Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 370652
Title Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: A combined virtual screening and biological assay approach
Author(s) Scarsi, M.; Podvinec, M.; Roth, A.; Hug, H.; Kersten, A.H.; Albrecht, H.; Schwede, T.; Meyer, U.A.; Rucker, C.
Source Molecular pharmacology 71 (2007)2. - ISSN 0026-895X - p. 398 - 406.
Department(s) Chair Nutrition Metabolism and Genomics
Publication type Refereed Article in a scientific journal
Publication year 2007
Keyword(s) type-2 diabetes-mellitus - ppar-gamma - ligand-binding - clinical pharmacokinetics - alpha/gamma agonist - insulin-resistance - nuclear receptors - agents - acid - nateglinide
Abstract Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPAR) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPAR and exhibit PPAR agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPAR target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPAR agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPAR target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPAR. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPAR agonists. In addition, we provide a unified concept of the PPAR binding ability of seemingly disparate compound classes.
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