Methods for treating metabolic disorders using fgf

Abstract

The method provides methods and compositions for treating metabolic disorders such as impaired glucose tolerance, elevated blood glucose, insulin resistance, dyslipidemia, obesity, and fatty liver.

What is claimed is: 
     
         1 . A method for treating a diabetic, hyperglycemic, and/or insulin resistant individual who has a body mass index (BMI) of 25 or higher, comprising administering an FGF-1 compound having at least 80% identity to human FGF 1 and comprising an amino acid substitution at position Tyr-15, Arg-35, Asn-92, Tyr-94, Lys-101, His-102, Trp-107, Lys-112, Lys-113, Lys-118, Arg-122, Lys-128, Leu-133, or Leu-135. 
     
     
         2 . The method of  claim 1 , wherein the FGF-1 compound is administered intravenously. 
     
     
         3 . The method of  claim 1 , wherein the FGF-1 compound is administered subcutaneously. 
     
     
         4 . The method of  claim 1 , wherein the FGF-1 compound is administered at a dose of 0.01-1 mg FGF-1 per kg body weight. 
     
     
         5 . The method of  claim 1 , wherein the FGF-1 compound is administered once per day. 
     
     
         6 . The method of  claim 1 , wherein the FGF-1 compound is administered in combination with an additional therapeutic compound. 
     
     
         7 . The method of  claim 6 , wherein the additional therapeutic compound is an alpha-glucosidase inhibitor, amylin agonist, dipeptidyl-peptidase 4 (DPP-4) inhibitor, meglitinide, sulfonylurea, or a peroxisome proliferator-activated receptor (PPAR)-gamma agonist. 
     
     
         8 . The method of  claim 7 , wherein the PPAR-gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, or tesaglitazar. 
     
     
         9 . The method of  claim 8 , wherein the TZD is pioglitazone, rosiglitazone, rivoglitazone, or troglitazone. 
     
     
         10 . The method of  claim 1 , wherein the FGF-1 compound comprises at least 80% sequence identity to amino acids 1-140, amino acids 1-141, amino acids 14-135, or amino acids 13-135 of FGF1. 
     
     
         11 . The method of  claim 1 , wherein the FGF-1 compound comprises at least 80% sequence identity to amino acids 14-135 of FGF-1. 
     
     
         12 . The method of  claim 1 , wherein the FGF-1 compound comprises at least 90% sequence identity to amino acids 1-141 of FGF-1. 
     
     
         13 . The method of  claim 1 , wherein the FGF-1 compound comprises at least 95% sequence identity to amino acids 1-141 of FGF-1. 
     
     
         14 . The method of  claim 1  wherein the FGF-1 compound comprises at least 98% sequence identity to amino acids 1-141 of FGF-1. 
     
     
         15 . The method of  claim 1 , wherein the FGF-1 compound is administered daily, twice daily, every other day, bi-weekly, weekly, or monthly. 
     
     
         16 . The method of  claim 1 , wherein the individual has a BMI of greater than 30. 
     
     
         17 . The method of  claim 1 , wherein the individual has a BMI of 35 to 40. 
     
     
         18 . The method of  claim 1 , wherein the at least one substitution is a conservative substitution. 
     
     
         19 . A method for treating a diabetic, hyperglycemic, and/or insulin resistant individual who has a fatty liver disease, comprising administering a FGF-1 compound comprising at least 80% of human FGF-1 and an amino acid substitution at residue R35 to the individual in an amount effective to reduce liver steatosis. 
     
     
         20 . The method of  claim 19 , wherein the fatty liver disease is nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or simple fatty liver (steatosis). 
     
     
         21 . A method for treating an individual having type II diabetes or who is insulin resistant, comprising administering a FGF-1 compound comprising at least 80% of human FGF-1 and an amino acid substitution at residue Tyr-15, Arg-35, Asn-92, Tyr-94, Lys-101, His-102, Trp-107, Lys-112, Lys-113, Lys-118, Arg-122, Lys-128, Leu-133, or Leu-135 to the individual in an amount effective to reduce blood glucose levels.