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J. Biol. Chem., Vol. 278, Issue 31, 28359-28362, August 1, 2003

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Minireview

In Vivo Mutagenesis of the Insulin Receptor^*

Haruka Okamoto   and Domenico Accili  ¶

From the Department of Medicine and Institute of Human Nutrition, College of Physicians & Surgeons of Columbia University, New York, New York 10032

Mice bearing targeted gene mutations that affect insulin receptor (Insr) function have contributed important new information on the pathogenesis of type 2 diabetes. Whereas complete Insr ablation is lethal, conditional mutagenesis in selected tissues has more limited consequences on metabolism. Studies of mice with tissue-specific ablation of Insr have indicated that both canonical (e.g. muscle and adipose tissue) and noncanonical (e.g. liver, pancreatic -cells, and brain) insulin target tissues can contribute to insulin resistance, albeit in a pathogenically distinct fashion. Furthermore, experimental crosses of Insr mutants with mice carrying mutations that affect insulin action at more distal steps of the insulin signaling cascade have begun to unravel the genetics of type 2 diabetes. These studies are consistent with an oligogenic inheritance, in which synergistic interactions among few alleles may account for the genetic susceptibility to diabetes. In addition to mutant alleles conferring an increased risk of diabetes, these studies have uncovered mutations that protect against insulin resistance, thus providing proof-of-principle for the notion that certain alleles may confer resistance to diabetes.

^* This minireview will be reprinted in the 2003 Minireview Compendium, which will be available in January, 2004. This work was supported by National Institutes of Health Grants DK57539 and DK58282, Juvenile Diabetes Research Foundation Grant 893, and the American Diabetes Association. This is the first article of six in the "New Animal Models for Study of Metabolism" Minireview Series.

^¶ To whom correspondence should be addressed: Berrie Research Pavilion, 1150 St. Nicholas Ave., New York, NY 10032. Tel.: 212-851-5332; Fax: 212-851-5331; E-mail: da230{at}columbia.edu.

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