Trends in Endocrinology & Metabolism
Tissue-specific roles of IRS proteins in insulin signaling and glucose transport
Introduction
Diabetes mellitus results from a combination of defective insulin secretion from pancreatic β cells and failure of peripheral tissues to respond to the hormone. Recent developments reveal that at the core of both defects lie alterations in the insulin receptor substrate (IRS) proteins, in particular the IRS1 and IRS2 isoforms 1, 2. Tyrosine phosphorylation of these proteins constitutes the first event beyond activation of the IR tyrosine kinase that unleashes the intracellular transmission of insulin signals. Moreover, IRS1 and IRS2 are also integrators of feedback signals and communication from other cellular pathways that participate in fine-tuning insulin action and, when overstimulated, might contribute to the genesis of insulin resistance. A paramount need in the field is to understand the relative contributions of each of these two isoforms in insulin signaling and in the development of insulin resistance.
Studies over the past few years have revealed that many tissues in the body respond to insulin and contribute to carbohydrate, lipid, ion and protein metabolism. Hence, in addition to the classical insulin-responsive tissues (liver, muscle and adipose), insulin also elicits responses in the kidney, brain and β cells, among others. One of the best-documented metabolic action of insulin is the stimulation of glucose uptake by muscle and adipose cells, brought about by a gain in plasma membrane levels of glucose transporters, predominantly the glucose transporter 4 (GLUT4) isoform. Here, we review the quest to unravel the distinct and overlapping roles of IRS1 and IRS2 in diverse organs, with a particular focus on insulin-dependent GLUT4 translocation in muscle and fat cells.
Section snippets
Structural organization of IRS proteins
IRS proteins have no intrinsic catalytic activity but contain several domains that mediate interaction with the receptor and with IRS effectors. An amino-terminal pleckstrin homology (PH) domain is adjacent to a phosphotyrosine-binding (PTB) domain, and the carboxy-terminal domain encodes numerous tyrosine and serine residues prone to phosphorylation 3, 4, 5. No Src homology 2 or 3(SH2 or SH3) domains have been identified in IRS proteins. The PTB domain interacts with the
IRS isoforms
IRS1 was first identified in hepatoma cells using an antiphosphotyrosine antibody and was subsequently identified in several tissues, including muscle, heart, liver, adipocyte and kidney [9]. IRS1 has a molecular size of 131 000 kDa and migrates with an apparent molecular weight of 185 000 on SDS–polyacrylamide gels. The PH domain of IRS1 is required to elicit an optimal signal response, although the precise mechanism by which this is achieved is unclear. When this domain is deleted,
IRS and glucose uptake via GLUT4 in adipose cells in culture
Muscle and fat tissues are the main sites responsible for dietary glucose uptake. GLUT4 is the predominant glucose transporter isoform expressed in these tissues, where insulin causes GLUT4 translocation from intracellular storage sites to the plasma membrane 21, 22.
Intense effort has been directed to dissecting the specific contribution of each IRS isoform to the regulation of glucose uptake (Table 1). In earlier studies, overexpression of human IRS1 in rat adipose cells increased the level of
Glucose homeostasis in IRS1 and IRS2 gene knockout mice
To better understand the role of individual IRS isoforms in the diverse molecular mechanisms activated by insulin, gene knockout mice were developed with selective annulment of the IRS1 [27] or IRS2 [2] genes. Analysis of metabolic indices and physiological parameters in tissues from these mice supported the concept that each of these proteins has unique functions. Mice homozygous for targeted disruption of the IRS1 gene were retarded in embryonic and postnatal growth. Although these mice did
IRS protein reduction in immortalized cell lines
As highlighted above, IRS1 and IRS2 knockout mice reveal a whole-body interplay of signals, including compensatory outcomes. However, because the animals are insulin resistant, with varying degrees of hyperinsulinemia, hyperglycemia and dyslipidemia impinging on insulin signaling in peripheral tissues, the direct effects of IRS1 and IRS2 within each tissue is difficult to evaluate. To overcome this problem, the relative contribution of IRS1 versus IRS2 to glucose uptake and GLUT4 translocation
Concluding remarks
IRS proteins are sites of diversification of insulin outcomes, and these proteins display distinct functions, although when their natural level of expression is altered, there might be compensatory responses. These responses are tissue- and cell-type-specific, making the repertoire of physiological actions of these proteins diverse and intricate. Gene knockout in animals offers the opportunity to understand complex phenotypes and organ-to-organ communication and compensation. However, to
Acknowledgements
We thank Phil Bilan for critical reading of this manuscript. The work from the authors' laboratory reviewed was supported by grants from the Canadian Diabetes Association and the Canadian Institutes of Health Research.
References (59)
The pleckstrin homology domain in insulin receptor substrate-1 sensitizes insulin signaling
J. Biol. Chem.
(1995)Heterologous pleckstrin homology domains do not couple IRS-1 to the insulin receptor
J. Biol. Chem.
(1997)Interaction of insulin receptor substrate-2 (IRS-2) with the insulin and insulin-like growth factor I receptors. Evidence for two distinct phosphotyrosine-dependent interaction domains within IRS-2
J. Biol. Chem.
(1996)Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591-786
J. Biol. Chem.
(1996)Insulin receptor substrate (IRS)-2 is dephosphorylated more rapidly than IRS-1 via its association with phosphatidylinositol 3-kinase in skeletal muscle cells
J. Biol. Chem.
(1997)Dynamics of insulin signaling in 3T3-L1 adipocytes. Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2
J. Biol. Chem.
(1998)Use of bismannose photolabel to elucidate insulin-regulated GLUT4 subcellular trafficking kinetics in rat adipose cells. Evidence that exocytosis is a critical site of hormone action
J. Biol. Chem.
(1993)Insulin receptor substrate 1 mediates the stimulatory effect of insulin on GLUT4 translocation in transfected rat adipose cells
J. Biol. Chem.
(1994)Role of insulin receptor substrate-1 and pp60 in the regulation of insulin-induced glucose transport and GLUT4 translocation in primary adipocytes
J. Biol. Chem.
(1997)Insulin receptor substrate-2 is not necessary for insulin- and exercise-stimulated glucose transport in skeletal muscle
J. Biol. Chem.
(1999)