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Department of Experimental and Clinical Medicine, University of Catanzaro-Magna Graecia, 88100 Catanzaro, Italy; and
* Laboratory of Molecular Medicine, Department of Internal Medicine, University of Rome-Tor Vergata, 00133 Rome, Italy
1Correspondence: Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Graecia, Via Tommaso Campanella, 115, 88100 Catanzaro, Italy. E-mail:sesti{at}unicz.it
Insulin receptor substrate (IRS) molecules are key mediators in insulin
signaling and play a central role in maintaining basic cellular
functions such as growth, survival, and metabolism. They act as docking
proteins between the insulin receptor and a complex network of
intracellular signaling molecules containing Src homology 2 (SH2)
domains. Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have
been identified that differ as to tissue distribution, subcellular
localization, developmental expression, binding to the insulin
receptor, and interaction with SH2 domain-containing proteins. Results
from targeted disruption of the IRS genes in mice have provided
important clues to the functional differences among these related
molecules, suggesting they play different and specific roles in vivo.
The available data are consistent with the notion that IRS-1 and IRS-2
are not functionally interchangeable in tissues that are responsible
for glucose production (liver), glucose uptake (skeletal muscle and
adipose tissue), and insulin production (pancreatic ß cells). In
fact, IRS-1 appears to have its major role in skeletal muscle whereas
IRS-2 appears to regulate hepatic insulin action as well as pancreatic
ß cell development and survival. By contrast, IRS-3 and IRS-4 genes
appear to play a redundant role in the IRS signaling system. Defects in
muscle IRS-1 expression and function have been reported in
insulin-resistant states such as obesity and type 2 diabetes. Several
polymorphisms in the IRS genes have been identified, but only the
Gly
Arg972 substitution of IRS-1, interacting with
environmental factors, seems to have a pathogenic role in the
development of type 2 diabetes. In contrast, polymorphisms of the other
IRS genes do not appear to contribute to type 2 diabetes.—Sesti, G.,
Federici, M., Hribal, M. L., Lauro, D., Sbraccia, P., Lauro, R.
Defects of the insulin receptor substrate (IRS) system in human
metabolic disorders.
Key Words: insulin signaling • IRS-1 • IRS-2 • IRS-3 • IRS-4 • type 2 diabetes
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