Use of Exendins and Agonists Thereof for the Treatment of Gestational Diabetes Mellitus

Abstract

Methods for treating gestational diabetes which comprise administration of an effective amount of an exendin or an exendin agonist, alone or in conjunction with other compounds or compositions that lower blood glucose levels.

1 - 33 . (canceled) 
     
     
         34 . A method for treating gestational diabetes mellitus in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an exendin peptide or an exendin agonist peptide to treat the gestational diabetes mellitus. 
     
     
         35 . The method of  claim 34 , wherein the exendin peptide or exendin agonist peptide is administered continuously to the subject. 
     
     
         36 . The method of  claim 34 , wherein the exendin peptide or exendin agonist peptide is administered to the subject by injection. 
     
     
         37 . The method of  claim 34 , wherein the exendin peptide or exendin agonist peptide is administered to the subject by subcutaneous injection. 
     
     
         38 . The method of  claim 34 , wherein the therapeutically effective amount is 1 μg to 500 μg per day. 
     
     
         39 . The method of  claim 34 , wherein the therapeutically effective amount is 1 μg to 100 μg per day. 
     
     
         40 . The method of  claim 34 , wherein the therapeutically effective amount is 1 μg to 50 μg per day. 
     
     
         41 . The method of  claim 34 , wherein the exendin peptide or exendin agonist peptide is an exendin-3 peptide or an exendin-4 peptide. 
     
     
         42 . The method of  claim 34 , wherein the exendin peptide or exendin agonist peptide comprises an amino acid sequence of SEQ ID NO. 1, 2, 6, 7, 8, 9, 40, or 41. 
     
     
         43 . The method of  claim 34 , wherein the exendin peptide or exendin agonist peptide comprises an amino acid sequence of SEQ ID NO. 3: 
       
         
           
                 
                 
               
                   Xaa 1  Xaa 2  Xaa 3  Gly Thr Xaa 4  Xaa 5  Xaa 6  Xaa 7  Xaa 8   
                     
                 
                     
                 
                   Ser Lys Gln Xaa 9  Glu Glu Glu Ala Val Arg Leu Xaa 10   
                 
                     
                 
                   Xaa 11  Xaa 12  Xaa 13  Leu Lys Asn Gly Gly Xaa 14  Ser 
                 
                     
                 
                   Ser Gly Ala Xaa 15  Xaa 16  Xaa 17  Xaa 18 -Z; 
                 
             
                
                
                
                
                
                
                
               
            
           
         
       
       wherein:
 Xaa 1  is His, Arg or Tyr; 
 Xaa 2  is Ser, Gly, Ala or Thr; 
 Xaa 3  is Asp or Glu; 
 Xaa 4  is Phe, Tyr or naphthylalanine; 
 Xaa 5  is Thr or Ser; 
 Xaa 6  is Ser or Thr; 
 Xaa 7  is Asp or Glu 
 Xaa 8  is Leu, Ile, Val, pentylglycine or Met; 
 Xaa 9  is Leu, Ile, pentylglycine, Val or Met; 
 Xaa 10  is Phe, Tyr or naphthylalanine; 
 Xaa 11  is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; 
 Xaa 12  is Glu or Asp; 
 Xaa 13  is Trp, Phe, Tyr, or naphthylalanine; 
 Xaa 14 , Xaa 15 , Xaa 16  and Xaa 17  are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine 
 Xaa 18  is Ser, Thr or Try; and 
 Z is —OH or —NH 2 . 
 
     
     
         44 . A method for treating gestational diabetes mellitus in a subject in need thereof comprising administering to the subject a peptide comprising the amino acid sequence of SEQ ID NO. 2 in an amount of 1 μg to 100 μg per day to treat the gestational diabetes mellitus. 
     
     
         45 . The method of  claim 44 , wherein the exendin peptide or exendin agonist peptide is administered to the subject by injection. 
     
     
         46 . The method of  claim 44 , wherein the exendin peptide or exendin agonist peptide is administered to the subject by subcutaneous injection. 
     
     
         47 . The method of  claim 44 , wherein the peptide is administered in an amount of 1 μg to 50 μg per day. 
     
     
         48 . The method of  claim 44 , further comprising administering an insulin, an amylin agonist peptide, or a combination thereof. 
     
