Cellular Events Defining Insulin Action

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Understanding the cellular mechanism(s) of action in the insulin-sensitive tissues responsible for insulin resistance would be important in the goal of identifying its genetic basis. Further, an understanding of the cellular defect would allow both the development of effective therapies and optimal use of current therapies.

As stated, the aspect of insulin resistance that has been the most well described is inefficient glucose uptake and utilization in peripheral tissues in response to -o insulin stimulation (1,5). Specifically, this is represented by a reduction in the |

insulin-stimulated storage of glucose as glycogen in both muscle and liver in vivo (1,5). The primary mechanism in muscle appears to be a block in the glucose g transport and phosphorylation step and both genetic and environmental factors appear to induce this defect (5). A brief overview of the cellular factors regulating Ja insulin action will be presented in order to fully understand the potential cellular abnormalities contributing to insulin resistance.

Figure 2 Schematic representing clinical and laboratory findings in the natural history of type 2 diabetes. (Reprinted with permission from Ref. 92.)

The insulin signaling cascade, which results in the biological action of insulin in insulin-sensitive peripheral tissues (e.g., fat or muscle) begins with specific binding to high-affinity receptors on the plasma membrane of the target tissue (Fig. 3) (21,22). The insulin receptor is a large transmembrane protein consisting of a- and P-subunits. Insulin initiates its cellular effects by binding to the a-subunit of its receptor (whose structure establishes the specificity for insulin binding) and thus leads to the autophosphorylation of specific tyrosine residues of the P-subunit (21,22). The P-subunit possesses tyrosine kinase activity and this process enhances the tyrosine kinase activity of the receptor toward other protein substrates. Considerable evidence demonstrates that activation of insulin receptor kinase plays an essential role for many, if not all, of the biological effects of insulin (21-24). Further, insulin receptor tyrosine kinase plays a major role in signal transduction distal to the receptor, as activation results in tyrosine phos-phorylation of insulin receptor substrates (IRSs), including IRS-1, IRS-2, IRS-3, IRS-4, Grb-2, and SHC (21,22,25-29). The IRS proteins are cytoplasmic pro- |

teins with multiple tyrosine phosphorylation sites that, following insulin stimulation, serve as ''docking sites'' for cytosolic substrates that contain specific recog- g nition domains, termed SH2 domains (Fig. 3) (30-32). These structural domains <j on the IRS proteins provide an extensive potential for interaction with down- M stream signaling molecules via the multiple phosphorylation motifs, including p85^/p, p50, Grb-2, SHP-2, and Nck (21,22,25-32). Thus, since the divergence a

Figure 3 Schematic representing proposed signals in the insulin signaling cascade. (Reprinted with permisson from Ref. 117.)

of insulin signaling pathways within the cell may reside at the level of the IRS docking proteins, the IRS proteins have been appropriately referred to as the ''metabolic switches'' of the cell.

The specific cellular events promoting glucose uptake after insulin stimulation are less well defined but appear to involve the enzyme phosphatidylinositol-3 kinase (PI-3 kinase). Insulin stimulation increases the amount of PI-3 kinase associated with IRS, and PI-3 kinase activity is directly activated by docking with the IRS proteins (21,22,26,27,31). Specifically, binding of IRSs to the regulatory subunit of phosphatidylinositol-3-OH kinase at SHC homology 2 domains results in activation of PI-3 kinase, which appears necessary for insulin action on glucose transport (33-36), glycogen synthesis (37), protein synthesis (38), antilipolysis (34), and gene expression (39). As activation of PI-3 kinase appears to be of crucial importance for glucose transporter (e.g., Glut-4) translocation from intra- -o cellular vesicles to the plasma membrane after insulin stimulation (34,40,41) and |

glycogen synthase (GS) activation (two major cellular events of insulin action), £

the study of upstream intracellular signals (e.g., IRS phosphorylation, PI-3 kinase g activity) that regulate glucose uptake and glycogen synthesis would provide a cellular basis for understanding insulin resistance. Activation of PI-3 kinase also appears to be critical for transducing the metabolic effects of insulin, as inhibition

& u of PI-3 kinase activation blocks insulin's ability to stimulate glucose transport. However, other growth factor receptors have been shown to activate PI-3 kinase to the same extent as the insulin receptor, but they do not stimulate glucose transport. Therefore, it appears that, although PI-3 kinase is necessary for the action of insulin, it is not sufficient in and of itself to account for the glucose uptake process. Thus, current evidence suggests that IRS proteins increase tyrosine phosphorylation after insulin stimulation and bind to and regulate intracellular enzymes containing SH2 domains. As such, the IRS proteins serve as a ''docking site'' for several adaptor proteins and this allows the cellular signal to diverge throughout the target cell (21,22,26,27,30-32).

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