulin mimetic compounds by their inhibition of epinephrine-stimulated free fatty acid release from adipocytes. These novel insulin mimetics functioned at a markedly lower concentration than two widely studied insulin mimetics, zinc(ii) complexes and vanadium compounds, and also showed novel, beneficial effects on endothelial cell function (a key determinant of secondary complications in diabetes). The discovery of new insulin mimetics using 6-NBDG validates the use of this probe in the development of large-scale, cell-based screening systems based on the uptake of fluorescent-tagged glucose analogues. This research should aid the development of novel strategies to discover new drugs and drug targets for combating the increasing prevalence of diabetes. |
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Authors:
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Da-Woon Jung; Hyung-Ho Ha; Xuexiu Zheng; Young-Tae Chang; Darren R Williams |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-06 |
Journal Detail:
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Title: Molecular bioSystems Volume: 7 ISSN: 1742-2051 ISO Abbreviation: Mol Biosyst Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-19 Completed Date: 2011-05-24 Revised Date: 2011-05-26 |
Medline Journal Info:
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Nlm Unique ID: 101251620 Medline TA: Mol Biosyst Country: England |
Other Details:
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Languages: eng Pagination: 346-58 Citation Subset: IM |
Affiliation:
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Small Molecule Regulators and Biosystems Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-Gu, Gwangju 500-712, Republic of Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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3T3-L1 Cells 4-Chloro-7-nitrobenzofurazan / analogs & derivatives*, chemistry Animals Deoxyglucose / analogs & derivatives*, chemistry Fluorescent Dyes / chemistry* Glucosamine / analogs & derivatives*, chemistry Insulin / chemistry, pharmacology* Mice Molecular Mimicry* Triazines / chemistry, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose; 0/Fluorescent Dyes; 0/Triazines; 10199-89-0/4-Chloro-7-nitrobenzofurazan; 108708-22-1/6-deoxy-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)aminoglucose; 11061-68-0/Insulin; 154-17-6/Deoxyglucose; 3416-24-8/Glucosamine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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