Abraham Silvers

Prevalence of Plasma Lipoprotein Abnormalities in a Free-Living Population of the Central Valley, California

In an epidemiologic study of 1,118 free-living volunteers, aged 25 to 79 (552 male, 566 female) drawn from eight counties of the Central Valley, California, the following determinations were included: a medical history, blood pressure, resting electrocardiogram, plasma total cholesterol and glycerides (following a light, fat-free breakfast), and (when lipids were considered to be elevated) plasma lipoproteins determined by electrophoresis. A subgroup of the entire study population (494 male, 503 female) free of overt diabetes and electrocardiographic abnormalities, and with diastolic blood pressure not above 100 mm Hg, that was considered to be clinically “normal,’ forms the basis of this report.Significant sex differences for mean levels of total cholesterol were absent or of small magnitude at all age decades up to and including the seventh. In contrast, glyceride levels for men were significantly higher than for women aged 25-59, and differences were substantial. Beyond the seventh decade, females had higher mean levels of both plasma total cholesterol and glycerides.The type IV lipoprotein pattern was the most common abnormality (8.6%) within the entire normal population and was 2.7 times as common in men (13%) as in women (4.8%). Type II pattern was less common overall (3.7%) and was more frequent in women than in men. Types III (0.2 to 0.4%) and V (0.2%) were both very uncommon, and type I was not encountered. Results were similar when the entire population (normal and abnormal) was considered.These findings suggest that sex differences in plasma total-cholesterol level cannot account for the known male preponderance in coronary heart disease within the population studied. Prolonged elevation of plasma glycerides (usually expressed as the type IV pattern) in males during the years when atherogenesis is occurring might account for the sex difference.

Derivation of a three compartment model describing disappearance of plasma insulin-131-I in man.

Insulin-(131)I was administered intravenously to normal subjects, to patients with maturity-onset diabetes and normal renal function, and to nondiabetic patients with renal failure. The ensuing plasma disappearance curves of immunoprecipitable radioactive insulin were determined, and these data were analyzed in a variety of ways. Firstly, fractional irreversible loss rates of insulin from plasma were calculated and found to be greatly diminished in patients with renal failure (t((1/2)) = 39 min), as compared with normal (t((1/2)) = 15 min) and diabetic subjects (t((1/2)) = 12 min). Secondly, plasma insulin-(131)I disappearance curves were resolved into sums of three exponentials by the method of peeling, and values for the resultant three slopes and half-lives were determined. Patients with normal renal function had similar values for all parameters, while those patients with renal failure were differentiated on the basis of the slope of the last component, with a prolongation of its half-life to 275 min (approximately twice normal). Finally, a three pool model was formulated to describe the kinetics of plasma insulin disappearance in man, representing plasma (pool 1), interstitial fluid (pool 2), and all tissues in which insulin is utilized and degraded (pool 3). The proposed model adequately describing the disappearance curves of insulin-(131)I observed in all patients indicated that volumes (per cent body weight) of pool 1 (4.04) and pool 2 (10.11), calculated on the basis of the model and the experimental data, corresponded closely to estimates of plasma and interstitial fluid volumes obtained by independent means. It also demonstrated that patients with renal failure were characterized by a decreased removal rate of insulin from pool 3 and an increased recycling rate of insulin from pool 3 to pool 2. It is concluded that the proposed model represents a reasonable description of the kinetics of insulin distribution and degradation, and that its use provides quantitative insights into the physiology of insulin metabolism.

Insulin delivery rate into plasma in normal and diabetic subjects

Removal of insulin-(131)I from plasma was studied in normal and diabetic subjects with both single injection and continuous infusion of isotope techniques. Patients were studied either in the fasting state or during steady-state hyperglycemia produced by a continuous intravenous glucose infusion. Steady-state plasma insulin concentration during these studies ranged from 10 to 264 muU/ml. Labeled insulin specific activity time curves consisted of more than one exponential, indicating that a multicompartmental system for insulin metabolism exists. A mathematical technique which is applicable to non-first order processes was used to calculate the rate at which insulin was lost irreversibly from the plasma insulin pool. A direct, linear relationship was found between insulin irreversible loss rate and plasma insulin concentration over the range of concentrations studied. This linearity implies lack of saturability of the insulin removal mechanism. Since the plasma insulin pool was in a steady state during these studies, insulin irreversible loss rate was equal to the rate at which newly secreted insulin was being delivered to the general circulation. Therefore, these results indicate that changes in plasma insulin concentration result from parallel changes in the rate of insulin delivery and not from changes in the opposite direction of the rate of insulin removal. A wide range of insulin delivery rates was found among patients with similar plasma glucose concentrations, suggesting that there exists considerable variability in responsiveness to endogenous insulin among these patients.

Is there a Delay in the Plasma Insulin Response of Patients with Chemical Diabetes Mellitus

We have compared the plasma glucose and immunoreactive insulin responses to oral glucose, intravenous glucose and intravenous tolbutamide of twenty normal subjects with those of eleven patients with chemical diabetes. The two groups were similar in terms of age, sex and degree of adiposity. The insulin response of patients with chemical diabetes was greater at every time interval during all these tests. Thus, we could document no defect in the rapidity of insulin response to these stimuli in patients with chemical diabetes. These results do not support the view that the commonest metabolic abnormality in patients with diabetes is a delay in the insulin response.

