Lawrence H. Louis

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 ...

INTERMITTENT ALDOSTERONISM IN PERIODIC PARALYSIS: DEPENDENCE OF ATTACKS ON RETENTION OF SODIUM, AND FAILURE TO INDUCE ATTACKS BY RESTRICTION OF DIETARY SODIUM

WE have reported that spontaneous attacks of periodic paralysis are preceded by large increases of urinary aldo-sterone and by intense retention of sodium (Conn et al. 1956). This is followed shortly by sequestration of potassium within the body, both serum and urinary potassium falling abruptly and intensely. Serum-sodium often rises to abnormally high values as serum-potassium reaches its lowest ones. As the attack subsides a great diuresis of sodium occurs together with a less intense increase of urinary potassium. Serum-sodium and serum-potassium return to normal together. By this time urinary aldosterone has returned to base-line values. We have explored further the role of retention of sodium in setting off potassium sequestration-i.e., acute hypo-kalsemia and hypokaluria. Two young men with the familial type of periodic paralysis were the subjects of this study. One of them, living in our laboratory, submitted cheerfully to 11 months of a rigid metabolic balance regime. The other was studied for 30 days to test in a different person the applicability of the metabolic principles discovered in the first one. The subjects are not related. Fig. I-Induction of episode of periodic paralysis by 2-methyl-9-cx-fluorohydrocortisone and high sodium intake. The aim of this short communication is to disseminate quickly information which is of immediate practical value to patients with this disorder. Extensive data will be published later. At this time we wish merely to outline some of our results and conclusions. Fig. 2-Changes in electrolyte metabolism during episode of periodic paralysis induced by administration of glucose and insulin. Method Two levels of sodium intake were used-8 and 208 m.eq. per day. The composition of the daily ration was otherwise the same, the high sodium regime differing from the low by addition of sodium chloride to the basic diet. Chloride ion, the only other variable, was 27 m.eq. per day on the low, and 229 m.eq. per day on the high, sodium ration. Potassium intake was constant at 132 m.eq. per day. Results Under both of these dietary conditions a series of identical experiments were carried out, each designed to induce an episode of periodic paralysis. The following facts were disclosed : (1) When the diet contained the larger quantity of sodium the administration of glucose and insulin,, or of 2-methyl-9-a-fluorohydrocortisone (an extremely potent mineralocorticoid) produced complete (from the neck down) and prolonged (24-48 hours) paralysis (figs. 1 and 2). (2) When glucose and insulin induce an episode of …

A diabetogenic polypeptide from bovine adenohypophysis similar to that excreted in lipoatrophic diabetes.

Abstract A polypeptide has been isolated from bovine adenohypophysis which antagonizes the hypoglycemic effect of exogenous insulin and which, per se, induces loss of carbohydrate tolerance in men and dogs. Mild acid hydrolysis of the active polypeptide yields a compound which retains the same biological properties. Characteristics of the active principle and its hydrolytic product is the long duration of their activities, the greatest intensity of the effects being observed between 34 and 60 hours after a single intramuscular injection. Both substances are devoid of ACTH activity. The active polypeptide resembles closely the insulin antagonist isolated from the urine of patients with lipoatrophic diabetes previously reported from this laboratory. Details of the isolation and physiologic effects of the active substance and its hydrolytic product are described.

Diabetogenic Polypeptide From Human Pituitaries Similar to That Excreted by Proteinuric Diabetic Patients

A polypeptide exhibiting diabetogenic body weight to dogs resulted in significant and antiinsulin properties has been iso- intolerance to glucose and resistance to lated from human pituitary glands by exogenous insulin 10 and 34 hours a procedure slightly modified from that after injection. Comparison of glucose with which a similar polypeptide was tolerance tests in the same animals dispreviously isolated from the adeno- closes that the diabetogenic potency of hypophysis of cattle, sheep and pigs. The the substance from human pituitaries is isoelectric point of the compound is ap- much greater than that of human growth proximately pH 4.1 which is the same hormone or ovine prolactin. The molecuas that of the compound isolated from lar weight of the substance as determined the adenohypophysis of the other three by the dodecyl sulfate-polyacrylamide gel species and from urine of patients with electrophoresis method is 20,600. A lipoatrophic diabetes and proteinuric dia- modified procedure for the isolation and betics without lipoatrophy. Administra- purihcation of the polypeptide has been tion of 1 mg polypeptide per kilogram of outlined.

A Diabetogenic Polypeptide from Hog and Sheep Adenohypophysis Similar to that Found in Lipoatrophic Diabetes

Abstract A polypeptide possessing physical and biological properties similar to that excreted in the urine by patients with lipoatrophic diabetes was previously isolated from bovine adenohypophysis. A similar principle has now been obtained from the anterior lobes of hog and sheep pituitaries by the same procedures of isolation. The material from these animals also induces hyperglycemia and insulin resistance both in humans and dogs. The substance exhibits no similarity in physicochemical properties to either growth hormone or prolactin. Its presence in the pituitary gland of all three species of animals so far studied suggests that the peptide is a naturally occurring substance but its physiological significance is unknown. Its physicochemical and biological similarity to the urinary polypeptide found in lipoatrophic diabetes suggests a relationship.

