HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/6/E1694    most recent 00430.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kim, J. J. Articles by Accili, D. Search for Related Content PubMed PubMed Citation Articles by Kim, J. J. Articles by Accili, D.

Analysis of compensatory -cell response in mice with combined mutations of Insr and Irs2

¹Deparment of Pediatrics, University of California, San Diego, California; ²Department of Medicine, Columbia University, New York, New York; ³Department of Medicine, Kobe University, Kobe, Japan; ⁴Children's Hospital, Harvard Medical School, Boston, Massachusetts; ⁵Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York

Submitted 18 August 2006 ; accepted in final form 9 February 2007

Type 2 diabetes results from impaired insulin action and -cell dysfunction. There are at least two components to -cell dysfunction: impaired insulin secretion and decreased -cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired -cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, 70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased -cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as -cell mass gradually declined, indicating that replication-defective -cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous -cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of -cell dysfunction in type 2 diabetes should positively affect both aspects of -cell physiology.

insulin receptor; insulin receptor substrate-2; insulin resistance; -cell compensation; genetics; insulin signaling; knockout mice