Remedies for diseases caused by insulin resistance

Abstract

The present invention relates to a remedy for diseases caused by insulin resistance, which comprises, as an active ingredient, a substance exhibiting activity for inhibiting the binding of the full-length insulin receptor substrate-1 (IRS-1) or insulin receptor substrate-2 (IRS-2) or a portion of the same to the full-length 14-3-3 protein or a portion of the same; and to a screening method for a remedy for diseases caused by insulin resistance, which comprises assaying the activity for inhibiting the binding. By means of the screening method, there can be obtained a remedy for diseases caused by insulin resistance, such as diabetes, diabetic microangiopathies (diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy), impaired glucose tolerance, hyperinsulinemia, hyperlipemia, arteriosclerosis, hypertension, obesity, ischemic heart diseases, ischemic brain disorders, and peripheral arterial embolism.

1 . A remedy for a disease caused by insulin resistance, which comprises, as an active ingredient, a substance exhibiting activity for inhibiting the binding of a full-length or a portion of insulin receptor substrate-1 (IRS-1) or a full-length or a portion of insulin receptor substrate-2 (IRS-2) to a full-length or a portion of 14-3-3 protein.  
     
     
         2 . A remedy according to  claim 1 , wherein the portion of IRS-1 or IRS-2 is a serine-residue-containing oligopeptide in the amino acid sequence of IRS-1 or IRS-2, or a phosphorylated product of the oligopeptide.  
     
     
         3 . A remedy according to  claim 1  or  2 , wherein the disease caused by insulin resistance is diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, impaired glucose tolerance, hyperinsulinemia, hyperlipemia, arteriosclerosis, hypertension, obesity, ischemic heart disease, ischemic brain disorder, or peripheral arterial embolism.  
     
     
         4 . A screening method for a remedy for a disease caused by insulin resistance, which comprises assaying activity for inhibiting the binding of a full-length IRS-1 or IRS-2 or a portion of the same to a full-length 14-3-3 protein or a portion of the same.  
     
     
         5 . A screening method according to  claim 4 , wherein the portion of IRS-1 or IRS-2 is a serine-residue-containing oligopeptide in the amino acid sequence of IRS-1 or IRS-2, or a phosphorylated product of the oligopeptide.  
     
     
         6 . A screening method for a remedy for a disease caused by insulin resistance, which comprises assaying activity for inhibiting the binding of a protein containing phosphotyrosine binding domain (PTB domain) of IRS-1 or IRS-2, or a phosphorylated protein to a protein containing a binding site of 14-3-3 protein to tryptophan hydroxylase (the box-1 region).  
     
     
         7 . A screening method according to any one of  claims 4  to  6 , wherein the disease caused by insulin resistance is diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, impaired glucose tolerance, hyperinsulinemia, hyperlipemia, arteriosclerosis, hypertension, obesity, ischemic heart disease, ischemic brain disorder, or peripheral arterial embolism.  
     
     
         8 . A remedy for a disease caused by insulin resistance, which comprises, as an active ingredient, a substance selected by use of the screening method as described in any one of  claims 4  to  7 .  
     
     
         9 . A pharmaceutical composition for a disease caused by insulin resistance, which comprises a substance exhibiting activity for inhibiting the binding of a full-length IRS-1 or IRS-2 or a portion of the same to a full-length 14-3-3 protein or a portion of the same, and a pharmaceutically acceptable carrier.  
     
     
         10 . A pharmaceutical composition according to  claim 9 , wherein the portion of IRS-1 or IRS-2 is a serine-residue-containing oligopeptide in the amino acid sequence of IRS-1 or IRS-2, or a phosphorylated product of the oligopeptide.  
     
     
         11 . A pharmaceutical composition according to  claim 9  or  10 , wherein the disease caused by insulin resistance is diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, impaired glucose tolerance, hyperinsulinemia, hyperlipemia, arteriosclerosis, hypertension, obesity, ischemic heart disease, ischemic brain disorder, or peripheral arterial embolism.  
     
     
         12 . Use of a substance exhibiting activity for inhibiting the binding of a full-length IRS-1 or IRS-2 or a portion of the same to a full-length 14-3-3 protein or a portion of the same for producing a remedy for a disease caused by insulin resistance.  
     
     
         13 . Use according to  claim 12 , wherein the portion of IRS-1 or IRS-2 is a serine-residue-containing oligopeptide in the amino acid sequence of IRS-1 or IRS-2, or a phosphorylated product of the oligopeptide.  
     
     
         14 . Use according to  claim 12  or  13 , wherein the disease caused by insulin resistance is diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, impaired glucose tolerance, hyperinsulinemia, hyperlipemia, arteriosclerosis, hypertension, obesity, ischemic heart disease, ischemic brain disorder, or peripheral arterial embolism.  
     
     
         15 . A treatment method for a disease caused by insulin resistance, which comprises administering to a patient in need thereof an effective amount of a substance exhibiting activity for inhibiting the binding of a full-length IRS-1 or IRS-2 or a portion of the same to a full-length 14-3-3 protein or a portion of the same.  
     
     
         16 . A treatment method according to  claim 15 , wherein the portion of IRS-1 or IRS-2 is a serine-residue-containing oligopeptide in the amino acid sequence of IRS-1 or IRS-2, or a phosphorylated product of the oligopeptide.  
     
     
         17 . A treatment method according to  claim 15  or 16, wherein the disease caused by insulin resistance is diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, impaired glucose tolerance, hyperinsulinemia, hyperlipemia, arteriosclerosis, hypertension, obesity, ischemic heart disease, ischemic brain disorder, or peripheral arterial embolism.  
     
     
         18 . A pharmaceutical composition for a disease caused by insulin resistance, which comprises a substance selected by use of the screening method as described in any one of  claims 4  to  7  and a pharmaceutically acceptable carrier.  
     
     
         19 . Use of a substance selected by use of the screening method as described in any one of  claims 4  to  7  for producing a remedy for a disease caused by insulin resistance.  
     
     
         20 . A treatment method for a disease caused by insulin resistance, which comprises administering to a patient in need thereof an effective amount of a substance selected by use of the screening method as described in any one of  claims 4  to  7 .