Submitted on August 18, 2006
Accepted on February 9, 2007
Analysis of compensatory 
cell repsonse in mice with combined mutations of Insulin Receptor and Irs2
Jane J. Kim1, Yoshiaki Kido2, Philipp E. Scherer3, Morris F White4, and Domenico Accili5*
1 Pediatrics, University of California, San Diego, La Jolla, California, United States; Medicine, Columbia University, New York, New York, United States
2 Medicine, Kobe University, Kobe, Japan
3 Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States
4 Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
5 Medicine, Columbia University, New York, New York, United States
* To whom correspondence should be addressed. E-mail: da230{at}columbia.edu.
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.
