US2006019910A1PendingUtilityA1

Methods for treating and preventing insulin resistance and related disorders

51
Individually held — no corporate assignee on recordPriority: Apr 17, 1998Filed: Oct 29, 2004Published: Jan 26, 2006
Est. expiryApr 17, 2018(expired)· nominal 20-yr term from priority
Inventors:Andrew Greenberg
G01N 33/92
51
PatentIndex Score
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Cited by
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Claims

Abstract

The invention provides methods, therapeutics and kits for treating and preventing diseases or conditions associated with excessive lipolysis, in particular TNF-α induced lipolysis, and/or excessive free fatty acid levels. Exemplary conditions include insulin-resistance, diabetes, in particular NIDDM, obesity, glucose intolerance, hyperinsulinemia, polycystic ovary syndrome, and coronary artery disease. In a preferred embodiment, the method includes administering to a subject in need a pharmaceutically effective amount of an inhibitor of the JNK signal transduction pathway and/or an inhibitor of the MAPK/ERK signal transduction pathway.

Claims

exact text as granted — not AI-modified
1 - 18 . (canceled)  
     
     
         19 . A method for treating a metabolic complication associated with insulin resistance, comprising administering to a patient in need of such treatment a compound that inhibits a c-Jun amino-terminal kinase (JNK).  
     
     
         20 . The method of  claim 19 , wherein the compound inhibits phosphorylation of JNK.  
     
     
         21 . The method of  claim 19 , wherein the compound inhibits the interaction between the kinase and a substrate of the kinase.  
     
     
         22 . The method of  claim 19 , wherein the JNK is JNK1.  
     
     
         23 . The method of  claim 19 , wherein the JNK is JNK2.  
     
     
         24 . The method of  claim 19 , wherein the JNK is JNK1 and JNK2.  
     
     
         25 . The method of  claim 19 , wherein the compound is a small molecule.  
     
     
         26 . A method of improving insulin resistance in an individual, comprising administering to an individual in need of such treatment a compound that inhibits a c-Jun amino-terminal kinase (JNK).  
     
     
         27 . A method of treating or preventing the development of obesity in an individual, comprising administering to an individual in need of such treatment a compound that inhibits a c-Jun amino-terminal kinase (JNK).  
     
     
         28 . A method of diagnosing insulin resistance or risk of developing insulin resistance, comprising measuring the level of c-Jun amino-terminal kinase (JNK) activity in an individual's tissue, wherein an increase in activity compared to a normal control indicates that said individual is suffering from or at risk for developing insulin resistance.  
     
     
         29 . A method of diagnosing insulin resistance or risk of developing insulin resistance, comprising measuring the level of c-Jun amino-terminal kinase (JNK) expression in an individual's tissue, wherein an increase in expression compared to a normal control indicates that said individual is suffering from or at risk for developing insulin resistance.  
     
     
         30 . The method of  claim 28  or  29 , wherein the JNK is JNK1.  
     
     
         31 . A method of inhibiting fat accumulation in liver tissue, comprising contacting the liver tissue with a compound that inhibits JNK.  
     
     
         32 . The method of  claim 31 , wherein the compound inhibits phosphorylation of JNK.  
     
     
         33 . The method of  claim 31 , wherein the compound inhibits the interaction between the kinase and a substrate of the kinase.  
     
     
         34 . The method of  claim 31 , wherein the JNK is JNK1.  
     
     
         35 . The method of  claim 31 , wherein the JNK is JNK2.  
     
     
         36 . The method of  claim 31 , wherein the JNK is JNK1 and JNK2.  
     
     
         37 . The method of  claim 31 , wherein the compound is a small molecule.  
     
     
         38 . A method for identifying a composition that reduces TNF-α induced lipolysis comprising: 
 (a) contacting an adipocyte with a composition and TNF-α, and    (b) determining the level of lipolysis,    wherein a lower level of lipolysis in the presence of the composition relative to the level of lipolysis in the absence of the composition indicates that the composition reduces TNF-α induced lipolysis.    
     
