Jerome W. Conn

Stimulation of insulin secretion by amino acids.

In previous studies we have demonstrated that in healthy subjects the ingestion of protein meals results in large increases in plasma levels of insulin and have concluded that this is an important physiologic phenomenon (1, 3). In those experiments the magnitude of the increases in plasma insulin exceeded that expected from the small increases in plasma leucine measured (3). In addition, chlorpropamide pretreatment failed to accentuate the protein-induced changes in blood glucose and plasma free fatty acids (3), although it greatly augments such leucine-induced changes (4, 5). These findings suggested that amino acids other than leucine or amino acids in combination with leucine stimulate the release of insulin (1, 3, 6). The studies described below were performed to assess in healthy subjects the effects upon plasma levels of insulin of the administration of single amino acids and combinations of amino acids with and without leucine. Essential 1 I-amino acids were administered intravenously individually or as mixtures. Plasma levels of insulin, amino nitrogen, free fatty acids, and blood levels of glu-

Clinical characteristics of primary aldosteronism from an analysis of 145 cases

Abstract With the passage of time the clinical characteristics of primary aldosteronism have been clearly defined. The condition is an easily recognized and fascinating form of curable hypertension. A small number of cases of primary aldosteronism with severe secondary renal damage will present difficulties in diagnosis. This should not distract attention from the cases in which the diagnosis is simple and straightforward. In three quarters of these cases a dramatic cure is produced by surgical removal of a small adrenal cortical adenoma. In the remainder significant improvement can be expected following surgery. Pitfalls in diagnosis have been charted.

An Approach to the Prediction of Diabetes Mellitus by Modification of the Glucose Tolerance Test with Cortisone

A large proportion of presently nondiabetic individuals who have a family history of diabetes mellitus will eventually manifest the disease. If one could separate those who harbor the potentiality for diabetes from those who do not, further study of inciting factors would be possible. It is conceivable that impairment of reserve isletcell function may exist in such individuals even though carbohydrate tolerance can be demonstrated to be normal at the present time. The present study was begun in 1950 with the following objectives: to attempt to unmask the potential diabetic who manifests normal carbohydrate tolerance by present testing methods; and to determine whether or not the established diabetogenic activity of corticotropin and/or cortisone could be used to bring to the surface a subclinical defect in the metabolism of carbohydrate. It became necessary, as the initial step in this investigation, to establish a single testing dose of either corticotropin (ACTH) or cortisone which would not modify significantly carbohydrate tolerance in people with no family history of diabetes, but which would modify significantly carbohydrate tolerance of a considerable number of individuals with known family histories of diabetes mellitus. This has been accomplished and forms the basis of one of our major findings, namely, that 24 per cent of presently nondiabetic relatives of diabetics react to this test in a specific way, while this same response is observed in the control group in but 3 per cent of subjects. As will be detailed below, the total dose of cortisone employed in this test is 100 or 125 mg. of cortisone administered orally as two doses during an eight and one half-hour period prior to the oral glucose tolerance test.

Insulin secretion in response to protein ingestion.

W\e have reported previously that the oral or intravenous administration of the amino acid l-leucine to healthy subjects results in increases in plasma insulin and decreases in blood glucose and plasma free fatty acids (2, 3). After the administration of leucine to healthy subjects pretreated with either chlorpropamide or tolbutamide (2, 3), and also to some patients with functioning islet cell tumors of the pancreas (4), increments in plasma leucine caused increases in plasma insulin and decreases in blood glucose that were significantly greater than those observed in healthy subjects not pretreated with sulfonylurea drugs. Wehave also shown that increased release of insulin from the pancreatic beta cells is the mechanism by which leucine increases peripheral levels of insulin (5). Wesuggested that a rising plasma level of leucine is a physiologic stimulus for the release of insulin, and that the more pronounced sensitivity to leucine hypoglycemia produced experimentally by. administration of sulfonylureas and observed in some patients with idiopathic hypoglycemia or insulin-secreting tumors of the pancreas represents a great exaggeration of a normal physiologic phenomenon (6, 7). In an effort to determine the effect of leucine on insulin release under physiologic circumstances, protein meals rich in leucine were fed to healthy subjects, and the levels of plasma insulin, leucine, amino nitrogen, free fatty acids, and blood glucose

