Insulin receptor substrate-2--a new candidate gene for NIDDM?

The pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) includes the development of insulin resistance and, at a later stage, impairment of b-cell response. In the past few years, different elements, including the proto-oncogene, Shc, and the insulin receptor substrate (IRS) proteins, have been found to have important roles in the insulin signaling network. Whithers et al. (1) have now demonstrated that IRS-2 is crucial for intact insulin and b-cell function. By knocking out the IRS-2 gene, they created a mouse model showing the typical features of human NIDDM, including insulin resistance and b-cell dysfunction. Understanding of this discovery is aided by scrutiny of the current model of insulin signaling and the outcome in the IRS-1 knockout mouse (reviewed in (2) and (3)). Insulin binding to its a2b2-heterotetrameric receptor leads to autophosphorylation and activation of the tyrosine kinase of the b-subunit. Even though the subsequent phosphorylation of and interaction with intracellular proteins activates a complex signaling network, two major pathways can be distinguished that diverge at the level of the IRS and Shc. Phosphorylation of Shc by the insulin receptor tyrosine kinase leads to stimulation of the mitogen activated protein kinase (MAPK) pathway, which is involved in mitogensis, but also in glucose clearance, and ultimately results in glucose transporter 1 (GLUT1) translocation to the cell membrane and glycogen synthesis via stimulation of the ribosomal S6 kinase pp90. The link between Shc and MAPK is provided by the growth factor receptor bound (Grb-2) and son of sevenless (Sos), which bind to the phosphotyrosine of Shc and activate the proto-oncogene, p21, by allowing GTP binding. p21 then initiates a cascade of serine/threonine kinases including the raf-1, the MAP kinase-kinase (MEK) and finally the MAPK. The other major pathway consists of tyrosine phosphorylation of members of the IRS family, leading to activation of phosphatidylinositol 3-kinase (PI3-K). This enzyme plays an important part in a variety of biological events including mitogenesis, vesicle sorting, receptor internalization and glucose homeostasis. Stimulation of PI3-K results in protein synthesis via activation of the pp70, and in translocation of GLUT4 which, in contrast to the ubiquitous GLUT1, is exclusively responsible for glucose uptake into insulinsensitive tissues. Most elements that interact directly with IRS, such as PI3-K or the proteins fyn, syp, nck and Grb-2/Sos, contain so-called SH2 (Src homology-2) domains that bind to the tyrosine phosphorylation sites of the IRS protein. As mentioned above, Grb-2 and Sos are also involved in linking Shc with p21, and thereby confer crosstalk of the two pathways by activating ras in an IRS-dependent but also an independent fashion. However, p21 also seems to activate PI3-K directly, providing an additional interaction with IRS signaling. There are also elements lacking SH2 domains (SV40 large T antigen, 14-3-3 proteins, b3 integrins) that bind IRS independently of phosphotyrosine but the role of these elements, and those of fyn, syp and nck, remain unknown. Signal specificity in the Shc or IRS system seems to be conferred by distinct tissue distribution or phosphorylation patterns of the signaling proteins as, otherwise, redundancy is remarkable. In addition to the insulin receptor, a variety of other cell membrane receptors (insulin-like growth factor 1, growth hormone, interleukine (IL) and interferon receptors) use the same intracellular substrates, and several Shc and IRS isoforms have been identified. IRS-1 was first described as a portion of a 185-kDa phosphoprotein (pp185) isolated from insulin-stimulated hepatoma cells by means of precipitation by antiphosphotyrosine antibodies. The surprising facts that the IRS-1 knockout mouse (IRS-1) was not diabetic and had only mild insulin resistance and mainly a 50% growth retardation, suggested the presence of compensatory elements. In fact, pp185 contains a highmolecular-weight portion first noted after IL-4 stimulation and therefore designated 4PS (IL-4 phosphoprotein substrate), which was then cloned from myeloid cells and, because of homology with IRS-1, renamed IRS-2 (4). In common with IRS-1, IRS-2 stimulates PI3-K and provides binding sites for SH2 domains, suggesting that it could substitute for the lack of IRS-1 and be responsible for the mild phenotype of the IRS-1 mice. Accordingly, IRS-2 expression seems to be upregulated in these IRS-1 mutant mice (5). In order to define the role of IRS-2, Whithers et al. (1) inactivated the IRS-2 gene by homologous recombination. The IRS-2 knockout mice (IRS-2) survived, and lack of IRS-2, in addition to normal IRS-1 expression, was confirmed in the tissues of these mutant mice. Interestingly, IRS-2 had a phenotype very distinct from that of IRS-1. Compared with those in wild-type mice, plasma glucose concentrations were already increased 3 days after birth; at 6 weeks of age the mice showed glucose intolerance and fasting hyperglycemia, and at European Journal of Endocrinology (1998) 139 263–264 ISSN 0804-4643 H IG H L IG H T