     
         39 . A method for identifying a composition that reduces lipolysis comprising: 
 (a) contacting an adipocyte with a composition and an agent that induces lipolysis, and    (b) determining the level of lipolysis,    wherein a lower level of lipolysis in the presence of the composition relative to the level of lipolysis in the absence of the composition indicates that the composition reduces lipolysis.    
     
     
         40 . A method for identifying a composition that reduces lipolysis comprising: 
 (a) contacting a fibroblast cell with a composition and an agent that induces lipolysis, and    (b) determining the level of lipolysis,    wherein a lower level of lipolysis in the presence of the composition relative to the level of lipolysis in the absence of the composition indicates that the composition reduces lipolysis.    
     
     
         41 . The method of  claim 38 ,  39 , or  40 , wherein said composition is a JNK inhibitor.  
     
     
         42 . The method of  claim 38 ,  39 , or  40 , wherein said composition is an ERK1/2 inhibitor.  
     
     
         43 . The method of  claim 38 ,  39 , or  40 , wherein said composition is a MEK inhibitor.  
     
     
         44 . The method of  claim 38 ,  39 , or  40 , wherein said composition is a p38 activator.  
     
     
         45 . The method of  claim 38 ,  39 , or  40 , wherein said level of lipolysis is measured by levels of free fatty acid or glycerol in the cell medium.  
     
     
         46 . A method for identifying a composition that is useful for treating a disease relating to an increase in free fatty acids and/or glycerol comprising: 
 (a) contacting an adipocyte with a composition and TNF-α and    (b) determining the level of lipolysis,    wherein a lower level of lipolysis in the presence of the composition relative to the level of lipolysis in the absence of the composition indicates that the composition is useful for treating a disease relating to an increase in free fatty acids and/or glycerol.    
     
     
         47 . A method for identifying a composition that is useful for treating a disease relating to an increase in free fatty acids and/or glycerol comprising: 
 (a) contacting an adipocyte with a composition and an agent that induces lipolysis, and    (b) determining the level of lipolysis,    wherein a lower level of lipolysis in the presence of the composition relative to the level of lipolysis in the absence of the composition indicates that the composition is useful for treating a disease relating to an increase in free fatty acids and/or glycerol.    
     
     
         48 . A method for identifying a composition that is useful in treating a disease relating to an increase in free fatty acids and/or glycerol comprising: 
 (a) contacting a fibroblast cell with a composition and an agent that induces lipolysis, and    (b) determining the level of lipolysis,    wherein a lower level of lipolysis in the presence of the composition relative to the level of lipolysis in the absence of the composition indicates that the composition is useful for treating a disease relating to an increase in free fatty acids and/or glycerol.    
     
     
         49 . The method of  claim 46 ,  47 , or  48 , wherein said composition is a JNK inhibitor.  
     
     
         50 . The method of  claim 46 ,  47 , or  48 , wherein said composition is an ERK1/2 inhibitor.  
     
     
         51 . The method of  claim 46 ,  47 , or  48 , wherein said composition is a MEK inhibitor.  
     
     
         52 . The method of  claim 46 ,  47 , or  48 , wherein said composition is a p38 activator.  
     
     
         53 . The method of  claim 46 ,  47 , or  48 , wherein said level of lipolysis is measured by levels of free fatty acid or glycerol in the cell medium.  
     
     
         54 . The method of  claim 46 ,  47 , or  48 , wherein said disease is hyperlipidemia, hyperglycemia, hyperinsulinemia, obesity, impaired glucose tolerance, insulin resistant non-impaired glucose tolerance, non-diagnostic glucose tolerance, insulin resistance, diabetic complications, fatty liver, polycystic ovary syndrome, gestational diabetes mellitus, hypertension, non-insulin dependent diabetes mellitus, stroke, myocardial infarction, cardiovascular disease, atherosclerosis, or endothelial function abnormality.

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