Effect of acute uremia on insulin removal by the isolated perfused rat liver and muscle

The effect of acute uremia on insulin removal by liver and muscle was investigated by measuring the extraction of porcine insulin during recycling perfusion of isolated liver and hindlimb from nephrectomized rats. Insulin removal by the liver was not affected by uremia, and hepatic extraction of insulin by normal and uremic livers averaged 38% at perfusate insulin concentrations ranging from 50 to 600 μU/ml. In contrast, insulin extraction by normal hindlimb averaged 13.4% at comparable insulin concentrations, and this was reduced to 4.3% as a result of acute uremia. A similar reduction in insulin extraction was noted when hindlimb from uremic animals was perfused with normal blood media or when normal hindlimb was perfused with uremic blood. These findings indicate that the efficiency of insulin removal by the liver is unaffected by uremia and is approximately threefold higher than that for hindlimb muscle. On the other hand, it is apparent that skeletal muscle, by virtue of its mass and relatively high blood flow, is also an important organ system for insulin removal. Furthermore, the data suggest that the 68% reduction in insulin extraction by hindlimb from uremic rats may contribute to the prolongation of insulin removal from plasma that is characteristic of patients with renal failure.     

Plasma glucose and insulin responses to oral glucose in nonobese subjects and patients with endogenous hypertriglyceridemia

Plasma glucose and insulin responses to a 50-gm oral glucose challenge were determined in 396 nonobese subjects: 220 patients with endogenous hypertriglyceridemia and 176 normal persons. These groups were further subdivided on the basis of relative body weight: 1.0-1.1 and 1.1-1.2. Patients with endogenous hypertriglyceridemia whose obesity index was between 1.0 and 1.1 had significantly increased plasma glucose (more than 25%, P less than 0.001) and insulin (more than 18%, P less than 0.01) responses. Similar findings were also observed in patients with endogenous hypertriglyceridemia whose index of obesity was between 1.1 and 1.2, ie, there was a 25% increase in the plasma glucose response (P less than 0.001) and a 37% increase in the plasma insulin response (P less than 0.001). Thus, endogenous hypertriglyceridemia can occur in nonobese individuals, and these patients have an increase in their plasma glucose and insulin responses when weight-matched with nonobese normal subjects.     

Age-related changes in very low density lipoprotein metabolism in normal rats

Plasma triglyceride (TG) concentrations rise with age, and we have carried out studies of very low density lipoprotein (VLDL) kinetics in the rat in an effort to define the cause of this phenomenon. Efficiency of VLDL-TG secretion by perfused rat liver decreases as rats age from $\text{1}\text{1}\text{2}\text{–12}\text{mo}$. However, this is compensated for by an increase in liver weight, and VLDL-TG secretion per perfused liver does not change with age. In contrast, total VLDL-TG secretion by the intact rat increases significantly as rats grow from $\text{1}\text{1}\text{2}\text{–12}\text{mo}$ of age, and this increase is proportionate to the age-related increase in liver weight. The ability of the older rat to maintain VLDL-TG secretion proportionate to liver weight is most likely due to the concomitant rise in plasma free fatty acid concentration that occurs with age. However, the efficiency with which VLDL-TG is removed from plasma is not maintained as rats age. Consequently, the age-related rise in plasma TG concentration is due to an increase in VLDL-TG secretion proportionate to secretory mass, accompanied by a relative decline in efficiency of VLDL-TG removal from plasma.     

Functional homogeneity of pancreatic islets of aging rats

Islets from different regions of pancreases of aging rats were compared for size and variations in response to glucose stimulation. The results show that pancreatic islets from the ventral-duodenal and splenic regions of 12-mo-old retired breeder Spraque-Dawley rats are comparable in all respects measured: thus, pancreatic regional differences cannot explain the age-associated reduction in beta cell secretory response noted in previous studies.     

