George J. Hamwi

Serum Insulin, Carbohydrate, and Lipid Abnormalities in Patients with Premature Coronary Heart Disease

Excerpt Abnormal glucose metabolism and elevated serum lipids have been intimately related to atherosclerosis. Coronary atherosclerosis is more prevalent in diabetics than in nondiabetics (1). Conv...

Experimental Diabetic Glomerulosclerosis

With the advent of adequate replacement therapy for diabetes mellitus and the subsequent prolongation of life, degenerative vascular disease has become a problem of paramount importance. Unfortunately the study of degenerative vascular disease is complicated by its chronicity. The nodular glomerular lesions described by Kimmelstiel and Wilson in 1936 remain obscure in origin, but—if critical histologic criteria are met—represent a form of degenerative vascular disease seen only in patients with diabetes mellitus. The study of these lesions as well as of degenerative vascular disease in general would benefit greatly by the availability of an experimental method for the rapid production of diabetic glomerulosclerosis. In 1951 Rich et al reported that rabbits treated with cortisone for three weeks developed nodular glomerular lesions. Following this report we undertook the study of glomerular changes produced by the administration of various adrenal CQrtical steroids in the hope that we might produce typical diabetic glomerulosclerosis.

Observations on the Mechanism of Action of Clomiphene (MRL-41)

Serial follicle stimulaint hormone (FSH) and luteinizing hormone (LH) determinations (by the methods of Steelman and Pohley and Parlow respectively) in 4 23-53 year old anovulatory patients given short-term clomiphene treatment (100-400 mg orally/day for 6 days) were employed in studying the mechanism of clomiphene action. Serial determinations of 3 estrogens (estrone estradiol and estriol) were also determined using thin-layer absorption chromatography before Kober color development. FSH levels rose in all cases during or immediately following clomiphene therapy. LH did not rise prior to a rise in estrogens. The estradiol fraction was found to contain at least 3 different components. During clomiphene therapy the estradiol fraction fell. Since the estradiol fraction was composed of 2 compounds in addition to estradiol and since it fell during treatment it was postulated that it was the unidentified estrogens whose excretion had decreased. It was suggested that this fall in unidentified estrogens may be responsible for the increase in FSH release observed during treatment.

The Mechanism of Action of Hypoglycemic Guanidine Derivatives

Renewed interest in guanidine derivatives as possible oral therapeutic agents in the treatment of diabetes has followed the discovery by Ungar et al. that certain biguanides are hypoglycemic agents of low toxicity. This report is concerned with the mechanism of action of this new group of compounds as exemplified by one of them, phenethylbiguanide (DBl), as compared with that of other guanidine derivatives. As long ago as 1918, Watanabe showed that guanidine elicited a pronounced hypoglycemic response in rabbits. However, the toxic manifestations of this substance precluded its trial as a possible therapeutic agent in diabetes mellitus. An intensive search by Frank et al. led to the synthesis of decamethylenediguanidine (Synthalin) which was found to exhibit enhanced hypoglycemic activity associated with markedly diminished toxicity. However, after intensive clinical trial the therapeutic use of Synthalin as an oral hypoglycemic agent was abandoned. Disagreeable side effects including nausea and weakness were frequent. Furthermore, except for lowering blood sugar and diminishing glycosuria, Synthalin therapy did not really correct the aberrant metabolism of the diabetic individual. Elevations in blood and urinary lactate, citrate and other organic acids were observed. In a balance study of diabetics undergoing Synthalin therapy, Kaufmann-Cosla and Vasilco found that urinary glucose was supplanted by large excretions of other organic compounds.

Alterations in adrenal cortical function in fasting obese subjects

Abstract The effect of short periods of starvation on adrenal function was evaluated in a group of obese females. Normal plasma cortisol levels were maintained during the fast period, while urinary excretion of 17-hydroxycorticoids, 17-ketosteroids, and unconjugated 11-hydroxycorticoids fell. Evidence indicates that a reduction of cortisol secretion occurs during brief periods of fasting. In addition, the measurement of urinary 11-hydroxycorticoids may be a rapid and efficient method for differentiating exogenous obesity from Cushings syndrome.

The diabetogenic action of human growth hormone: Glucose - fatty acid interrelationships

Abstract Intravenous glucose tolerance was determined in seven normal subjects. Growth hormone administered 4 1 2 hours prior to the tests resulted in an elevation of plasma free fatty acids and an impairment in glucose tolerance. When 5 - methylpyrazole - 3 - carboxylic acid, an inhibitor of lipolysis, was administered 4 1 2 hours prior to the tests, there was a significant decrease in plasma free fatty acid levels and a slight improvement in glucose tolerance which was not statistically significant. When both compounds were administered 4 1 2 hours prior to the tests, the circulating free fatty acid levels were low and glucose tolerance was significantly improved when compared to the results seen after growth hormone alone but significantly impaired when compared to the results seen after administration of the pyrazole derivative alone. It is concluded that the impairment of glucose tolerance produced by growth hormone is partially but not entirely mediated by the elevated plasma free fatty acid levels produced by the hormone. The mechanism responsible for the residual impairment is unknown.

