Combination therapy for the treatment of diabetes and conditions related thereto and for the treatment of conditions ameliorated by increasing a blood GLP-1 level
The present invention concerns combination of an amount of a GPR119 agonist with an amount of a dipeptidyl peptidase IV (DPP-IV) inhibitor such that the combination provides an effect in lowering a blood glucose level or in increasing a blood GLP-1 level in a subject over that provided by the amount of the GPR119 agonist or the amount of the DPP-IV inhibitor alone and the use of such a combination for treating or preventing diabetes and conditions related thereto or conditions ameliorated by increasing a blood GLP-1 level. The present invention also relates to the use of a G protein-coupled receptor to screen for GLP-1 secretagogues.
1. A method of identifying a GLP-1 secretagogue, comprising
(a) contacting a GPR119 agonist with a mammalian enteroendocrine cell in vitro; and
(b) determining whether the GPR119 agonist stimulates GLP-1 secretion from the mammalian enteroendocrine cell;
wherein the ability of the GPR119 agonist to stimulate GLP-1 secretion from the mammalian enteroendocrine cell is indicative of the agonist being a GLP-1 secretagogue.
2. The method of claim 1 , wherein the GPR119 agonist is an agonist of human GPR119.
3. The method of claim 1 , wherein the GPR119 agonist is a small molecule.
4. The method of claim 1 , wherein the GPR119 agonist is orally active.
5. The method of claim 1 , wherein the GPR119 agonist is a selective GPR119 agonist.
6. The method of claim 1 , wherein the GPR119 agonist has an EC50 of less than 10 μM.
7. The method of claim 1 , wherein the enteroendocrine cell is a A GLUTag-cell line.
8. The method of claim 1 , wherein the GPR119 agonist has a selectivity for GPR119 over corticotrophin releasing factor-1 (CRF-1) receptor of at least about 100-fold.
9. The method of claim 1 , wherein the GPR119 agonist has an EC50 of less than 1 μM.
10. The method of claim 1 , wherein the GPR119 agonist has an EC50 of less than about 100 nM.
11. The method of claim 1 , wherein the GPR119 agonist is orally active and has an EC50 of less than about 100 nM.