Ability of exercise to inhibit carbohydrate-induced hypertriglyceridemia in rats

The ability of spontaneous running to prevent carbohydrate-induced hypertriglyceridemia was studied in young, nonobese rats. Exercise-trained and sedentary rats were fed a diet consisting of (as percent total calories) 12% fat, 22% protein, and 66% carbohydrate. The source of the carbohydrate was varied, and experiments were carried out with sucrose and glucose as the sole dietary carbohydrate. Plasma triglyceride (TG) levels rose in response to both forms of dietary carbohydrate in both sedentary and exercise-trained rats, but the magnitude of the elevation was greatly attenuated in the exercise-trained group. Plasma insulin concentrations were also significantly lower in exercise-trained rats. Measurements of hepatic very low density lipoprotein (VLDL)-TG secretion rate and adipose tissue lipoprotein lipase (LPL) activity were made in an effort to determine how exercise-training prevented the development of carbohydrate-induced hypertriglyceridemia. The results of these studies indicated that perfused livers of exercise-trained rats secreted significantly less VLDL-TG, whereas adipose tissue LPL activity of the two groups was similar. On the basis of these results, it is postulated that the ability of exercise-training to inhibit carbohydrate-induced hypertriglyceridemia is due to an increase in insulin sensitivity resulting from chronic exercise. As a result, the postprandial insulin responses to high carbohydrate diets would be relatively reduced in exercise-trained rats, leading to decreased hepatic VLDL-TG secretion, and lower plasma triglyceride concentrations.     

Hyperinsulinemia in fructose-induced hypertriglyceridemia in the rat

Rats were fed diets containing (as percent of calories) 66% glucose or fructose, 22% casein, and 12% lard, for 1 wk. The effects of these diets on plasma triglyceride, glucose, and insulin concentrations were compared to those of control rats eating regular rat chow. Plasma triglyceride levels increased from a mean (± SE) control level of 85 ± 7 to 142 ± 9 (p < 0.001) and 380 ± 38 (p < 0.001) mg/dl in dextrose- and fructose-fed rats, respectively. Plasma insulin concentrations demonstrated a similar increase, rising from a mean (± SE) control value of 29 ± 4 μU/ml to 55 ± 10 μU/ml in dextrose-fed rats and to 85 ± 12 μU/ml in rats eating the fructose diet. Plasma glucose concentrations of the three groups were comparable. These results indicate that fructose-induced hypertriglyceridemia is associated with significant hyperinsulinemia.     

Relationship between insulin resistance,insulin secretion,very low density lipoprotein kinetics,and plasma triglyceride levels in normotriglyceridemic man

We have previously postulated that resistance to insulin-mediated glucose uptake was the basic metabolic abnormality in patients with endogenous hypertriglyceridemia. In this situation, glucose tolerance would tend to deteriorate, and could only be maintained by the increased secretion of insulin. Although the ensuing hyperinsulinemia might prevent the development of glucose intolerance, we suggested that it would also lead to increased hepatic very low density (VLDL) triglyceride (TG) synthesis and secretion. In the current study we have quantified these four metabolic variables in 16 nonobese human subjects with plasma TG concentrations < 175 mg/dl. The results demonstrate the following degree of correlation: insulin resistance

insulin response to food

VLDL-TG secretion rate

plasma TG concentration. These data indicate that nonobese subjects with normal TG levels have the same relationship between degree of insulin sensitivity, insulin response to food, VLDL-TG secretion, and TG concentration previously described in patients with endogenous hypertriglyceridemia.     

Effect of fructose feeding on insulin secretion and insulin action in the rat

Insulin secretion and insulin action were studied in rats fed either a diet containing (as percent of calories) 66% fructose, 22% protein, and 12% fat, or standard rat chow (60% vegetable starch, 29% protein, 11% fat) for 7 days. Plasma glucose concentration following either an oral glucose or fructose load ($\text{180 mg}\text{100 g body weight}$) were slightly higher in the fructose-fed rats, and this was associated with a much greater elevation of plasma insulin concentrations. The ability of insulin to stimulate disposal of glucose load was determined during the continuous infusion of epinephrine, propranolol, glucose, and insulin. Under these conditions the steady state plasma insulin levels were the same in the two groups of rats, whereas the steady state plasma glucose levels were almost twice as high in the fructose fed rats. Thus, fructose feeding for 7 days resulted in an increase in the insulin response to an oral carbohydrate challenge, as well as to a loss of normal insulin sensitivity.     

