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Insulin Binding a-a Link

0(-Subunits

figure 7-29 Schematic model of the insulin receptor tetramer. The a-subunits, which are entirely extracellular, consist of 735 amino acids and define the insulin-binding site. The two a-subunits are joined to each other by a disulfide bond; each a-subunit is also linked to a /3-subunit by a disulfide bond. The fi-subunits span the membrane; they have 193 extracellular amino acids, 23 transmembrane amino acids organized in an a-helix, and an intracellular domain of 402 amino acids. The approximate locations of the various domains are indicated. [Modified with permission from Kahn, C. R., and White, M. F. (1995). Molecular mechanism of insulin action. In "Endocrinology" (L. J. DeGroot, M. Besser, H. G. Burger, J. L. Jameson, D. L. Loriaux, J. C. Marshall, W. D. Odell, J. T. Potts, Jr., and A. H. Rubenstein, eds), 3rd edi., Vol. 2, 1373-1388. W. B. Saunders Co., Philadelphia. PA.]

Ligand binding Cooperativity

Signal transduction Substrate binding Internalization

Kinase activation

Kinase activation Divergent effects

? Role in growth regulation figure 7-29 Schematic model of the insulin receptor tetramer. The a-subunits, which are entirely extracellular, consist of 735 amino acids and define the insulin-binding site. The two a-subunits are joined to each other by a disulfide bond; each a-subunit is also linked to a /3-subunit by a disulfide bond. The fi-subunits span the membrane; they have 193 extracellular amino acids, 23 transmembrane amino acids organized in an a-helix, and an intracellular domain of 402 amino acids. The approximate locations of the various domains are indicated. [Modified with permission from Kahn, C. R., and White, M. F. (1995). Molecular mechanism of insulin action. In "Endocrinology" (L. J. DeGroot, M. Besser, H. G. Burger, J. L. Jameson, D. L. Loriaux, J. C. Marshall, W. D. Odell, J. T. Potts, Jr., and A. H. Rubenstein, eds), 3rd edi., Vol. 2, 1373-1388. W. B. Saunders Co., Philadelphia. PA.]

ras proteins are known to bind GTP in analogy with the G proteins.

As indicated in Figure 7-28, one of the principal cytoplasmic effects of the activated insulin receptor is to stimulate glucose uptake in muscle and adipose tissue. The principal pathway for glucose entry into the cell is via a Na+-independent glucose transporter, which facilitates the movement of glucose down a concentration gradient (outside to inside the cell).

There is a family of glucose transporter isoforms (see Table 7-9). From the perspective of insulin action, the most important transporter is GLUT-4; it is expressed in the prime target organs of insulin action, e.g., skeletal and cardiac muscles and adipose tissue. GLUT-4 is a 520-amino acid protein that can span the cell membrane 12 times (see Figure 7-31). It is believed that the response of insulin to stimulate the cellular uptake of glucose is mediated via energy-dependent recycling of the GLUT-4 (where it is catalytically inactive) from intracellular vesicles to the cellular membrane, where it catalyzes glucose uptake into the cell. Thus, when the insulin receptor is occupied, GLUT-4 moves to the cell membrane, and following removal of insulin the GLUT-4 returns to its intracellular pool. Exactly how insulin receptor kinase activation is coupled to glucose transporter migration remains to be elucidated.

B. Biological Actions

1. Introduction

The principal biological actions of insulin and glucose are complex and interdependent upon the presence or absence of the partner hormone and the delicate balance of anabolism and catabolism that is occurs throughout the body in response to changes in caloric intake, caloric composition, and the degree of physical activity. In most situations the roles of insulin and glucagon are antagonistic. Tables 7-10 and 7-11, respectively, summarize the actions of insulin and glucagon in their principal target tissues, the liver, muscle, and adipose tissue. Also, it should be appreciated that the fundamental intermediary metabolism capabilities of these three tissues and their "normal" oxidative substrates vary depending upon the prevailing metabolic condition. The actions of insulin and glucagon in the liver, muscle, and adipose tissue will be discussed separately. Figure 7-32 compares the major metabolic effects that are found in the absence and presence of insulin for liver, muscle, and adipose tissue.

2. Liver

The liver performs an indispensable role in maintaining an adequate blood level of glucose. It possesses the enzymatic capability either to generate glucose

Hormones, Second Edition

Glucose

Other 1RS's

Glucose

Other 1RS's

"IP-Receptor"

Level I

Level II

FIGURE 7-30 Model of insulin actions in a generic target cell. The responses to occupancy of the insulin receptor occur at three levels. Other details of the insulin receptor and signal transduction are presented in Figures 7-25 and 7-26. Abbreviations: IRS-1, insulin receptor substrate-1; PI 3'-kinase, phosphatidylinositide-3'-kinase; ras protein, a GTP-binding protein; MAP kinase, see text for discussion; PI-3,4,5-P, phosphatidylinositide-3,4,5-P3; Raf1. [Modified with permission from Kahn, C. R., and White, M. F. (1995). Molecular mechanism of insulin action. In "Endocrinology" (L. J. DeGroot, M. Besser, H. G. Burger, J. L. Jameson, D. L. Loriaux, J. C. Marshall, W. D. Odell, J. T. Potts, Jr., and A. H. Rubenstein, eds), 3rd edi., Vol. 2, pp. 1373-1388. W. B. Saunders Co., Philadelphia. PA.]

"IP-Receptor"

Growth & Gene Expression

Glycogen Synthesis

Protein Synthesis

Level I

Level II

Level III

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