Open-loop glucose-insulin control with threshold secretory mechanism: Analysis of intravenous glucose tolerance tests in man

Abstract The shape of the plasma insulin curve during a glucose tolerance test in man suggests that the threshold secretory process, as demonstrated in rat pancreatic perfusions, must be included in a model of insulin secretion, distribution, and removal for analysis of the data. A mathematical model was developed and subsequently applied to the intravenous tolerance test (IVGTT) obtained in human subjects. An important feature of the model is that the IVGTT is essentially a perturbation to an open-loop control system. A nonlinear regression analysis of the IVGTT in 23 normal subjects indicated that the model can account for the variety of insulin response curves found experimentally and provided the parameters of the system.

Study of the Relationship Between Plasma Insulin Concentration and Efficiency of Glucose Uptake in Normal and Mildly Diabetic Subjects

Removal of glucose-U-C-14 from plasma was studied in normal subjects and in patients with maturity-onset diabetes mellitus. All measurements were made after an overnight fast, during a period in which plasma glucose and immunoreactive insulin concentrations were not changing. The mean irreversible loss rate (ILR) of glucose from the plasma of normal subjects was not different from that of patients with diabetes: mean ILR (± the coefficient of variation) of all patients was 1.36 (± 14 per cent) mg. glucose/kg, body weight per min. This narrow range attests to the similarity of ILR in the patients studied. There was no correlation between glucose ILR and plasma glucose concentration, plasma immunoreactive insulin concentration, or ponderal index. In contrast, fractional glucose irreversible loss rate varied considerably from patient to patient, with a coefficient of variation of 35 per cent. Furthermore, there was a strong negative correlation between plasma glucose concentration and fractional glucose irreversible loss rate (r = −0.82, p < .01). This decrease in efficiency of glucose removal from plasma of hyperglycemic patients was not related to an absolute lack of insulin. It is concluded that net glucose utilization in the fasting state is similar in normal and mildly diabetic patients, and that fasting hyperglycemia is due to a decrease in efficiency of glucose removal which cannot be attributed to absolute insulin deficiency.

High risk subjects and the cost of large field trials

IN RECENT years the large-scale field trial designed to test the efficacy of prophylactic treatments has become a major tool in coronary heart disease research. The basic design of such a trial for coronary heart disease or, similarly, chronic degenerative diseases generally, consists of two groups of subjects, designated a control group and an experimental or treatment group. The goal of the trial is to detect a difference in disease incidence (if any) between the two groups. Of central importance in the design of any such trial is the minimum sample size required to show the hypothesized effect. Closely related to this minimum sample size is the selection of criteria to determine the admissibility of subjects to the study. In designing this type of study, investigators tend to favor admission only of high risk subjects to the study. One of the arguments advanced for this policy is that if high risk subjects are entered in the study there will be more opportunity for detection of treatment effects and the number of subjects required for study will be smaller. This paper discusses the relationship between subject selection criteria, sample size and the cost of a field trial and shows that, for the coronary heart disease examples below, the use of higher risk subjects in clinical trials is not generally effective in increasing statistical power or decreasing costs and in certain circumstances can actually decrease the power of the trial. To reach these conclusions we have extended the general methodology in Halperin et al. [l] to include subjects with varying degrees of risk and risk reduction potential. Thus, we consider those situations in which the a priori subject risk is not uniform over all subjects. In such trials higher risk subjects may be preferred for various reasons. Clearly, if the objective is to evaluate some treatment for primary disease, one would choose subjects with the disease-for example, in reno-vascular hypertension, surgery would be performed only on patients with high blood pressure. Sometimes ethics dictates that the subjects be patients in advanced stages of the disease, such as in many phase-I and phase-II studies in the treatment of cancer. In secondary treatment studies, moreover, the subjects are high risk patients by definition-for example, patients who have just recovered from a heart attack.

Digital on line computer display to investigate the structure of metabolic systems

Abstract An on-line digital computer display program is developed for studying the kinetics of metabolic systems. The program provides the capability to simulate the model, to visually observe the results of simulation, and to modify the parameters for attaining a more appropriate simulation in a time period ranging from seconds to minutes. The applicability of this procedure in the development of metabolic models is illustrated in two basically different experimental situations in which isotopes are used. The program is used to develop in man a three-compartment model describing the disappearance of radiolabeled insulin from plasma and a thirteen-compartment model describing the product curve of plasma radiolabeled triglyceride. We demonstrated that the logic, accuracy, and arithmetic capabilities of the digital computer combined with digital graphic on-line procedures provides an effective technique for derivation of physiological models.

Automated digital graphic procedures to study biological systems

Abstract A computer program using a graphic display was devised for studying the kinetics of metabolic systems. The program allows simulation of these systems and immediate observation of the success of these simulations, and provides for automatic modification of the system parameters to obtain optimal fits to data. Examples of the applicability of this method are given which demonstrate its speed and efficiency in different types of experiments relevant to unsolved and complex human biological problems. The program was used to develop a catenary compartmental model describing the distribution of radioactively labeled insulin in plasma and other physiological compartments in man. Its use was further demonstrated in the study of several models that may describe the distribution and degradation of radioactively labeled glucose. To evaluate the uniqueness of these models, the precision of each model parameter was calculated. We felt that a unique model constituted the beginning of a more rigorous study of the metabolic system under consideration.

Relationship between insulin sensitivity and insulin secretion rate: not necessarily hyperbolic.

There is general acceptance that the physiological relationship between insulin sensitivity and insulin secretion is hyperbolic. This conclusion has evolved from studies in which one test assessed both variables, and changes in plasma insulin concentration were used as a surrogate measure for insulin secretion rate. The aim of this study was to see if a hyperbolic relationship would also emerge when separate and direct measures were used to quantify both insulin sensitivity and insulin secretion rate.