Methods of treatment of type 2 diabetes

Abstract

The present invention relates generally to the field of diabetes. More particularly, it concerns the identification of genes responsible for NIDDM1 for use in diagnostic and therapeutic applications. The present invention demonstrates that the NIDDM1 locus is, in fact, the calpain 10 gene. The invention further relates to the discovery that analysis of mutations in calpain genes and gene products can be diagnostic for type 2 diabetes. The invention also contemplates methods of treating diabetes in view of the fact that calpain mutations can cause diabetes. Further, the invention relates to novel polynucleotides of the NIDDM1 locus and polypeptides encoded by such polynucleotides.

1 - 30 . (canceled)  
     
     
         31 . A method of modulating an insulin secretory response in an animal comprising the step of administering a modulator of calpain function to the animal.  
     
     
         32 . (canceled)  
     
     
         33 . (canceled)  
     
     
         34 . The method of  claim 31 , wherein the modulator of calpain function is an antagonist of a calpain polypeptide.  
     
     
         35 . A method of modulating insulin mediated glucose transport in an animal comprising the step of administering a modulator of calpain function to the animal.  
     
     
         36 . (canceled)  
     
     
         37 . The method of  claim 35 , wherein the modulator of calpain function is an agonist of a calpain polypeptide.  
     
     
         38 . (canceled)  
     
     
         39 . A method of treating diabetes in an animal comprising the step of modulating calpain function in the animal by administering a modulator of calpain function to the animal.  
     
     
         40 . (canceled)  
     
     
         41 . The method of  claim 39 , wherein the modulator of calpain function is an agonist or antagonist of a calpain polypeptide.  
     
     
         42 . The method of  claim 41 , wherein the modulator of calpain function is an antagonist of a calpain polypeptide.  
     
     
         43 . The method of  claim 39 , wherein a calpain function in at least a β-cell, a muscle cell, or a fat cell is modulated.  
     
     
         44 . (canceled)  
     
     
         45 . The method of  claim 39 , wherein the modulator of calpain function is an inhibitor of a calpain polypeptide.  
     
     
         46 . The method of  claim 43 , further defined as a method comprising inhibiting calpain activity in a β-cell with a modulator of calpain function.  
     
     
         47 . The method of  claim 43 , further defined as a method comprising stimulating calpain activity in a muscle cell or fat cell with a modulator of calpain function.  
     
     
         48 . The method of  claim 43 , further defined as a method comprising stimulating calpain activity in a fat call or muscle cell with a modulator of calpain function and inhibiting calpain activity in a β-cell with a modulator of calpain function.  
     
     
         49 . The method of  claim 34 , wherein the antagonist is a peptide, peptide analog, or small molecule.  
     
     
         50 . The method of  claim 49 , wherein the antagonist is a peptide or peptide analog.  
     
     
         51 . The method of  claim 50 , wherein the peptide is calpeptin or calpain inhibitor 2.  
     
     
         52 . The method of  claim 49 , wherein the antagonist is a small molecule.  
     
     
         53 . The method of  claim 52  wherein the small molecule is a thiol protease inhibitor.  
     
     
         54 . The method of  claim 53 , wherein the thiol protease inhibitor is E-64-d.  
     
     
         55 . The method of  claim 31 , wherein the animal is a human.  
     
     
         56 . The method of  claim 34 , wherein the antagonist is administered to a β cell.  
     
     
         57 . The method of  claim 34 , wherein the animal is diagnosed with diabetes.  
     
     
         58 . The method of  claim 57 , further comprising administering a conventional diabetes therapy.  
     
     
         59 . The method of  claim 58 , wherein the conventional diabetes therapy is administration of sulfonylureas, biguanides, glyburide, tolazamide, tolbutamide, chlorpropamide, micronized and non-micronized glyburide, glimepiride, glypizide, metformin, or phenformin.  
     
     
         60 . The method of  claim 57 , wherein the animal is diagnosed with diabetes via analysis of a calpain-encoding nucleic acid sequence.  
     
     
         61 . The method of  claim 60 , wherein the calpain-encoding sequence is a calpain 10-encoding sequence.  
     
     
         62 . The method of  claim 35 , wherein the step of modulating calpain function comprises providing a human calpain 10 polypeptide to the animal.  
     
     
         63 . The method of  claim 62 , wherein the calpain 10 polypeptide is a native calpain 10 polypeptide.  
     
     
         64 . The method of  claim 63 , wherein the calpain 10 polypeptide is encoded by a nucleic acid having a nucleotide sequence as set forth in SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, or SEQ ID NO:18.  
     
     
         65 . The method of  claim 62 , wherein the provision of a calpain 10 polypeptide is accomplished by inducing expression of a calpain 10 polypeptide.  
     
     
         66 . The method of  claim 62 , wherein the provision of a calpain 10 polypeptide is accomplished by introducing a calpain 10-encoding nucleic acid to the animal.