ApoIII and the Treatment and Diagnosis of Diabetes

Abstract

The present invention provides methods of identifying candidate compounds for the treatment of type I diabetes comprising contacting pancreatic β cells with an amount of apolipoprotein CIII (“apoCIII”) effective to increase intracellular calcium concentration, in the presence of one or more test compounds, and identifying those test compounds that inhibit an apoCIII-induced increase in intracellular calcium concentration in the pancreatic β cells. The present invention also provides methods for treating patients with type I diabetes comprising administering to the patient an amount effective of an inhibitor of apoCIII to reduce apoCIII-induced increase in intracellular calcium concentration in pancreatic β cells.

We claim: 
     
         1 . A method of identifying candidate compounds for the treatment of diabetes comprising contacting pancreatic β cells with an amount of apolipoprotein CIII (“apoCIII”) effective to increase intracellular calcium concentration in the presence of one or more test compounds and identifying those test compounds that inhibit an apoCIII-induced increase in intracellular calcium concentration in the pancreatic β cells. 
     
     
         2 . The method of  claim 1  wherein the apoCIII comprises sialylated apoCIII. 
     
     
         3 . The method of  claim 1  wherein the apoCIII is substantially purified. 
     
     
         4 . The method of  claim 1  further comprising synthesizing the test compounds that inhibit an apoCIII-induced increase in intracellular calcium concentration in the pancreatic β cells. 
     
     
         5 . A method for treating patients with diabetes comprising administering to a patient with diabetes an amount effective of an inhibitor of apoCIII to reduce apoCIII-induced increase in intracellular calcium concentration in pancreatic β cells, wherein the inhibitor is selected from the group consisting of an apoCIII-selective antibody, an antisense oligonucleotide directed against the apoCIII mRNA, and a small interfering RNA directed against the apoCIII mRNA. 
     
     
         7 . A method for diagnosing diabetes or a propensity to develop diabetes in a subject comprising
 (a) determining an amount of sialylated apoCIII in a blood serum sample from a subject;   (b) comparing the amount with an amount of sialylated apoCIII in a control blood serum sample; and   (c) diagnosing those subjects with an elevated amount of sialylated apoCIII in the blood serum sample relative to the control as having diabetes, or having a propensity to develop diabetes.   
     
     
         8 . A method for identifying diabetic patients to be treated with anti-apoCIII therapy, comprising
 (a) determining an amount of apoCIII in a blood serum sample from a diabetic subject and comparing it to a control blood serum sample; and   (b) identifying those subjects with an elevated amount of apoCIII in the blood serum sample relative to the control blood serum sample as being subjects to be treated with anti-apoCIII therapy.