Methods and Assays for Detecting and Treating Hypoglycemia

Abstract

Methods for regulating glucagon release and of treating hypoglycemia, and for screening drug candidates for heating hypoglycemia. The methods are useful for treating diabetes melititus and screening drug candidates for potential efficacy.

1 . A method of treating hypoglycemia comprising administering an effective amount of a compound that activates an ionotropic glutamate receptor to stimulate glucagon release. 
     
     
         2 . The method of  claim 1 , wherein the compound activates the glutamate receptor subunit GluR6. 
     
     
         3 . The method of  claim 1 , wherein the ionotropic glutamate receptor is a AMPA/kainate type receptor. 
     
     
         4 . The method of  claim 1 , wherein the compound is selected from the group consisting of kainate, AMPA, and (2S,4R)-4-Methylglutamic acid, (RS)-2-Amino-3-(4-chloro-3-hydroxy-5-isoxazolyl)propionic acid, 4,6-Bis(benzoylamino)-1,3-benzenedicarboxylic acid, (±)-4-(4-Aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine, 1-(4′-Aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one, 1,4-Dihydro-6-(1H-imidazol-1-yl)-7-nitro-2,3-quinoxalinedione hydrochloride, GABA, and Bicuculline. 
     
     
         5 . The method of  claim 1 , wherein the compound is a glutamate analog. 
     
     
         6 . The method of  claim 1 , wherein the compound is administered at a dose of about 5 mg/kg/day to about 200 mg/kg/day. 
     
     
         7 . The method of  claim 1 , wherein the hypoglycemia is associated with diabetes mellitus. 
     
     
         8 . (canceled) 
     
     
         9 . A method of stimulating glucagon release comprising administering a compound that activates glutamate receptor subunit GluR6 of an ionotropic glutamate receptor to stimulate glucagon release. 
     
     
         10 . The method of  claim 9 , wherein the ionotropic glutamate receptor is a AMPA/kainate type receptor. 
     
     
         11 . The method of  claim 9 , wherein the compound is selected from the group consisting of kainate, AMPA, and GABA. 
     
     
         12 . The method of  claim 9 , wherein the compound is a glutamate analog. 
     
     
         13 . The method of  claim 9 , wherein the compound is administered at a dose of about 5 mg/kg/day to about 200 mg/kg/day. 
     
     
         14 . An assay for in vitro screening for modulators useful in treating diabetes comprising: providing islet cells in two groups, wherein the first group is a control and the second group is administered a dose of streptozotocin sufficient to destroy the .beta, cells present; administering a test compound to both the first and second group; and measuring the potentiation of glucagon release in the first and second groups to determine the effect of the test compound, wherein a decreased in cytoplasmic calcium mobilization and/or glucagon release is indicative of a compound that is useful as a modulator.