Title:Divergent Roles of IRS (Insulin Receptor Substrate) 1 and 2 in Liver and Skeletal Muscle
Volume: 24
Issue: 17
Author(s): Sabine Sarah Eckstein*, Cora Weigert and Rainer Lehmann
Affiliation:
- Division of Clinical Chemistry and Pathobiochemistry, Central Laboratory, University Hospital Tübingen, 72076, Tübingen,Germany
Keywords:
Insulin receptor substrate, skeletal muscle, liver, metabolism, insulin resistance, phosphorylation, degradation.
Abstract: IRS1 and IRS2 are the most important representatives of the IRS protein family
and critical nodes in insulin/IGF1-signaling. Although they are quite similar in their structural
and functional features they show tissue-specific differences. In this review, we outline the
functions of IRS1 and IRS2 in skeletal muscle and liver with regard to their importance for
metabolism, growth and differentiation. Mechanisms contributing to IRS1 and IRS2 dysregulation
in disease states as well as consequences thereof are discussed. IRS1 plays the dominant
role in skeletal muscle. It is crucial for normal growth and differentiation of myofibers,
insulin-dependent glucose uptake and glycogen synthesis. The presence of IRS2 in skeletal
muscle is negligible for insulin-induced glucose uptake and the general role of IRS2 in muscle
is still not fully understood. In liver IRS1 and IRS2 are important to mediate insulindependent
regulation of glucose and lipid metabolism and complement each other in the diurnal
regulation thereof. IRS1 in the liver is more important for signaling in the late refeeding
period, whereas IRS2 signaling is mostly dominating in the period directly after food intake
and during fasting. Importantly, the expression level of IRS1 and IRS2 is different within the
liver lobule, which could be an explanation for the phenomenon of selective insulin resistance.
Dysregulated muscular or hepatic abundance and/or phosphorylation status of IRS1 and
IRS2 are important factors in the pathogenesis of insulin resistance, type 2 diabetes and muscle
wasting.
