Methods of treating metabolic disorders associated with lipodystrophies and defects in insulin production or signaling

Abstract

The invention relates to the identification of new therapeutic methods for the FGF21 polypeptide or protein, or mutants, variants, and fusions thereof, for instance, in treating metabolic diseases associated defects in insulin signaling (e.g. insulin receptor mutation disorders (INSR disorders) and/or autoimmune insulin receptor disorders (Type B insulin Resistance)), defects in insulin production such as type 1 diabetes mellitus, mixed dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and other metabolic disorders, and various lipodystrophies such as HIV-HAART induced partial-lipodystrophy, and in reducing the mortality and morbidity of critically ill patients.

1 . A method of treating an insulin receptor disorder (INSR disorder) comprising administering to a subject in need thereof a therapeutically effective amount of (a) an isolated human FGF21 polypeptide; or (b) an FGF21 protein variant. 
     
     
         2 . The method of  claim 1 , wherein the INSR disorder is Type 1 diabetes mellitus. 
     
     
         3 . The method of  claim 1 , wherein the INSR disorder is dyslipidemia. 
     
     
         4 . The method of  claim 1 , wherein the INSR disorder is hyperglycemia. 
     
     
         5 . The method of  claim 1 , wherein the INSR disorder is hypoglycemia. 
     
     
         6 . The method of  claim 1 , wherein the INSR disorder is glucose intolerance. 
     
     
         7 . The method of  claim 1 , wherein the INSR disorder is HIV-HAART Induced Partial Lipodystrophy. 
     
     
         8 . The method of  claim 1 , wherein the INSR disorder is metabolic syndrome. 
     
     
         9 . The method of  claim 1 , wherein the INSR disorder is nonalcoholic fatty liver disease (NAFLD). 
     
     
         10 . The method of  claim 1 , wherein the FGF21 protein variant is Variant 76. 
     
     
         11 . The method of  claim 1 , wherein the FGF21 protein variant is an Fc fusion protein. 
     
     
         12 . The method of  claim 11 , wherein the Fc fusion protein is selected from Table 1. 
     
     
         13 . The method of  claim 11 , wherein the Fc fusion protein is Variant 101. 
     
     
         14 . A method of treating an insulin receptor disorder (INSR disorder) comprising administering to a subject in need thereof a therapeutically effective amount of an FGF21 protein variant, wherein the FGF21 protein variant is administered in the form of a pharmaceutical composition comprising a therapeutically effective amount of an FGF21 protein variant in admixture with a pharmaceutically or physiologically acceptable formulation agent selected for suitability with the mode of administration. 
     
     
         15 . A method of treating an insulin receptor disorder (INSR disorder) comprising administering to a subject in need thereof a therapeutically effective amount of an FGF21 protein variant covalently-modified with one or more PEG subunits.