Frank L. Engel

A Lipolytic Action of Epinephrine and Norepinephrine on Rat Adipose Tissue in vitro.

Summary Epinephrine and norepinephrine stimulate production of nonesterified fatty acids from rat adipose tissue when incubated in vitro in rat plasma, presumably by stimulating the hydrolysis of neutral fats within the tissue. Incubation under nitrogen markedly inhibits this effect of epinephrine and appears to increase production of fatty acids from control tissues. The d-isomers of epinephrine and norepinephrine are much less active in this system than the physiological 1-isomers. indicating a specificity in tissue response. Some implications of this lipolytic activity are discussed.

Fat Mobilization by Purified Corticotropin in the Mouse.

Summary Purified corticotropin and growth hormone both stimulate lipid mobilization from the epididymal fat depots of fasting mice. Hydrocortisone failed to induce lipid loss in intact mice and inhibited fat mobilization in adrenalectomized mice, indicating that the lipid mobilizing effect of corticotropin is not mediated by adrenal stimulation. Furthermore, inhibition of fat loss by hydrocortisone in adrenalectomized mice could be overcome by simultaneous administration of corticotropin. The results demonstrate an extra-adrenal action of corticotropin on fat mobilization in the intact animal similar to that induced by growth hormone.

A congenital, familial syndrome of adrenocortical insufficiency without hypoaldosteronism*

Summary Congenital adrenocortical insufficiency is reported in a boy whose male sibling died shortly after birth with no identifiable adrenal tissue at postmortem examination. Evidence is presented to support the belief that this represents a syndrome of congenital, familial, selective hydrocortisone deficiency. Clinical and laboratory investigation of the surviving sibling indicated an apparently complete absence of 17-hydroxycorticosteroid production, even after prolonged ACTH administration, in spite of normal aldosterone excretion while on ad lib. sodium intake. Suggestions as to a possible etiology in this condition are discussed.

Extra-adrenal Actions of Adrenocorticotropin

Publisher Summary Until recently, the concept has been firmly entrenched that the tropic hormones are devoid of action on tissues other than their respective target glands. From time to time in the past, extra-adrenal actions have been attributed to adrenocorticotropin (ACTH), but usually they were either discounted by the demonstration of an active contaminant in the hormone preparation used or were dismissed on the grounds that they were due to a contaminant which had not been detected. While ACTH has been isolated from the adenohypophysis, purified, and characterized as a polypeptide consistsing of 39 amino acids, it, has not been proved that the hormone which is secreted to act on the adrenal cortex has the same structure as the active peptide prepared chemically. Indeed, several investigators have suggested that there is a corticotropin precursor. This problem is not unique for ACTH, as is apparent from the recent claim that the physical properties of both circulating as well as extractable insulin in the pancreas are quite different from those of crystalline or partially purified insulin. Most hormones are now recognized as existing in the blood in forms bound to proteins. These must be dissociated before they become biologically active. In this chapter, the present status of the extra-adrenal actions of ACTH is reviewed. Consideration is given not only to those which seem well established, but also to others which are questionable, either because of uncertainty concerning the purity of the hormone or the techniques used, but which deserve to be reinvestigated by more reliable methods. Implications concerning the relationship of the structure of ACTH and its functions arise from the studies of extra-adrenal actions and are discussed.