Effect of Amino Acids and Proteins on Insulin Secretion in Man

Following the demonstration that administration of leucine accentuates the hypoglycemia of some patients with “idiopathic hypoglycaemia of childhood” (1956) and of some patients with pancreatic islet cell tumours (1959) we initiated studies to explore the mechanism of leucine-induced hypoglycaemia. Sensitivity to leucine-hypoglycaemia can be induced consistently in healthy subjects after administration of sulfonylurea compounds. Increased release of pancreatic insulin is the primary mechanism by which leucine causes a fall in blood glucose in sulfonylurea-induced as well as in naturally occurring leucine hypoglycaemia. Experimentally-induced sensitivity to leucine hypoglycaemia can be used as a model for the further study of leucine hypoglycaemia. Potentiation of insulin activity has not been demonstrated to play a role in the production of leucine-induced hypoglycaemia in man. Leucine induces release of insulin and lowers blood glucose in healthy subjects without prior administration of hypoglycaemic agents, but to a quantitatively lesser extent than in sulfonylurea-induced leucine hypoglycaemia. The more pronounced sensitivity to leucine hypoglycaemia produced experimentally by administration of sulfonylureas and that observed in some patients with “idiopathic hypoglycaemia” or functioning islet cell tumours represents a great exaggeration of what appears to be a normal physiological phenomenon. To determine the effect of leucine on insulin release under physiologic circumstances, protein meals (cooked beef or chicken liver) rich in leucine were fed to healthy subjects. The increases in plasma insulin which resulted from the ingestion of the protein meals were considerably greater than those which would have been expected to have resulted from the modest increases in plasma leucine which occurred. These findings suggested that amino acids other than leucine or amino acids in combination with leucine stimulated the release of insulin. Essential 1-amino acids, either as mixtures or individually, were administered intravenously to healthy subjects. The various mixtures — whether they contained leucine or not — and most, but not all, of the individual amino acids stimulated the release of insulin. The most effective stimulus for insulin release was either a mixture of 10 essential amino acids or arginine given alone. Histidine was ineffective. Thus, the phenomenon of amino-acid-induced release of insulin does not depend on the presence of leucine in the infusion mixture. A variety of individual amino acids, induce the release of insulin, but there are large differences among these amino acids in their capacities to stimulate its secretion. Increases in blood glucose observed during some of the amino-acid infusions cannot be the major cause of the increases in plasma insulin. Rising plasma levels of certain amino acids after protein feeding can be considered to be physiologic stimuli for the secretion of insulin. It is speculated that the purpose of the insulinogenic response to protein ingestion is to aid in the utilization of absorbed amino acids and in their synthesis to protein. Leucine and arginine themselves, rather than one of their metabolites, are the potens stimuli to insulin release when these amino acids are administered. The mechanism by which leucine induces insulin release differs from that by which the other essential amino acids induce release of insulin. The magnitude of insulin secretion induced by the administration of mixtures of amino acids or ingested proteins depends not only upon the amount administered but also on the synergism between particular amino acids and in the case of mixed meals of protein and carbohydrate upon synergism between amino acids and glucose as well. Administration of human growth hormone and adrenalcortical steroids increases the sensitivity of the pancreatic islet cells to the insulin-releasing stimulus of amino acids. In non-obese, mildly diabetic subjects, increases in plasma insulin after administration of the 10-amino-acid mixture and of arginine were smaller than in healthy subjects. The history of the study of “leucine hypoglycaemia” and related phenomena is an example of how the exploration of a seemingly uncommon metabolic aberration observed in pathologic states and its experimental reproduction may lead to the recognition of what appear to be important physiologic relationships. In this instance the participation of amino acids in control of secretion of insulin (and also of growth hormone and glucagon) have evolved.

Primary aldosteronism, a new clinical entity.

Excerpt Aldosterone, the newly discovered normal adrenal secretory product,1-6has attracted the attention of a great many clinical investigators because of its apparent role in the pathogenesis of ...

