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Exploring off‐target binding of thiazolidinediones and a novel mechanism for restoring insulin sensitivity (854.2)
Author(s) -
Exner Eric,
Hoffmann Brian,
Sem Daniel,
Greene Andrew
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.854.2
Subject(s) - insulin resistance , insulin receptor , insulin , insulin sensitivity , receptor , peroxisome proliferator activated receptor , mechanism of action , type 2 diabetes mellitus , effector , peroxisome , phosphorylation , kinase , mechanism (biology) , signal transduction , pharmacology , medicine , chemistry , diabetes mellitus , biology , endocrinology , microbiology and biotechnology , biochemistry , in vitro , philosophy , epistemology
The prevalence of type 2 diabetes mellitus (T2DM) is increasing. As insulin resistance is a major feature of T2DM, this will necessitate the increased use of drugs that restore insulin sensitivity. Thiazolidinediones (TDZs) comprise one such class of drugs and are thought to act through peroxisome proliferator‐activated receptor gamma (PPARγ); however, this mechanism is not completely understood, as neither antagonists nor transcriptional/translational inhibitors of PPARγ abolish the effects of these drugs. Moreover, TDZs have been reported to elicit serious side effects that could be mediated through interactions of TDZs with effectors other than PPARγ. We developed a novel method to determine off‐target binding interactions of drugs, which we applied to TDZs. In addition to interactions that could be related to side effects, we observed affinity for salt‐inducible kinase 2 (SIK‐2), which could represent a novel mechanism of action for the insulin sensitizing effects of TDZs. SIK‐2 impairs insulin receptor signal transduction during conditions of nutrient deprivation by phosphorylating insulin receptor substrate 1 (IRS‐1). This study tests the hypothesis that TDZs prevent SIK‐2 mediated phosphorylation of IRS‐1, thus restoring or preserving insulin sensitivity and outlines a method for utilization of existing, effective molecules to identify novel targets for the development of safer therapeutics. Grant Funding Source : Supported in part by National Heart, Lung, and Blood Institute Grant HL‐082798 to A. S. Greene