Irs modulators

Abstract

This invention is directed to a general method for the chronic treatment, potential cure, or prevention of various metabolic and related diseases in people, including diabetes, by modulating IRS2 activity in cells and tissues in the body. IRS1 and IRS2 are part of the insulin or insulin-like growth factor signaling pathway. By upregulating the levels or functional activity of IRS2, insulin is used more efficiently by the body to control nutrient levels. By upregulating IRS2 levels or functional activity in pancreatic β-cells, glucose sensing and insulin secretion are enhanced.

1 - 17 . (canceled) 
     
     
         18 . A method of restoring or enhancing insulin sensitivity in a cell comprising upregulating IRS1 function. 
     
     
         19 . A method of restoring or enhancing pancreatic β-cell function comprising upregulating IRS1 function. 
     
     
         20 . A method of treating a disease characterized by reduced or insufficient signaling through IRS1 comprising upregulating IRS1 function. 
     
     
         21 . The method of  claim 20 , wherein the disease is a metabolic disease. 
     
     
         22 . The method of  claim 20 , wherein the disease is diabetes. 
     
     
         23 . The method of  claim 20 , wherein the disease is obesity. 
     
     
         24 . The method of  claim 20 , wherein the disease is female infertility. 
     
     
         25 . The method of  claim 20 , wherein the disease is a central nervous system disorder. 
     
     
         26 . The method of  claim 18 , wherein the upregulation of IRS1 RS2 function comprises activation of IRS1. 
     
     
         27 . The method of  claim 18 , wherein the upregulation of IRS1 function comprises activation of a dimeric or multimeric complex that includes IRS1. 
     
     
         28 . The method of  claim 27 , wherein the complex further includes a tyrosine kinase receptor or an SH2 domain containing protein. 
     
     
         29 . The method of  claim 18 , wherein the upregulation of IRS1 function comprises inhibition of phosphorylation of carboxy terminal serine residues of IRS1. 
     
     
         30 . The method of  claim 18 , wherein the upregulation of IRS1 function comprises enhanced expression of IRS1. 
     
     
         31 . The method of  claim 18 , wherein the upregulation of IRS1 function comprises inhibition of degradation of IRS1. 
     
     
         32 . The method of  claim 18 , wherein the upregulation of IRS1 activity comprises specifically enhancing interaction between IRS2 and an IRS2 binding partner selected from the group consisting of 14-3-3, pin1, a protein kinase C isoform, a protein kinase B isoform, Tor kinase, Jnk1, and an SH2 domain comprising protein. 
     
     
         33 . A method of determining whether a small molecule is an activator or an inhibitor of IRS2 which comprises:
 a) providing a test cell which overproduces IRS1 and exhibits an increase in binding of an IRS1-binding protein to IRS1, relative to a control cell which produces IRS1 at a lower level, or does not produce the protein at all, and which exhibits a lesser amount of binding of said protein to IRS1;   b) causing the small molecule to come into contact with the intact test cell;   c) measuring the amount of the IRS1 binding protein bound to IRS1.   
     
     
         34 . A method of identifying a small molecule capable of increasing the level of expression from an IRS1 promoter in a mammalian cell which comprises:
 a) providing a test cell which contains said IRS1 promoter operably linked to a reporter gene such that increased expression of the IRS1 promoter sequence using a substance known to be capable of upregulating the endogenous IRS1 gene results in an increase in reporter protein levels;   b) causing said small molecule to come into contact with the intact test cell, and   c) determining whether an increase in reporter protein level in the test cell has occurred.