HORMONAL ASPECTS OF KETOSIS

The problem of ketosis has just been considered from the biochemical viewpoint, with emphasis on the mechanism by which the liver synthesizes ketone bodies and the peripheral tissues utilize them (Bressler, 1962). This review examines ketosis from the physiological standpoint by evaluating some of those factors that influence the net balance of ketone body production and utilization by the whole organism and which thereby determine whether or not ketosis occurs. Ketosis is defined here as a state in which ketone bodies accumulate in the extracellular fluid in concentrations greater than during conditions of carbohydrate plenty. It results whenever ketogenesis by the liver exceeds ketone body utilization by other tissues. I t is generally a physiological phenomenon, reflecting those alterations in metabolism that normally accompany a shift from carbohydrate to fat metabolism, but may be pathological as a concomitant of the profound disturbance in carbohydrate utilization of diabetes mellitus. It becomes of clinical significance to the physician and veterinarian whenever ketonemia is great enough to cause acidosis or to exert toxic effects on tissues, such as the brain. Reduced to its simplest terms, ketosis may be expected to develop whenever the availability of Carbohydrate in the metabolic mixture is relat,ively or absolutely deficient in relation to the amount of fat being cataboliaed. Under any given condition, in turn, the utilizability of the carbohydrate available is determined by the amount of insulin which can be supplied. Thus the metabolic key to ketosis is utilizable carbohydrate and the endocrine key to carbohydrate utilizability is insulin. All other factors are of secondary importance. In TABLE 1 are listed some of the circumstances in which lipide catabolism is disproportionately great in relation to Carbohydrate utilization and in which, therefore, ketosis may be expected to occur. It is clear from this list that the same end may be reached by different routes. Thus, carbohydrate supply may be relatively or absolutely inadequate in the

The significance of the metabolic changes during shock

While shock is an ever-present problem in medicine, it assumes increased importance during war when mass military and civilian casualities occur. Without adequate measures for the prevention and treatment of shock, it is safe to say that a high proportion of the injured would succumb to this malady. Since World War I, great strides have been made in both the understanding and the therapy of this syndrome. Almost all investigators will, now agree that, with the proper use of transfusions of whole blood plasma, or appropriate blood substitutes, shock can be prevented or successfully overcome in the vast majority of injured. In a small proportion of cases, however, once peripheral circulatory failure is initiated, it seems to progress relentlessly to death despite seemingly adequate therapy. When continued bleeding, infection, and other complications are eliminated as sustaining factors in the shock of these individuals, this situation is referred to as irreversible shock and represents a special challenge both for investigation as well as treatment. Because of the proven value of blood and blood substitutes in all but so-called irreversible shock (and even “irreversibility” sometimes indicates inadequate use of blood), major emphasis in the shock problem has rightly been in the direction of processing and storing whole blood and plasma as well as in developing new and better blood substitutes to overcome the problem of understandable limitations in the supply of human blood and its derivatives. Farther removed from the immediate practical problems related to shock have been those investigations concerned with the metabolic aspects of the shock problem. Prior to World War 11, only isolated and sporadic observations had been made in this area. During this conflict, systematic studies on the metabolic pattern of shock were undertaken in a number of laboratories, notably those at Yale, Toronto, Wisconsin, Columbia, Vanderbilt, Harvard, and the University of Sheffield in England. There has evolved from these studies a fairly well-defined metabolic pattern, the description of which is the subject of this dissertation. Various investigators entered this problem with different objectives, such as the demonstration of the appearance of a toxic metabolite following injury or shock which might initiate or sustain shock, or proof of a specific metabolic failure of one or more vital organs to which might be attributed irreversibility of shock. None of these objectives was achieved. I t can be safely stated that the only definite conclusion which can now be reached from these studies is that, with the exception of some of the earlier alterations, all of the metabolic changes described during shock can be attributed to the consequences of hypoxia affecting different organs and tissues of the body to varying degrees

The electroencephalogram in acth and cortisone treated patients

Abstract 1. 1. In 40 courses of therapy (of 37 patients treated with ACTH or cortisone) EEGs were evaluated before and during treatment. 2. 2. The EEG was unchanged in 19 or 47.5 per cent and showed questionable improvement in nine or 22.5 per cent, for a total of 70 per cent. 3. 3. The EEG showed marked or definite improvement during treatment, in 7 of 12 patients in this series who had abnormal control electroencephalograms. Thus, 32.4 per cent of the patients had abnormal pre-treatment records and 58.7 per cent of these showed definite improvement. 4. 4. EEG abnormalities progressed or developed in only four of 37 patients, and in one, the abnormal changes were attributed to the progression of the disease process, and not the effect of the hormone. 5. 5. There was no specific EEG correlation with electrolyte changes and mental changes during the treatment. 6. 6. The occurrence of abnormal EEGs in some patients with rheumatoid arthritis, lupus erythematousus and periarteritis nodosa is noted.

