Compounds useful to treat metabolic disorders
AssigneesPresident and Fellows of Harvard College, The Brigham and Women's Hospital, Inc.
InventorsGokhan S. Hotamisligil, Ediz Calay, Amir Tirosh, Gurol Tuncman, Motohiro Sekiya
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Abstract
The present invention provides a method to identify and use compounds for the inhibition of abnormal or dysregulated hepatic glucose production that results in elevated blood glucose levels and associated metabolic disorders. The invention is based on the surprising discovery that the glucagon forms an obligate binding complex with aP2, which is necessary for activation of the glucagon G-coupled protein receptor.
Claims18
-10. (canceled)
A method of identifying a compound capable of neutralizing glucagon/adipocyte binding protein complex (glucagon/aP2) agonism of glucagon receptor (GCGR) comprising:
- i. introducing aP2 and glucagon, or glucagon/aP2, into a first cellular assay comprising cells expressing GCGR;
- ii. determining a biological activity of GCGR in the cells in the first cellular assay;
- iii. introducing aP2 and glucagon, or glucagon/aP2 into a second cellular assay comprising cells expressing GCGR, wherein the aP2 and glucagon, or glucagon/aP2, is introduced in the presence of the compound;
- iv. determining a biological activity of GCGR in the cells in the second cellular assay;
- and,
- v. comparing the biological activity of GCGR in the first cellular assay with the biological activity of GCGR in the second cellular assay;
- wherein a reduction in GCGR biological activity in the second assay compared to the GCGR biological activity in the first assay is indicative of a compound that neutralizes glucagon/aP2 agonism of GCGR.
A method of neutralizing glucagon/aP2 agonism of GCGR in a human comprising administering to the subject a compound that neutralizes the ability of glucagon/aP2 from binding to GCGR.
-19. (canceled)
A method of treating a human with a disorder mediated by the dysregulation of hepatic glucose production comprising administering to the human a compound that neutralizes the ability of a glucagon/aP2 to agonize GCGR, wherein the compound does not directly bind to GCGR.
Dependencies are inferred from the claim text.