Removal of insulin by perfused rat liver: Effect of concentration

The kinetics of insulin removal by isolated rat liver were investigated by measuring the rate of disappearance of insulin from the perfusate during recycling perfusion and by comparing the extraction of insulin over a wide range of constant arterial hormone levels during nonrecycling perfusion. In the recycling studies, insulin was removed from the perfusing medium at a uniform rate between 5 and 45 min. The reaction velocity constant, or hepatic clearance, during this period of uniform disappearance averaged 1.8 ml/min and represented 34% of the volume flow through the liver. In the nonrecycling flow-through studies at constant arterial insulin concentration, an initial period of accelerated hepatic uptake of insulin was seen. This period lasted for 3 to 7 min, was seen at every level of arterial insulin concentration, and was followed by a period of constant hepatic insulin removal. The hepatic removal rate during the period of constant uptake increased in a linear fashion until arterial insulin concentration reached 500 μU/ml and attained a maximal value at concentrations over 800 μU/ml. These findings indicate that the time course of hepatic insulin uptake by the perfused rat liver consists of two phases—an initial rapid phase, possibly associated with insulin binding, followed by a sustained rate of insulin removal, which probably represents insulin utilization and degradation. The rate of hepatic insulin removal was found to be proportional to arterial insulin concentration over a range of 20 to 500 μU/ml. Above this concentration, hepatic removal processes became saturated, reaching a maximal value of 183 μU of insulin per gram of liver per minute.     

Evidence of an age-related decline in mitochondrial glycerophosphate dehydrogenase activity of isolated rat islets

The activities of three enzymes--two mitochondrial and one microsomal--were measured in isolated islets of Langerhans from 2-month-old and 12-month-old rats. Mitochondrial glycerophosphate dehydrogenase activity (expressed as nanomoles of iodonitrotetrazolium reduced per minute per milligram of protein), decreased (P less than 0.01) from a mean (+/- SEM) of 73.2 +/- 11.2 (2-month-old) to 34.7 +/- 5.9 (12-month-old). In contrast, activities of neither mitochondrial monoamine oxidase nor microsomal NADH cytochrome-c reductase changed with age. These results demonstrate that the activity of the glycerophosphate shuttle decreases as rats grow older, and it raises the possibility that the consequent difficulty in regenerating cytosolic NAD+ may play a role in the insulin secretory defect associated with aging.     

Use of estrogen-treated rats as a bioassay for evaluating catabolism of very low density lipoproteins

Estradiol-treated rats have markedly reduced circulating very low density lipoprotein (VLDL)-triglyceride (TG) pool sizes, and may provide a useful model to study the effect of differences in VLDL-TG composition on their in vivo catabolism. The results presented describe this approach, and its use to document impaired VLDL-TG catabolism of prelabeled VLDL in plasma injected from diabetic donor rats.     

Prevention of age-related hypertriglyceridemia by caloric restriction and exercise training in the rat

Plasma triglyceride concentrations were determined in three experimental groups of rats as they grew from $\text{1}\text{1}\text{2}\text{–12}\text{mo}$ of age. One group was kept sedentary and allowed food ad lib (control), the second group was allowed to eat and exercise in a running wheel ad lib, and the third calorically-restricted in order to maintain weight equal to that of the exercising rats. The exercise-trained and calorically-restricted rats gained less weight than did the control rats, and the age-related rise in plasma triglyceride concentration in control rats was totally abolished in the other two groups. In addition, exercise training and caloric restriction inhibited the increase in plasma insulin concentrations noted to occur with age in the control rats. These data indicate that there are two effective ways to prevent the development of hypertriglyceridemia that occurs with age in otherwise normal rats.     

Studies of the mechanism of fructose-induced hypertriglyceridemia in the rat

Carbohydrate-induced hypertriglyceridemia is easily produced in the rat, and fructose has been shown to be particularly potent in this regard. In this study we have compared the effects of feeding rats diets high (66% of total calories) in fructose or glucose on various aspects of carbohydrate and lipid metabolism. The results confirmed previous observations that fructose (456 +/- 276 mg/dl) was more potent (p less than 0.001) in raising plasma TG concentration than was glucose (242 +/- 13 mg/dl), and indicated that the difference in magnitude of hypertriglyceridemia produced by the two carbohydrates was closely related to the ability of the test diets to increase VLDL-TG secretion (r = 0.85, p less than 0.001). Both glucose and fructose feeding led to comparable degrees of hyperinsulinemia, and plasma TG concentrations increased before hyperinsulinemia evolved in fructose-fed rats. Therefore, it was concluded that fructose can act directly on the liver to increase VLDL-TG secretion, and that fructose-induced hypertriglyceridemia can occur in the absence of hyperinsulinemia. On the other hand, the rise in plasma TG concentration produced by fructose was reduced dramatically in exercise-trained rats, and this was associated with a decrease in plasma insulin concentration. Based upon these observations, we suggest that fructose feeding produces hypertriglyceridemia by directly stimulating hepatic VLDL-TG secretion, as well as by producing insulin resistance and hyperinsulinemia, and that it is the combined effect of these two separate actions which accounts for the magnitude of fructose-induced hypertriglyceridemia.     

