Genetic manipulation of IRS proteins: animal modelsfor understanding the molecular basis of diabetes

ABSTRACT

The identifi cation of insulin receptor substrate (IRS) proteins in the 1990srepresents a key phase of diabetes research as it has enabled ourpresent understanding of the molecular basis of insulin and insulin-likegrowth factor (IGF) action. The generation of mice with targeted deletionsof the four major IRS proteins has revealed invaluable information aboutthe biological functions of these signaling molecules and has providednovel insights into the role of defective insulin signaling in the developmentof diabetes and metabolic diseases. Irs1-defi ciency in mice causesreduced body size, beta cell hyperplasia, and increased life-span. Disruptionof Irs2 has demonstrated that this branch of the insulin/IGF signalingcascade has an important role in peripheral insulin action and pancreaticbeta-cell growth and function. Global disruption of IRS2 signalingin mice causes diabetes due to failed beta cell compensation in the presenceof peripheral insulin resistance. Gene targeting of Irs3 or Irs4 didnot produce remarkable phenotypes suggesting that either they play veryspecifi c roles in limited tissues or that their absence may be compensatedfor by other signaling mechanisms. A complete understanding ofthe cellular events mediated by IRS1 and IRS2 will reveal new strategiesto prevent or cure diabetes and other metabolic diseases(AU)