Method of restoring the incretin effect

Abstract

The present invention relates to methods of treating metabolic syndrome, Type 2 diabetes mellitus, atherogenic dyslipidemia and/or obesity. The present invention also relates to methods of restoring the incretin effect, to restoring physiologic control of glucagon levels, to restoring first-phase insulin secretion, and to restoring the physiologic glucose-dependent insulin secretion. The methods of the present invention comprise administration of a selective κ-receptor antagonist, such as guanidinylated naltrindole (GNTI), or pharmaceutically acceptable derivatives thereof to a subject in need thereof.

1 - 19 . (canceled) 
     
     
         20 . A method of restoring first-phase insulin secretion in a subject comprising administering to a subject an effective amount of a selective κ-receptor antagonist, or a pharmaceutically acceptable derivative thereof. 
     
     
         21 . The method of  claim 20 , wherein the selective κ-receptor antagonist is GNTI. 
     
     
         22 . The method of  claim 20 , wherein the selective κ-receptor antagonist is administered weekly or daily. 
     
     
         23 . The method of  claim 22 , wherein the selective κ-receptor antagonist is administered weekly in an amount from about 30 ng to about 300 ng per kg of body weight weekly. 
     
     
         24 . The method of  claim 22 , wherein the selective κ-receptor antagonist is administered daily in an amount from about 8 ng to about $0 ng per kg of body weight daily. 
     
     
         25 . The method of  claim 20 , wherein the selective κ-receptor antagonist is administered sublingually, orally, enterally, parenterally, topically, systemically or injected intravascularly, subcutaneously, peritoneally. 
     
     
         26 . The method of  claim 20 , further comprising co-administration of an effective amount of an insulinogenic agent. 
     
     
         27 . The method of  claim 26 , wherein the insulinogenic agent is an extended release composition. 
     
     
         28 . The method of  claim 20 , wherein a μ-agonist is not co-administered. 
     
     
         29 . A method of restoring the physiologic glucose dependent insulin secretion in a subject comprising administering to a subject an effective amount of a selective κ-receptor antagonist, or a pharmaceutically acceptable derivative thereof. 
     
     
         30 . The method of  claim 29 , wherein the selective κ-receptor antagonist is GNTI. 
     
     
         31 . The method of  claim 29 , wherein the selective κ-receptor antagonist administered weekly or daily. 
     
     
         32 . The method of  claim 31 , wherein the selective κ-receptor antagonist is administered weekly in an amount from about 30 to about 300 ng per kg, of body weight weekly. 
     
     
         33 . The method of  claim 31 , wherein the selective κ-receptor antagonist is administered daily in an amount from about 8 to about 80 ng per kg of hod weight daily. 
     
     
         34 . The method of  claim 29 , wherein the selective κ-receptor antagonist is administered sublingually, orally, enterally, parenterally, topically, systemically or injected intravascularly, subcutaneously, peritoneally. 
     
     
         35 . The method of  claim 29 , further comprising co-administration of an effective amount of an insulinogenic agent. 
     
     
         36 . The method of  claim 35 , wherein the insulinogenic agent is an extended release composition. 
     
     
         37 . The method of  claim 29 , wherein a μ-agonist is not co-administered. 
     
     
         38 - 77 . (canceled)