     
         49 . A method for treating gestational diabetes mellitus in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a peptide comprising the amino acid sequence of SEQ ID NO. 4 to treat the gestational diabetes mellitus; wherein SEQ ID NO. 4 is: 
       
         
           
                 
                 
               
                   Xaa 1  Xaa 2  Xaa 3  Gly Xaa 5  Xaa 6  Xaa 7  Xaa 8  Xaa 9  Xaa 10   
                     
                 
                     
                 
                   Xaa 11  Xaa 12  Xaa 13  Xaa 14  Xaa 15  Xaa 16  Xaa 17  Ala 
                 
                     
                 
                   Xaa 19  Xaa 20  Xaa 21  Xaa 22  Xaa 23  Xaa 24  Xaa 25  Xaa 26   
                 
                     
                 
                   Xaa 27  Xaa 28 -Z 1 ; 
                 
             
                
                
                
                
                
                
                
               
            
           
         
       
       wherein:
 Xaa 1  is His, Arg or Tyr; 
 Xaa 2  is Ser, Gly, Ala or Thr; 
 Xaa 3  is Asp or Glu; 
 Xaa 5  is Ala or Thr; 
 Xaa 6  is Ala, Phe, Tyr or naphthylalanine; 
 Xaa 7  is Thr or Ser; 
 Xaa 8  is Ala, Ser or Thr; 
 Xaa 9  is Asp or Glu; 
 Xaa 10  is Ala, Leu, Ile, Val, pentylglycine or Met; 
 Xaa 11  is Ala or Ser; 
 Xaa 12  is Ala or Lys; 
 Xaa 13  is Ala or Gln; 
 Xaa 14  is Ala, Leu, Ile, pentylglycine, Val or Met; 
 Xaa 15  is Ala or Glu; 
 Xaa 16  is Ala or Glu; 
 Xaa 17  is Ala or Glu; 
 Xaa 18  is Ala or Val; 
 Xaa 20  is Ala or Arg; 
 Xaa 21  is Ala or Leu; 
 Xaa 22  is Ala, Phe, Tyr or naphthylalanine; 
 Xaa 23  is Ile, Val, Leu, pentylglycine, tert-butylglycinc or Met; 
 Xaa 24  is Ala, Glu or Asp; 
 Xaa 25  is Ala, Trp, Phe, Tyr or naphthylalanine; 
 Xaa 26  is Ala or Leu; 
 Xaa 27  is Ala or Lys; 
 Xaa 28  is Ala or Asn; 
 
       
         
           
                 
                 
                 
               
                   Z 1  is 
                   OH, 
                     
                 
                     
                 
                     
                   NH 2 , 
                 
                     
                 
                     
                   Gly-Z 2 , 
                 
                     
                 
                     
                   Gly Gly-Z 2 , 
                 
                     
                 
                     
                   Gly Gly Xaa31-Z 2 , 
                 
                     
                 
                     
                   Gly Gly Xaa 31  Ser-Z 2 , 
                 
                     
                 
                     
                   Gly Gly Xaa 31  Ser Ser-Z 2 , 
                 
                     
                 
                     
                   Gly Gly Xaa 31  Ser Ser Gly-Z 2 , 
                 
                     
                 
                     
                   Gly Gly Xaa 31  Ser Ser Gly Ala-Z 2 , 
                 
                     
                 
                     
                   Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36 -Z 2 , 
                 
                     
                 
                     
                   Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36  Xaa 37 -Z 2 , 
                 
                     
                   or 
                 
                     
                 
                     
                   Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36  Xaa 37  Xaa 38 -Z 2 ; 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         Xaa 31 , Xaa 36 , Xaa 37  and Xaa 38  are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; and 
         Z 2  is —OH or —NH 2 ; 
       
       provided that no more than three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 8 , Xaa 10 , Xaa 11 , Xaa 12 , Xaa 13 , Xaa 14 , Xaa 15 , Xaa 16 , Xaa 17 , Xaa 18 , Xaa 20 , Xaa 21 , Xaa 24 , Xaa 25 , Xaa 26 , Xaa 27  and Xaa 28  are Ala. 
     
     
         50 . The method of  claim 49 , wherein the exendin peptide or exendin agonist peptide is administered to the subject by subcutaneous injection. 
     
     
         51 . The method of  claim 49 , wherein the therapeutically effective amount is 1 μg to 100 μg per day. 
     
     
         52 . The method of  claim 49 , wherein the therapeutically effective amount is 1 μg to 50 μg per day. 
     
     
         53 . The method of  claim 49 , further comprising administering an insulin, an amylin agonist peptide, or a combination thereof.