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Originally published In Press as doi:10.1074/jbc.R300009200 on June 4, 2003
J. Biol. Chem., Vol. 278, Issue 31, 28359-28362, August 1, 2003
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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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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