A Urinary Diabetogenic Peptide in Proteinuric Diabetic Patients

A polypeptide exhibiting diabetogenic and anti-insulin properties has been isolated from the urine of 33 of the 35 proteinuric diabetic patients. This material could not be found in the urine of 34 normal subjects and 32 diabetic patients without proteinuria. It was, however, detected chemically in one of seven nondiabetic patients with proteinuria, but the amount present was insufficient for biological testing. This polypeptide closely resembles, in physiochemical properties, that obtained from patients with lipoatrophic diabetes, as well as that isolated from the adenohypophyses of beef, sheep, and swine. The isoelectric point of the active polypeptide from all the above sources is approximately pH 4.1. In one diabetic subject who underwent hypophysectomy, this material disappeared from the urine following the operation. It is suggested that the source of the active principle isolated from the urine of diabetic patients with proteinuria is probably the pituitary gland. (Metabolism 18: No. 7, July, 556563, 1969) I N 1963 WE REPORTED that the urine of patients with lipoatrophic diabetes contains a diabetogenic po1ypeptide.l This has recently been confumed by others.2 We demonstrated that the peptide was capable of impairing glucose tolerance and of inducing insulin resistance when administered either to dogs or humans. The present study was designed to explore the possibility that a similar substance might be found in the urine of diabetic patients without lipodystrophy since a chance observation had disclosed its presence in an obese, maturity-onset diabetic. l Freshly collected urine samples from 67 diabetic patients and 34 healthy subjects have been studied. The diabetogenic peptide was found in the urine of 33 of 35 diabetics with proteinuria but it was absent in all of 32 diabetics without proteinuria, as well as in the normal subjects. Seven additional subjects with proteinuria but without diabetes were studied. One of them exhibited a similar urinary material.

Induction of hyperinsulinemia and hyperglycemia in dogs by administration of diabetogenic bovine pituitary peptide.

Abstract A peptide exhibiting diabetogenic and anti-insulin properties isolated from bovine adenohypophysis was administered subcutaneously in single doses to four dogs for 2 to 3 consecutive days. Ten hours after each injection, the animals were given an oral glucose load and a series of blood samples were obtained for glucose and insulin determinations. In one dog, the procedure was repeated 13 days after the first one. In another animal, the same procedure was carried out three times. Glucose tolerance was clearly impaired and serum insulin rose excessively in three of the four animals. In the fourth animal the response was observed but only after the third injection. Thus, insulin resistance appears to be a major mechanism by which this peptide induces loss of carbohydrate tolerance.

METABOLIC EFFECTS OF SULFONYLUREAS IN NORMAL MEN and IN VARIOUS TYPES OF DIABETIC PATIENTS

The studies described in this report were initiated in an effort to elucidate the mechanism of action of the sulfonylurea compounds. It seemed to us that a broad clinical investigative approach, involving the study of a large number of conditions in which the metabolism of carbohydrate is disturbed, was most likely to eliminate quickly a number of possible modeg of action and to define more sharply the areas upon which further effort should be concentrated. Thus, extensive metabolic-balance studies and numerous individual testing procedures have been performed before, during, and following the administration of carbutamide (BZ-55) and/or tolbutamide (Orinasei) in the following subjects: (1) healthy young men; (2) three middle-aged, obese, stable diabetics; ( 3 ) an unstable diabetic of normal weight; (4) a patient with lipo-atrophic diabetes; ( 5 ) a totally depancreatized woman; (6) patients with coexisting diabetes mellitus and Addison’s disease, familial diabetes and Cushing’s syndrome, and diabetes and panhypopituitarism; and (7) an acromegalic with mild diabetes. Although the data reported below do not define a specific mode of action of the sulfonylurea compounds, they eliminate from consideration a number of important possibilities. Results

Glycostatic effect of a diabetogenic non-growth-promoting pituitary polypeptide☆

Abstract 1. 1. Treatment with a mg. of a non-growth-promoting bovine diabetogenic peptide or growth hormone in two divided doses, one at the beginning and one 7–9 hours later, to hypophysectomized rats during a 24-hour fast maintained their muscle glycogen at a normal level. 2. 2. Administration of bovine serum albumin or saline was accompanied by a sharp decrease of muscle glycogen. 3. 3. The minimum dose of highly purified bovine diabetogenic peptide which is capable of maintaining muscle glycogen at normal levels was found to be 0.2–0.3 mg. in 135–150-g. rats. 4. 4. Diabetogenic peptide maintains muscle glycogen in fasted hypophysectomizedadrenalectomized rats. 5. 5. Diabetogenic peptide does not promote growth as measured by the tibia test.

Lipoatrophic diabetes: an improved procedure for the isolation and purification of a diabetogenic polypeptide from urine.

N A PREVIOUS communication we described a method for isolating a diabetogenic polypeptide from the urine of patients with lipoatrophic diabetes.l This substance, designated as fraction 1, was shown to provoke insulin antagonism and loss of glucose tolerance when administered to dogs and men. Isolation of the compound and demonstration of its diabetogenic activities have now been confirmed.* However, interpretation of the results was somewhat clouded by the occurrance in man of mild toxic effects which included myalgia, cephalalgia and pyrexia. Further purification of the material was initially achieved by somewhat drastic treatment of the material with O.lN hydrochloric acid at a temperature of 100” C. From this solution an