A Rapid Test for Adrenocortical Insufficiency

Excerpt The use of repeated infusions of adrenocorticotrophic hormone (ACTH) requiring 24-hour urine collections for 1 to 3 days has gained widespread acceptance in defining the functional integrit...

Clinical utility of chemical induction of ovulation

Abstract The capacity of clomiphene (MRL-41) to induce ovulation in cases of secondary amenorrhea or irregular anovulatory menses of unknown etiology was evaluated in 32 patients. In 18 patients with secondary amenorrhea the compound induced at least two successive ovulatory menstrual cycles, as judged by vaginal smears and basal body temperature changes in 9 patients (50 per cent). An additional 3 patients (17 per cent) ovulated irregularly. Four pregnancies occurred in this group. Eleven (79 per cent) of 14 patients with irregular anovulatory menses ovulated regularly while taking this drug. Five pregnancies occurred in this group. Two dosage schedules were evaluated: 100 mg. per day for 20 days each month, and 200 mg. per day for 5 days only each month. In patients with irregular anovulatory menses there was no difference in the results with the two dosage schedules. In the group with secondary amenorrhea, however, the longer dosage schedule gave much better results. The major complication of therapy was the development of ovarian cysts in 19 patients (59 per cent), which regressed with cessation of therapy. The incidence of cysts decreased to 7 per cent with the short dosage schedule. Four patients had hot flashes similar to those seen in menopause. No other significant side effects were noted. The induction of ovulation in humans by the administration of clomiphene appears to be a useful therapeutic approach to the problems of patients with secondary amenorrhea or irregular anovulatory menses of unknown etiology. Studies on the mechanism of action of this drug will also lead to a better understanding of reproductive physiology.

Studies on the mechanism of the production of the testicular feminization syndrome

Abstract Studies in a patient with testicular feminization are reported. Evidence is presented that the gonads produce testosterone as measured in the gonadal vein blood and in the urine. Urinary testosterone levels increased in response to gonadal stimulation with Pergonal and decreased following gonadectomy. Low normal urinary levels of estrogen persisted following gonadectomy despite the administration of large amounts of testosterone. In vitro studies of the gonad demonstrated their biosynthetic capacity to produce testosterone. Administration of large doses of exogenous testosterone for a period of three months produced no manifestations of virilization. It is concluded that the syndrome represents end organ unresponsiveness to testosterone. This unresponsiveness was demonstrated after gonadectomy, and it is therefore unlikely that it is due to gonadal secretion of an antiandrogenic substance [19].

Metabolic abnormalities in premature coronary disease: effects of therapy.

Although the cause of atherosclerosis is unknown, many factors that are thought to increase the risk of developing clinical manifestations of the disease have been identified in man. Hemodynamic stresses, local trauma, thromboses, and metabolic injuries may increase the susceptibility of the arterial wall to degenerative changes.”l Other factors such as cigarette smoking, obesity, hypertension, and genetic influences have been reported to increase the risk of developing coronary heart d i ~ e a s e . ~ In the past two decades, a great deal of interest has been directed to the biochemical factors associated with atherosclerosis. The association of elevated serum lipid levels with vascular disease, and the premature development of atherosclerosis in patients with diabetes mellitus, have been demonstrated r e ~ e a t e d l y . ~ . ~ Also, individuals who have suffered a coronary occlusion a t an early age frequently have been noted to have lipid and carbohydrate a b n ~ r m a l i t i e s . ~ ’ ~ ’ ~ Insulin, a hormone fundamental to the regulation of both glucose and lipids, responds abnormally in a number of conditions. The serum insulin response to a glucose load in maturity-onset diabetes is characterized by a delayed secretion, and the levels are often elevated. Elevated or abnormal insulin levels have been reported in patients with essential hypertension, those with peripheral occlusive disease, and those with coronary heart disease.’l 1 Abnormal insulin responses have also been noted in association with high plasma triglycerides independent of clinical diabetes. ’* Obesity, another condition thought to predispose to coronary heart (artery) disease, is also associated with hyperinsulinism. It seemed reasonable, therefore, to extend the search for the various metabolic abnormalities that may be associated with the atherosclerotic process. Twenty-five patients with premature coronary heart disease were examined to determine the presence of abnormalities in serum lipids, glucose tolerance, or serum immunoreactive insulin response to a load of glucose. Experience obtained in the treatment of patients with diabetes mellitus has demonstrated that phenethyl biguanide (phenformin) lowers blood sugar, serum lipids, and insulin levels, the biochemical parameters that were found to be frequently abnormal in this group. Therefore, the response of these patients to treatment with phenformin was studied.