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 polypeptide according to  claim 1 , wherein the polypeptide comprises 24 amino acids corresponding to positions 7-30 of the sequence of rat GIP, SEQ ID NO:8, or effective alternative sequences thereto.  
     
     
         3 . A polypeptide having an amino acid sequence having the ability to signal through a GIP receptor, said polypeptide comprising at least those amino acids corresponding to positions 7-15 of GIP, SEQ ID No. 4.  
     
     
         4 . A glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist pharmaceutically acceptable composition comprising a polypeptide selected from the group consisting of amino acid sequences having at least 95% identity to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1, SEQ ID NO:  12 , SEQ ID NO: 13, and SEQ ID NO: 14, wherein said antagonist reduces intestinal uptake of glucose in a mammal when administered to said mammal.  
     
     
         5 . A pharmaceutical composition comprising a suitable pharmaceutical excipient and a polypeptide antagonist of glucose-dependent insulinotropic polypeptide (GIP) receptor.  
     
     
         6 . An isolated polypeptide comprised within a pharmaceutical composition for administration to a mammal wherein said polypeptide antagonizes or interferes with glucose-dependent insulinotropic polypeptide (GIP) binding to a GIP receptor in the mammal intestine to decrease glucose absorption from the intestine of the mammal.  
     
     
         7 . An isolated polypeptide comprised within a pharmaceutical composition for administration to a mammal exhibiting symptoms of type II diabetes wherein said polypeptide antagonizes or interferes with glucose-dependent insulinotropic polypeptide (GIP) binding to a GIP receptor in the mammal intestine to decrease gut glucose uptake and normalize glucose tolerance in said mammal.  
     
     
         8 . An isolated polypeptide comprised within a pharmaceutical composition for administration to a mammal wherein said polypeptide antagonizes or interferes with glucose-dependent insulinotropic polypeptide (GIP) binding to a GIP receptor in the mammal intestine to decrease serum glucose and serum insulin levels in a mammal, as compared to those serum glucose and insulin levels normally achieved in the mammal when untreated with said pharmaceutical composition.  
     
     
         9 . An isolated polypeptide comprised within a pharmaceutical composition for administration to a mammal wherein said polypeptide specifically antagonizes or interferes with glucose-dependent insulinotropic polypeptide (GIP) binding to a GIP receptor in the mammal intestine to decrease serum insulin levels.  
     
     
         10 . An isolated antibody that specifically interferes with the biological activity of glucose-dependent insulinotropic polypeptide (GIP), wherein said antibody lacks cross reactivity to a glucagon like peptide-1 (GLP-1).  
     
     
         11 . 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: 
 an antagonist for interfering with the biological activity of glucose-dependent insulinotropic polypeptide (GIP) in the mammal, said 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 blood insulin levels and (iv) decreases postprandial blood glucose 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 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.    
     
     
         12 . A pharmaceutical composition of  claim 4 , wherein said antagonist lacks cross reactivity with glucagon like peptide-1 (GLP-1) receptors.  
     
     
         13 . A pharmaceutical composition of  claim 4  wherein said antagonist does not substantially interfere with the biological activity of glucagon like peptide-1 (GLP-1).  
     
     
         14 . A pharmaceutical composition of  claim 4 , wherein the antagonist comprises an antibody that interferes with the biological activity of GIP without interfering with the biological activity of glucagon like peptide-1 (GLP-1).  
     
     
         15 . A pharmaceutical composition of  claim 4 , wherein the antagonist comprises an antibody that binds GIP without interfering with the biological activity of glucagon like peptide-1 (GLP-1).  
     
     
         16 . A pharmaceutical composition of  claim 4 , wherein the antagonist comprises an antibody that binds GIP and an antibody that binds GIP receptor without interfering with the biological activity of glucagon like peptide-1 (GLP-1).  
     
     
         17 . An isolated polypeptide glucose-dependent insulinotropic (GIP) antagonist consisting essentially of a polypeptide having the amino acid sequence of SEQ ID NO:5 wherein one neutral amino acid selected from position 3, 4, 8, 14, 17, 18 and 19 of SEQ ID NO:5 is replaced with a non-identical neutral amino acid selected from the group consisting of valine, proline, leucine, isoleucine, glycine, and alanine.  
     
     
         18 . The isolated polypeptide of  claim 17  wherein one or both isoleucines at positions 3 and 8 in SEQ ID NO:5 is replaced with an amino acid selected from the group consisting of valine, proline, leucine, glycine, and alanine.  
     
     
         19 . The isolated polypeptide of  claim 17  wherein the amino acid is selected from the group consisting of valine and proline.