Synergistic Effect of Essential Amino Acids and Glucose upon Insulin Secretion in Man

Arginine, leucine, or histidine, and glucose were each administered intravenously, in 30-gm. amounts on separate occasions to the same healthy subjects. Each of the amino acids and glucose in these same amounts were administered also as mixtures. Synergism in the stimulation of the release of insulin was demonstrated when the sum of the increases in plasma insulin which resulted from the separate administrations of an amino acid and glucose was exceeded by that obtained when they were administered as a mixture. A synergistic effect was exerted by each of the three amino acid-glucose combinations; it was greatest with arginine and glucose and least with histidine and glucose. Synergism probably results from the effects of these stimuli upon the pancreatic beta cell; it is not dependent upon humoral gastrointestinal factors released after the ingestion of these nutrients.

EVIDENCE THAT INSULIN RELEASE IS THE MECHANISM FOR EXPERIMENTALLY INDUCED LEUCINE HYPOGLYCEMIA IN MAN

In a previous report (1), we have described studies dealing with the experimental induction in man of sensitivity to leucine hypoglycemia. In healthy subjects, marked sensitivity to leucine hypoglycemia was consistently induced by prior administration of sulfonylureas, compounds that are known to stimulate islet-cell activity. On the other hand, after pretreatment with Novo Ultralente insulin, administration of leucine produced decreases in blood glucose levels that, although significant, were small and inconsistent. A modest but significant hypoglycemic effect was also produced in some healthy subjects by administering leucine without prior administration of hypoglycemic agents ( 1, 2). The magnitude of these decreases in blood glucose levels was similar to that observed after administration of leucine to subjects pretreated with Ultralente insulin. From the results of these studies, we concluded that in man release of additional insulin is the primary mechanism by which leucine decreases the blood sugar in experimentally induced sensitivity to leucine hypoglycemia. Earlier reports had demonstrated an increase in concentration of plasma insulin during leucine-induced hypoglycemia, both in infants with idiopathic hypoglycemia (3-5) and in patients with islet-cell tumors (1, 6-8). The present study, employing an immunoassay for insulin, was undertaken to determine the relationship between endogenous insulin and the induction of experimentally induced leucine hypo-

Postural Augmentation of Plasma Renin Activity and Aldosterone Excretion in Normal People

Peripheral plasma renin activity and aldosterone excretion rates have been measured in normal people during recumbency, recumbent exercise, tilting, and continuous ambulation. Upright posture induces a prompt elevation in peripheral plasma renin activity beginning in 15 minutes and peaking between 60 and 120 minutes. Aldosterone excretion is increased during 120 minutes of upright posture and correlates directly with the elevation in renin activity. Upright posture induces increased plasma renin activity regardless of the level of sodium intake in the preparatory diet. Concomitant measurements of endogenous creatinine clearance and the rates of excretion of sodium and potassium suggest that a fall in renal arterial perfusion resulting from upright posture induces increased release of renin and the subsequent secondary stimulation of aldosterone secretion. Our data indicate that the changes in plasma renin activity are due to changes in the amount of the enzyme rather than to changes in other elements of the reninangiotensin systm. This report discusses the physiologic importance of postural augmentation of renin production, emphasizing that for proper interpretation of values of plasma renin activity, posture as well as dietary factors must be considered and controlled.

Spontaneous Hypoglycemia as an Early Manifestation of Diabetes Mellitus

Among the many causes of spontaneous hypoglyia, functional hyperinsulinism is the one most frequently encountered. During the past several years we have been impressed by the large number of patients whose chief complaints are suggestive of functional hyperinsulinism (weakness, nervousness, tremor, hunger and sweating occurring several hours postprandially), but whose glucose tolerance tests disclose the presence of mild and usually unrecognized diabetes mellitus. The features which distinguish the oral glucose tolerance curve seen in these latter patients from the one observed in functional hyperinsulinism are shown in figure i and are detailed in table i. The purpose of this communication is to report our analyses of n o cases of mild diabetes with secondary hypoglycemia which have been observed at University Hospital during the past six years. Our findings indicate (i) that mild untreated diabetes mellitus is frequently associated with periodic, symptomatic spontaneous hypoglycemia, and (2) that symptoms of hypoglycemia occurring three to five hours after meals represent the earliest clinical manifestation of diabetes in many cases.