Effect of age on plasma triglyceride concentrations in man

Plasma triglyceride (TG) concentrations increase with advancing age. To determine if this phenomenon is due to age per se or to age-related changes in other metabolic variables, determination of fasting plasma TG, glucose, insulin, and free fatty acid (FFA) concentrations, as well as body mass index (BMI), were made on 167 normal subjects from 18 to 77 yr of age. Significant simple correlation coefficients (r) were found between TG concentrations and age (0.47), BMI (0.39) and fasting plasma glucose (0.40), insulin (0.24), and FFA (0.20) concentrations. Multiple regression analysis was used to determine the total amount of variability in TG concentration that could be accounted for by the combination of the examined metabolic parameters. A highly significant (p < 0.0001) total correlation of 0.57 was obtained, indicating that these variables could account for approximately one-third of the total variances. Partial correlation analysis (fixing four of the five variables) yielded a correlation coefficient of 0.35 (p < 0.001) between age and fasting TG concentration. Hence, age per se, or an age-dependent phenomenon, appears to be an independent factor with a role in determining plasma TG concentrations.     

Does day-long absolute hypoinsulinemia characterize the patient with non-insulin-dependent diabetes mellitus?

Plasma glucose and insulin responses to a standard oral glucose tolerance test (75 g of glucose) and to mixed meals were compared in 15 normal subjects and 15 patients with non-insulin-dependent diabetes mellitus (NIDDM). Fasting plasma glucose levels were above 140 mg/dL in all patients with NIDDM, and the two groups were weight matched. Plasma glucose levels were significantly higher in patients with NIDDM throughout the glucose tolerance test, and this was associated with a marked reduction in plasma insulin response. Plasma glucose levels were also higher in patients with NIDDM when measured hourly from 8 AM to 5 PM (mixed meals were consumed at 8 AM and 12 PM), but the plasma insulin concentration of the two groups were similar. Thus, the day-long circulating insulin levels of patients with NIDDM are not reduced. Consequently, these patients cannot be considered to be absolutely insulin deficient.     

Plasma glucose, insulin and lipid responses to high-carbohydrate low-fat diets in normal humans

Two levels of dietary carbohydrate (40% and 60% of calories) were incorporated into typical U.S. diets and fed for 10 days each to 11 healthy volunteers. Fasting blood samples were drawn on days 8, 9, and 10 of each dietary period and analyzed for glucose, insulin, cholesterol, triglyceride (TG) and high density lipoprotein (HDL)-cholesterol concentrations. In addition, plasma glucose, insulin and TG concentrations were determined before, and for 3 hr after the noon meal on days 8 and 10. No differences were observed in fasting plasma glucose, insulin or cholesterol concentrations. However, fasting plasma TG levels were significantly elevated on the 60% carbohydrate diet, and HDL-cholesterol concentrations were significantly decreased. Furthermore, the plasma insulin and triglyceride responses to the meal tolerance test during the 60% carbohydrate dietary period were significantly elevated. These results indicate that high-carbohydrate diets lead to changes in insulin, TG, and HDL-cholesterol concentrations which have been associated with an increase in incidence of coronary artery disease.     

Effect of high-carbohydrate-low-fat diets on plasma glucose,insulin and lipid responses in hypertriglyceridemic humans

Two levels of dietary carbohydrate (40% and 60% of calories) were incorporated into typical US diets and fed for 15 days each to eight patients with endogenous hypertriglyceridemia. Fasting blood samples were drawn on days 13, 14, and 15 of each dietary period, and analyzed for glucose, insulin, cholesterol, and triglyceride concentrations, as well as for triglyceride and cholesterol content of the various lipoprotein classes. In addition, these same measurements were made before and for three hours after the noon meal on days 14 and 15. Fasting plasma triglyceride (TG) and very-low-density lipoprotein (VLDL)-TG concentrations were significantly increased (P < 0.005) on the low-fat-high-carbohydrate diet. In addition, integrated postprandial insulin, TG, and VLDL-TG responses to the noon meal were significantly (P < 0.01?0.001) elevated on the low-fat-high-carbohydrate diet. No dietary-induced changes were noted in either the fasting or postprandial values of glucose cholesterol, chylomicron-TG, low-density lipoprotein-cholesterol, high-density lipoprotein (HDL)-cholesterol, HDL₂-cholesterol, or HDL₃-cholesterol. These results indicate that low-fat-high-carbohydrate diets accentuate the metabolic risk factors for coronary artery disease that are already present in patients with endogenous hypertriglyceridemia.     

