Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway.
Several established liver diseases of various causes are highly associated with hepatic insulin resistance, which is characterized by the desensitization of target cells to insulin. Peripheral insulin resistance is observed in most patients who have cirrhosis. Conversely, insulin-resistant diabetic patients are at increased risk for developing liver disease. Current therapeutic interventions in insulin resistance are limited and therefore likely to be advanced by new tailor-made drugs. Oltipraz, a prototype dithiolthione, inhibits transforming growth factor beta1 and has the ability to regenerate cirrhotic liver. We investigated the effects of oltipraz and synthetic dithiolthiones on hepatic insulin resistance and the molecular basis of action. Oltipraz and other dithiolethione compounds were tested on tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance and glucose homeostasis in vitro and in vivo via immunoblotting, plasmid transfection, kinase analysis, and functional assays. Oltipraz treatment inhibited the ability of TNF-alpha to activate p70 ribosomal S6 kinase-1 (S6K1) downstream of mammalian target of rapamycin, thus preventing insulin receptor substrate-1 serine phosphorylation and protecting insulin signals. Moreover, oltipraz activated AMP-activated protein kinase (AMPK), whose inhibition by a dominant negative mutant abolished S6K1 inhibition and protected insulin signaling, indicating that AMPK activation leads to S6K1 inhibition. In hepatocyte-derived cell lines, oltipraz inhibited glucose production. Oltipraz prevented hepatic insulin resistance in C57BL/6 mice challenged with endotoxin (or TNF-alpha), leptin-deficient mice, and mice fed a high-fat diet. Synthetic dithiolethiones comparably inhibited insulin resistance.


CONCLUSIONS
Our findings led to the identification of dithiolethione compounds that prevent insulin resistance through a mechanism involving AMPK-mediated S6K1 inhibition and thereby sensitize hepatic insulin response.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Eun Ju
EJ
Bae
Yoon Mee
YM
Yang
Jin Wan
JW
Kim
Sang Geon
SG
Kim
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D020738:Leptin / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008817:Mice, Mutant Strains; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors*; D013871:Thiones / Q000302:isolation & purification* / Q000494:pharmacology*; D013876:Thiophenes; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors*
D007328:Insulin; D020738:Leptin; D009097:Multienzyme Complexes; D011719:Pyrazines; D013871:Thiones; D013876:Thiophenes; D016211:Transforming Growth Factor alpha; C026209:oltipraz; D017346:Protein Serine-Threonine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D055372:AMP-Activated Protein Kinases; D005947:Glucose