THE INSULIN-GLUCOSE TOLERANCE TEST. A MODIFIED PROCEDURE FOR THE DETECTION OF HYPOGLYCEMIA UNRESPONSIVENESS IN PITUITARY AND ADRENAL INSUFFICIENCY

described the application of three carbohydrate tolerance tests to the diagnosis of disturbances in the endocrine control of metabolism. These were the glucose tolerance test, the insulin tolerance test, and the glucose-insulin tolerance test. When properly employed and interpreted, these tests are of considerable value. However, in practice, the insulin tolerance test has often proven disappointing in those situations in which it should be most valuable, i.e., conditions characterized by hypoglycemia unresponsive-ness. Characteristically in adrenal and pituitary insufficiency, and less so in hyperinsulinism, the response to insulin is somewhat exaggerated and the spontaneous rise in blood sugar after hypogly-cemia is much retarded. This is clear from the data of Fraser et al., when the individual curves for patients with hypopituitarism and Addisons disease are compared with the mean of the nor-mals, or conversely, when cases of myxedema or anorexia nervosa are compared to the mean of the panhypopituitary group. However, in practice , we have found considerable overlapping between the curves from cases of panhypopituitarism and Addisons disease and those from cases of myxedema and anorexia nervosa and with the normals, which makes individual curves-difficult to evaluate. While varying degrees of adrenal and pituitary insufficiency may occur in myxedema and anorexia nervosa, it is doubtful whether all the abnormal insulin tolerance tests in these conditions have this origin. Furthermore, the intravenous injection of insulin into patients with panhypopi-tuitarism or Addisons disease is attended by a very definite risk of severe or even fatal hypo-glycemia. For this reason, Fraser et al. recommended that one-half or one-third the usual dose of insulin be given to patients seriously suspected of suffering from these conditions. Often this results in equivocal responses and the necessity for repeating the test. Even in presumably normal individuals the symptoms of hypoglycemia may sometimes be sufficiently distressing as to make it desirable to terminate the procedure by giving glucose. The purpose of this communication is to describe a modification of the insulin tolerance test, the insulin-glucose tolerance test, which was designed to overcome some of the disadvantages of the former test. It is based on the observation by Somogyi (2) that in normal individuals the administration of glucose 30-60 minutes after insulin, i.e., during hypoglycemia, resulted in the development of greater hyperglycemia than the administration of the same amount of glucose without insulin. Thus, glucose magnified the normal homeostatic response to hypoglycemia. This response is presumably mediated by the …

Fatty Acid and Ketone Metabolism during Hemorrhage and Shock in the Rat.

Summary 1. Sublethal hemorrhage in the normal fasted rat without a significant rise in plasma amino nitrogen is followed by a prompt suppression of fasting ketosis but is without effect on the increase in blood ketones consequent to a 30-minute intravenous infusion of sodium octanoate. 2. Hemorrhagic shock with rising plasma amino nitrogen levels is associated with a significant and progressive hypoketonemia and an inhibition of the rise in blood ketones ordinarily seen after sodium octanoate infusion. 3. Adrenalecto-mized rats exhibit the same decline in blood ketone levels during hemorrhage and shock as do normal rats. 4. The significance of these results with respect to effects of hemorrhage and shock on ketone production and utilization in the rat is discussed.

Effect of Adrenocorticotropic Hormone and Cortisone Therapy on Human Plasma Aminopeptidase Activity.

Summary and conclusions 1. In a small control series the normal range of human plasma L-leucylglycylglycine-splitting (LGGase) activity has been established. 2. In 2 patients who responded to ACTH and Cortisone therapy, the pre-treatment LGGase activities were abnormally high and, concurrent with clinical remissions, plasma LGGase activities fell to normal levels only to rise again with onset of clinical relapses after cessation of therapy. 3. In 4 patients who did not respond to hormonal therapy, no change in plasma LGGase activity occurred irrespective of whether pre-treatment levels were high or normal. 4. Plasma LGGase activity was normal in a patient with Cushings syndrome and in a patient with Addisons disease but was significantly elevated in a second patient with Addisons disease complicated by arthritis. 5. These studies lend credence to the hypothesis that changes in plasma LGGase activity reflect changes in clinical status and are not necessarily mediated through the adrenal cortex.