Cushing's syndrome: a review of diagnostic tests.

This review presents an analysis and interpretation of the published experimental data that form the basis for laboratory tests commonly used for screening, definitive diagnosis, and differential diagnosis in Cushing's syndrome. The single-dose overnight dexamethasone suppression test is excellent for screening outpatients since this test has a very low incidence of false-negative results (1.9% of 154 patients with Cushing's syndrome). The definitive diagnosis of Cushing's syndrome is best established by combining basal state measurements of the daily urine-free cortisol excretion and late evening plasma cortisol levels with the 2-mg low-dose dexamethasone suppression test. The etiology of Cushing's syndrome is best determined by combining measurements of basal state plasma adrenocorticotropin (ACTH) levels with the 8-mg high-dose dexamethasone suppression test. Under certain conditions, the basal state daily urine excretion of 17-hydroxycorticosteroids and 17-ketogenic steroids, the insulin tolerance test, and the metyrapone test may be useful in the definitive or differential diagnosis of Cushing's syndrome.     

Patients with congestive cardiomyopathy as cardiac transplant recipients: Indications for and results of cardiac transplantation and comparison with patients with coronary artery disease

In recent years end-stage congestive cardiomyopathy has become an increasingly frequent clinical diagnosis in candidates for cardiac transplantation. Forty-six patients who underwent transplantation because of congestive cardiomyopathy and 59 because of coronary artery disease were studied between 1971 and 1978 at Stanford University. The overall 1 year survival rate was similar in the two groups: cardiomyopathy-transplant, 64 percent and coronary artery disease-transplant, 55 percent. The survival rate has improved substantially for both groups within the last decade: The 3 year survival rate for cardiomyopathy-transplant patients undergoing cardiac transplantation since 1974 is nearly 60 percent. In contrast, 36 similarly ill patients with cardiomyopathy not undergoing transplantation had a 1 year survival rate of 23 percent and a 3 year survival rate of 4 percent (p <0.001). Survival rates in the cardlomyopathy-transplant group were unaffected by age (greater or less than 40 years). Patients in this group under age 40 had a lower frequency of infection (1 per 313 patient-days versus 1 per 195 patient-days in the older group, p <0.05) and a significantly longer interval to second rejection episodes (p <0.05), a measure of rejection frequency. Cardiomyopathy-transplant patients under age 40 had fewer deaths due to rejection (17 percent) compared with older patients in this group (36 percent). Cardiac transplantation is an effective treatment for end-stage congestive cardiomyopathy.     

Effect of coronary arterial bypass surgery on exercise-induced ventricular arrhythmias. Long-term follow-up of a prospective randomized study.

The effect of coronary arterial bypass surgery on exercise-induced ventricular arrhythmias and their relation to sudden death was examined in 102 patients with stable angina pectoris randomly assigned to medical and surgical therapy (54 and 48 patients, respectively). Symptom-limited treadmill tests were performed at entry and at 1 and 5 years. The surgical group demonstrated significant improvement in exercise performance at 1 year compared with the medical group, and at 5 years exercise-induced ischemia as evidenced by S-T depression and exertional angina remained substantially decreased in the surgical group with little change in the medical group. However, the frequency and severity of exercise-induced ventricular arrhythmias in each group remained unchanged at 1 and 5 years from those at entry. Similar results were obtained from an evaluation of ventricular arrhythmias in the electrocardiogram at rest. With the exception of exercise-induced ventricular tachycardia and fibrillation, no relation was found between ventricular arrhythmias and sudden death. Coronary bypass grafting does not decrease the frequency or severity of exercise-induced or resting ventricular arrhythmias. In patients with stable angina pectoris, with the exception of ventricular tachycardia and fibrillation, exercise-induced ventricular arrhythmias are poor predictors of sudden death. The data suggest that exercise-induced ventricular arrhythmias may not be related to ischemia but to other effects of exercise such as cardiac stimulation by catecholamines or other factors.