Methods and compositions for modulating carbohydrate metabolism

Abstract

Methods and compositions for modulating carbohydrate metabolism in a host are provided. In the subject methods, diacylglycerol acyltransferase (DGAT) activity (specifically DGAT1 activity) is modulated, e.g., reduced or enhanced, to achieve a desired insulin and/or leptin sensitivity, thereby modulating carbohydrate metabolism, e.g., increasing or decreasing blood glucose levels, glucose uptake into cells and assimilation into glycogen. Also provided are pharmaceutical compositions for practicing the subject methods. The subject methods and compositions find use in a variety of applications, including the treatment of hosts suffering conditions associated with abnormal carbohydrate metabolism, such as obesity or diabetes.

What is claimed is:  
     
         1 . A method of modulating sensitivity of a host to insulin and/or leptin, said method comprising: 
 administering to said host an effective amount of one or more active agents that alter DGAT1 activity in said host to modulate sensitivity of said host to insulin and/or leptin.    
     
     
         2 . The method according to  claim 1 , wherein said agent decreases DGAT1 activity and said method is a method of increasing sensitivity of a host to insulin.  
     
     
         3 . The method according to  claim 1 , wherein said agent decreases DGAT1 activity and said method is a method of increasing sensitivity of a host to leptin.  
     
     
         4 . The method according to  claim 1 , wherein said agent increases DGAT1 activity and said method is a method of decreasing sensitivity of a host to insulin.  
     
     
         5 . The method according to  claim 1 , wherein said agent increases DGAT1 activity and said method is a method of decreasing sensitivity of a host to leptin.  
     
     
         6 . A method of modulating carbohydrate metabolism in a host, said method comprising: 
 administering to said host an effective amount of one or more active agents that modulate DGAT1 activity in said host and modulate carbohydrate metabolism in said host.    
     
     
         7 . The method according to  claim 6 , wherein said carbohydrate is glucose.  
     
     
         8 . The method according to  claim 7 , wherein said active agent modulates glucose uptake into cells of said host.  
     
     
         9 . The method according to  claim 8 , wherein said cells are selected from muscle and liver cells.  
     
     
         10 . The method according to  claim 7 , wherein said active agent increases glycogen synthesis in cells of said host.  
     
     
         11 . The method according to  claim 10 , wherein said cells are selected from muscle and liver cells.  
     
     
         12 . The method according to  claim 6 , wherein said carbohydrate is fat.  
     
     
         13 . The method according to  claim 12 , wherein said active agent modulates triacylglycerol synthesis.  
     
     
         14 . The method according to  claim 13 , wherein said active agent modulates levels of stored triacylglycerol in cells of said host.  
     
     
         15 . The method according to  claim 14 , wherein said cells are adipocyte cells.  
     
     
         16 . A method of treating a host suffering from a condition associated with abnormal carbohydrate metabolism, said method comprising: 
 administering to said host an effective amount of one or more active agents that modulate DGAT activity in said host and treat said host for said condition.    
     
     
         17 . The method according to  claim 16 , wherein said agent modulates sensitivity to insulin and/or leptin.  
     
     
         18 . The method according to  claim 16 , wherein said agent decreases DGAT1 activity in said host and the condition is obesity.  
     
     
         19 . The method according to  claim 18 , wherein said treatment comprises a reduction of host weight and/or body fat.  
     
     
         20 . The method according to  claim 16 , wherein said agent decreases DGAT activity in said host and the condition is diabetes.  
     
     
         21 . The method according to  claim 20 , wherein said agent treatment comprises a stabilization of blood glucose levels.  
     
     
         22 . The method according to  claim 16 , wherein said agent increases DGAT1 activity in said host and said condition is anorexia.  
     
     
         23 . The method according to  claim 16 , wherein said host is a human.  
     
     
         24 . The method according to  claim 16 , wherein said administering step comprises co-administering insulin and/or leptin or an activity mimetic thereof with an agent that modulates DGAT1 activity.  
     
     
         25 . A pharmaceutical preparation comprising a DGAT1 activity modulatory agent in a pharmaceutically acceptable vehicle.  
     
     
         26 . The pharmaceutical preparation according to  claim 25 , wherein said DGAT1 activity modulatory agent increases DGAT1 activity and decreases insulin and/or leptin sensitivity.  
     
     
         27 . The pharmaceutical preparation according to  claim 25 , wherein said DGAT1 activity modulatory agent decreases DGAT1 activity and increases insulin and/or leptin sensitivity.  
     
     
         28 . The pharmaceutical preparation according to  claim 25 , further comprising insulin, leptin or a mimetic thereof.  
     
     
         29 . A kit comprising: 
 (a) a pharmaceutical preparation comprising at least one active DGAT1 modulatory agent; and    (b) instructions for treating a host suffering from a condition associated with abnormal carbohydrate metabolism by administering to said host an effective amount of one or more active DGAT1 modulatory agents to treat said host for said condition.    
     
     
         30 . The kit according to  claim 29 , wherein said one or more active DGAT1 modulatory agents reduce DGAT1 activity and said instructions are instructions for treating obesity and/or diabetes.  
     
     
         31 . The kit according to  claim 29 , wherein said kit further includes insulin and/or leptin.