<p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p> <p>A central component of type 2 diabetes and the metabolic
syndrome is insulin resistance. Insulin exerts a multifaceted
and highly integrated series of actions via its intracellular
signaling systems. Generation of mice carrying null mutations
of the genes encoding proteins in the insulin signaling
pathway provides a unique approach to determining the
role of individual proteins in the molecular mechanism of
insulin action and the pathogenesis of insulin resistance and
diabetes. The role of the four major insulin receptor substrates
(IRS1-4) in insulin and IGF-1 signaling have been
examined by creating mice with targeted gene knockouts.
Each produces a unique phenotype, indicating the complementary
role of these signaling components. Combined heterozygous
defects often produce synergistic or epistatic effects,
although the final severity of the phenotype depends
on the genetic background of the mice. Conditional knockouts
of the insulin receptor have also been created using the
Cre-lox system. These tissue specific knockouts have provide
unique insights into the control of glucose homeostasis
and the pathogenesis of type 2 diabetes, and have led to development
of new hypotheses about the nature of the insulin
action and development of diabetes.</p>
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Exp Diabesity Res. 2003; 4(3):169-182