Specific antagonists for glucose-dependent insulinotropic polypeptide (GIP)

Abstract

In one embodiment, this invention provides an antagonist of glucose-dependent insulinotropic polypeptide (GIP) consisting essentially of a 24 amino acid polypeptide corresponding to positions 7-30 of the sequence of GIP. In another embodiment, this invention provides a method of preventing and treating obesity and non-insulin dependent diabetes mellitus (Type II) in a patient comprising administering to the patient an antagonist of glucose-dependent insulinotropic polypeptide (GIP). In yet another embodiment, this invention provides a method of improving glucose tolerance in a mammal comprising administering to the mammal an antagonist of glucose-dependent insulinotropic polypeptide (GIP).

1 . An antagonist of glucose-dependent insulinotropic polypeptide (GIP) consisting essentially of a 24 amino acid polypeptide corresponding to positions 7-30 of the sequence of GIP.  
     
     
         2 . A pharmaceutical composition for treating a mammal in need of treatment to improve or normalize glucose tolerance and reduce weight or avoid unacceptable weight gain, said pharmaceutical composition comprising: 
 a polypeptide antagonist comprising an amino acid sequence for binding to glucose-dependent insulinotropic polypeptide (GIP) receptors in the mammal for antagonizing the biological activity of GIP, said polypeptide antagonist when administered to a mammal in an amount effective (i) reduces intestinal uptake of postprandial glucose, (ii) reduces postprandial insulin release, (iii) decreases postprandial insulin blood levels and (iv) decreases postprandial glucose blood levels in the treated mammal, from those insulin and glucose blood levels normally attained in the mammal following a postprandial period when the mammal is untreated with said polypeptide antagonist, so that glucose tolerance is improved or normalized and reduced weight is achieved or unacceptable weight gain is avoided in the treated mammal, and    a pharmaceutically acceptable excipient.    
     
     
         3 . A pharmaceutical composition of  claim 2 , wherein said polypeptide antagonist, when administered to the mammal in an amount effective, does not adversely affect the insulintropic effects of a secretagogue in the treated mammal.  
     
     
         4 . A pharmaceutical composition of  claim 2 , wherein said secretagogue is glucagon like peptide-1 (GLP- 1 1).  
     
     
         5 . A pharmaceutical composition of  claim 2 , wherein said secretagogue is arginine.  
     
     
         6 . A pharmaceutical composition of  claim 2 , wherein said secretagogue is glucose.  
     
     
         7 . A pharmaceutical composition of  claim 2 , wherein said amino acid sequence comprises an N-terminal sequence that interferes with functional GIP signaling.  
     
     
         8 . A pharmaceutical composition of  claim 2 , wherein said N-terminal sequence is a hexamer sequence and said hexamer sequence is non-homologous to the N-terminal hexamer sequence of SEQ ID NO:1.  
     
     
         9 . A pharmaceutical composition of  claim 2 , wherein said polypeptide antagonist lacks cross reactivity with glucagon like peptide-1 (GLP-1) receptors.  
     
     
         10 . A pharmaceutical composition of  claim 2 , wherein said polypeptide antagonist does not substantially interfere with the biological activity of glucagon like peptide-1 (GLP-1).  
     
     
         11 . A method of developing a nonpeptide GIP antagonist comprising: 
 using a GIP antagonist to identify characteristics of the GIP antagonist or the antagonist properties of a GIP antagonist; and    developing a nonpeptide GIP antagonist which has characteristics similar to the GIP antagonist or antagonist properties of the GIP antagonist.    
     
     
         12 . An antagonist according to  claim 1 , wherein said antagonist comprises an amino acid sequence at least 95% identical to SEQ ID NO:8.  
     
     
         13 . An antagonist according to  claim 1 , wherein said polypeptide antagonist comprises SEQ ID NO:8.  
     
     
         14 . A pharmaceutical composition according to  claim 2 , wherein the antagonist is a polypeptide comprising an amino acid sequence at least 95% identical to SEQ ID NO:8.  
     
     
         15 . A pharmaceutical composition according to  claim 2 , wherein the antagonist comprises an amino acid sequence identical to SEQ ID NO:8.  
     
     
         16 . An isolated polypeptide comprising an amino acid sequence which specifically interferes with the biological activity of glucose-dependent insulinotropic polypeptide (GIP) when said polypeptide is administered to an animal in an amount effective to reduce intestinal uptake of glucose.  
     
     
         17 . A polypeptide according to  claim 15 , wherein said polypeptide comprises an amino acid identical to SEQ ID NO:2.  
     
     
         18 . The isolated polypeptide of  claim 15  wherein the aspartic acid at position 6 or 12 is replaced with glutamic acid.  
     
     
         19 . The isolated polypeptide of  claim 15  wherein the aspartic acid residues at positions 6 and 12 are replaced with glutamic acid.  
     
     
         20 . The isolated polypeptide of  claim 15  wherein histidine at position 9 is replaced with lysine.  
     
     
         21 . The isolated polypeptide of  claim 15  wherein histidine at position 9 is replaced with arginine.