Use of MIF and MIF Pathway Agonists

Abstract

The present invention relates to novel methods and compositions for increasing AMPK activity and glucose uptake comprising administering a macrophage migration inhibitory factor (MIF) pathway agonist in a subject in need thereof. The invention also relates to methods for selecting a subject for treatment with an agonist of MIF, identifying a subject at risk for developing a condition in which increased AMPK activity is desirable, and for predicting whether a subject is susceptible to a condition in which increased AMPK activity is desirable.

What is claimed is: 
     
         1 . A method of identifying a subject at risk of developing a condition in which increased AMPK activity is desirable, comprising genotyping the subject for the presence of a polymorphism associated with decreased MIF expression, wherein a subject having a polymorphism associated with decreased MIF expression is at an increased risk of developing a condition in which increased AMPK activity is desirable. 
     
     
         2 . The method of  claim 1 , wherein the condition in which increased AMPK activity is desirable is a condition selected from the group consisting of hypoxia, ischemia, and type 2 diabetes. 
     
     
         3 . The method of  claim 2 , wherein the ischemia is caused by myocardial infarction, coronary revascularization, stroke, vascular occlusion, organ transplant surgery, vascular surgery. 
     
     
         4 . A method of predicting the severity of a condition in which increased AMPK activity is desirable in a subject, comprising genotyping the subject for the presence of a polymorphism associated with decreased MIF expression, wherein a subject having a polymorphism associated with decreased MIF expression is at an increased risk of developing a more severe condition in which increased AMPK activity is desirable. 
     
     
         5 . The method of  claim 4 , wherein the condition in which increased AMPK activity is desirable is a condition selected from the group consisting of: hypoxia, ischemia, and type 2 diabetes. 
     
     
         6 . The method of  claim 5 , wherein the ischemia is caused by myocardial infarction, coronary revascularization, stroke, vascular occlusion, organ transplant surgery, vascular surgery. 
     
     
         7 . A method of predicting whether a subject is susceptible to a condition in which increased AMPK activity is desirable, comprising genotyping a subject for the presence of a polymorphism associated with decreased MIF expression, wherein a subject having a polymorphism associated with decreased MIF expression is more susceptible to the condition. 
     
     
         8 . The method of  claim 7 , wherein the condition in which increased AMPK activity is desirable is a condition selected from the group consisting of hypoxia, ischemia, and type 2 diabetes. 
     
     
         9 . The method of  claim 8 , wherein the ischemia is caused by myocardial infarction, coronary revascularization, stroke, vascular occlusion, organ transplant surgery, vascular surgery. 
     
     
         10 . The method of  claim 1 , wherein the polymorphism associated with decreased MIF expression is selected from the group consisting of: the presence of five CATT repeats in the −794 region of one or both alleles of the MIF gene, the presence of fewer than five CATT repeats in the −794 region of one or both alleles of the MIF gene, or the presence of guanine at position −173 of one or both alleles of the MIF gene. 
     
     
         11 . The method of  claim 1 , wherein a subject having a polymorphism associated with decreased MIF expression is a subject having a polymorphism selected from the group consisting of: the presence of five CATT repeats in the −794 region of one or both alleles of the MIF gene, the presence of fewer than five CATT repeats in the −794 region of one or both alleles of the MIF gene, or the presence of guanine at position −173 of one or both alleles of the MIF gene. 
     
     
         12 . The method of  claim 1 , wherein genotyping the subject for the presence of a polymorphism associated with decreased MIF expression comprises:
 (a) contacting a sample obtained from the subject with a polynucleotide probe that hybridizes specifically to a sequence comprising a polymorphism associated with decreased MIF expression; and   (b) determining whether hybridization occurs, wherein hybridization indicates whether the subject comprises a polymorphism associated with decreased MIF expression, thereby genotyping the subject for the presence of a polymorphism associated with decreased MIF expression.   
     
     
         13 . The method of  claim 12 , wherein the method further comprises:
 (c) contacting the sample with a control polynucleotide probe, wherein the control polynucleotide probe does not hybridize specifically to a sequence comprising a polymorphism associated with decreased MIF expression, and wherein hybridization of the polynucleotide probe but not the control polynucleotide probe indicates the presence of a MIF polymorphism associated with decreased MIF expression.   
     
     
         14 . The method of  claim 1 , wherein genotyping the subject for the presence of a polymorphism associated with decreased MIF expression comprises:
 (a) contacting a sample obtained from the subject with a pair of amplification primers, wherein said primers are capable of amplifying a portion of the MIF promoter comprising a polymorphism associated with decreased MIF expression;   (b) amplifying DNA in the sample, thereby producing amplified DNA;   (c) determining whether the amplified DNA comprises a polymorphism associated with decreased MIF expression, thereby genotyping the subject for the presence of a polymorphism associated with decreased MIF expression.   
     
     
         15 . The method of  claim 14 , wherein the determining step comprises sequencing the amplified DNA. 
     
     
         16 . A method of increasing phosphorylation of threonine at position 172 of the AMPK protein in a cell, comprising administering a MIF agonist to a subject in need thereof. 
     
     
         17 . A method of increasing AMPK-mediated GLUT4 activation in a cell, comprising administering a MIF agonist to a subject in need thereof. 
     
     
         18 . A method of increasing uptake of AMPK-mediated glucose into a cell, comprising administering a MIF agonist to a subject in need thereof. 
     
     
         19 . A method of increasing AMPK-mediated glycogen synthesis in a cell, comprising administering a MIF agonist to a subject in need thereof. 
     
     
         20 . A method of stimulating AMPK-mediated PFK-2 activity in a cell, comprising administering a MIF agonist to a subject in need thereof. 
     
     
         21 . A method of increasing AMPK-mediated glycolysis in a cell, comprising administering a MIF agonist to a subject in need thereof. 
     
     
         22 . A composition comprising one or more MIF agonists and at least one AMPK agonist. 
     
     
         23 . A composition comprising one or more MIF agonists and at least one additional therapeutic agent. 
     
     
         24 . The composition of  claim 23 , wherein said at least one additional therapeutic agent is a compound for treating a subject having, or at risk of developing, ischemia, organ transplant surgery, and type 2 diabetes 
     
     
         25 . The composition of  claims 22 , wherein the MIF agonist is selected from the group consisting of: a MIF polypeptide, a CD74 agonist, a CD44 agonist, a bivalent antibody that increases the interaction between MIF, CD74 and CD44, a bivalent antibody that increases the interaction between MIF and CD74, and a bivalent antibody that increases the interaction between CD74 and CD44, and a polynucleotide or cDNA molecule that encodes a MIF polypeptide, a CD74 agonist, a CD44 agonist, a bivalent antibody that increases the interaction between MIF, CD74 and CD44, a bivalent antibody that increases the interaction between MIF and CD74, a bivalent antibody that increases the interaction between CD74 and CD44, and any combination thereof.