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COMMENTS TWENTY YEARS LATER M. E. KRAHL* The principal themes of the preceding article are embodied in the following quotations therefrom: 1."To account for the manifold effects of insulin, a single mechanism of action is proposed. According to this scheme, insulin interacts with specific structural molecules of extracellular-intracellular boundaries, thereby initiating a series of intermolecular rearrangements which are propagated along the boundary and into the cell interior. . . . This action accounts for all the experimental findings and includes other current speculative mechanisms, such as facilitation of glucose transport, as special cases." "The problem of explaining the action of insulin . . . has thus become a problem in solid-state physics." "The consequences of insulin action fall into two categories: immediate effects . . . and delayed effects." 2."More extended studies on isolated adipose tissue would be of value, in view of the relatively simple metabolism of adipose cells." 3."It seems clear . . . that substances interacting with insulin will prove to be legion and that even the anti-insulin substances associated with a given situation such as diabetes or acidosis will vary in properties according to the species, genetic makeup, and other attributes of the individual donor." "The glucose uptake of excised diaphragms is lowered by prior injection of anterior pituitary products into hypophysectomized diaphragm *Department of Physiology, Stanford University, Stanford, California 94305. It is rare indeed for an author's predictions to be resurrected after 20 years, and perhaps unprecedented that he be invited to comment on them after so long a time span. I am immensely indebted to Dwight Ingle, the founder oíPerspectives, for the invitation to write the original article and for facilitating the publication of the derived monograph [I]. I am especially grateful to Richard Landau, the editor ??Perspectives, for the invitation to submit these comments. I must confess that I have recalled only the most successful extensions of my earlier speculations and ignored the rest. Perhaps a success rate of 1% for working hypotheses, as pointed out by several predecessors, does justify the effort. Because of space limitations I am unable to record important contributions by many investigators. I offer my apologies and refer to more complete coverage elsewhere [1-3]. Perspectives in Biology and Medicine ¦ Autumn 1977 | 31 donors. . . . The effect is obtainable only by injection and not by addition of the agents to the diaphragm in vitro." These themes were reviewed at Toronto on the fiftieth anniversary of the discovery of insulin [4]. My current comments follow: 1. Insulin interaction with membranes. —Insulin-sensitive cells have specific insulin receptors; insulin derivatives and related substances compete with insulin to a degree proportionate to their insulin-like activity [5-7]. The insulin receptor appears to be a glycoprotein with a molecular weight of about 300,000 [8]. It is located in the lipoprotein matrix of the membrane; destruction of the lipoprotein by phospholipases A or C, or digestion with neuraminadase, blocks the transmission of the insulin stimulus from the receptor [8]. Specific loci in the insulin molecule that are recognized by the receptor have been elucidated by solid state X-ray studies and allied chemical and biological investigations [9]. The critical amino acids and their positions in the A and B chains are, in approximate sequential arrangement: GIn (A5), GIy (Al); Tyr (A19), Tyr (B26), Phe (B25), Phe (B24); Asn (A21), GIy (B23), Arg (B22); Tyr (B16), Val (B12). The insulin stimulus is propagated from the receptor through the membrane and to the cell interior by one or more second messengers (controllers) to influence various metabolic events. One form of control is to increase the transport into the cell of watersoluble substrates such as glucose [10, 11] and certain amino acids [1214 ]. A second form of control by insulin is to suppress [15] the formation of cyclic AMP, to enhance cyclic AMP degradation [16], or perhaps to interfere with cyclic AMP action [17].1 A third form of control by insulin is to stimulate transport into the cell OfMg2+ and K+ via appropriate membrane ATPases [18, 19] and to alter the distribution of Ca2+ between cell compartments [20]. In particular, the adjustment ofMg2+ concentrations may provide a means for regulating the translation step in protein synthesis [21]. Insulin...


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