Speculations on the Action of Insulin, With a Note on Other Hypoglycemic Agents

SPECULATIONS ON THE ACTION OF INSULIN, WITH A NOTE ON OTHER HYPOGLYCEMIC AGENTS* M. E. KRAHL, Ph.D. Insulin is an anabolic hormone which favors storage ofexcess foodstuffs and formation of materials for growth (i). Insulin must be present for other anabolic hormones, such as growth hormone (2, 3) or testosterone (4), to produce optimal effects. The purpose ofthe present paper is to consider the intermolecular interactions entered upon by insulin and to speculate upon the means by which these interactions may facilitate anabolism. The following subjects are dealt with: first, in order to focus attention on the physiological events to be accounted for, tissue responses to insulin are summarized; next, the cellular metabolic events which may be the foci for insulin action are considered ; third, the known chemical interactions of insulin with other molecules and with cells are taken up; finally, a mechanism for the initiation and propagation of insulin action on tissues is proposed. A note on a possible chemical role for other hypoglycemic agents is appended. I. Physiological Responses ofIndividual Tissues to Insulin The detailed effects ofinsulin have been elucidated by observations upon tissue preparations ofvarious degrees ofcomplexity, ranging from whole animals to isolated pieces of muscle, adipose tissue, liver, or mammary gland. The emphasis here is on isolated tissues; the progression to simpler systems is conducive, at least in principle, to an increasing degree of insight into physiological and chemical events; the conclusions drawn must be, * Experimental work of the author has been aided by grants from the Life Insurance Medical Research Fund, from Eli Lilly and Company, and from the Wallace C. and Clara A. Abbott Memorial Fund ofthe University of Chicago. The author is Professor of Physiology, University of Chicago. 69 and appear to be, consistent with observations at all levels of tissue organization . Observations regarding the consequences of insulin excess and deficiency at other levels ofanimal organization have been reviewed elsewhere (5-17); no attempt to cover the complete literature will be made here. Major effects of insulin excess and deficiency upon the metabolism ot isolated tissues in vitro are summarized briefly in Table 1. In addition, insulin deficiency leads, directly or indirectly, to decreased synthesis of hyaluronic acid and chondroitin sulfuric acid in skin (36). Insulin apparently exerts no direct influence on the majority of brain cells (37), whose glucose metabolism is apparently regulated chiefly by the glucose level in the extracellular fluid surrounding them and perhaps by other chemical factors (38). It has been proposed that insulin may influence the metabolism of the anterior pituitary (39, 40). Further consideration of insulin action in this paper will be limited largely to muscle and fiver. More extended studies on isolated adipose tissue would be of value, in view ofthe relatively simple metabolism ofadipose tissue cells. A. STRIATED MUSCLE Insulin increases glucose utilization of eviscerated animals (11, 41-43), the heart-lung preparation (44, 45), the isolated hind limb (46), the isolated heart (47), and the isolated rat diaphragm (8, 10-12, 18). The rat diaphragm has been much studied lately because the effects ofinsulin are sufficiently reproducible to be used as the basis for insulin assay (48-50). As an example, glucose uptake ofnormal diaphragm in Krebs-bicarbonate solution was increased by insulin from 3.6 mg/gm/hr to 6.6 (52).1 Conversely, muscle from diabetic animals has a lower than normal glucose uptake: for the heart-lung preparation from a diabetic dog* Knowlton and Starling (44) found glucose uptake to be nearly zero as compared to the normal rate of4 mg/gm ofheart/hr. Cruickshank and Startup (45) confirmed this and showed that insulin would restore glucose uptake in the diabetic to normal. For the rat diaphragm, Krahl and Cori (20) obtained the following rates ofglucose uptake: for diaphragms from normal rats, 1.8 mg/gm/hr; from diabetic rats, 0.8 without added insulin and 1.4 with insulin added in vitro (see n. 1); Villee and Hastings (21) obtained similar results. I. The absolute rates of glucose uptake vary with the experimental conditions employed. Comparisons are valid only with respect to the concurrent controls. 70 M. E. Krahl · Insulin Action Perspectives in Biology and Medicine · Autumn 1957 TABLE...