Insulin delivery rate into plasma in normal and diabetic subjects

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Abstract

Removal of insulin-131I 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 μU/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.

Authors

Michael P. Stern, John W. Farquhar, Abraham Silvers, Gerald M. Reaven

Albumin metabolism: effect of the nutritional state and the dietary protein intake

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Nine malnourished and nine children who had recovered from malnutrition were given a single injection of albumin-131I and were studied during consecutive periods in which the dietary protein was changed.

Authors

W. P. T. James, A. M. Hay

Studies of muscle capillary basement membranes in normal subjects, diabetic, and prediabetic patients

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A technique is described for the measurement of muscle capillary basement membranes by electron microscopic examination of needle biopsies of the quadriceps muscle. With this procedure it has been possible to obtain an objective evaluation of the significance of capillary basement membrane hypertrophy in diabetic microangiopathy. The results of such studies of muscle capillary basement membrane thickness in 50 normal, 51 diabetic, and 30 prediabetic patients have demonstrated the following. First, that the average capillary basement membrane width of diabetic patients is over twice that of normal subjects; moreover, such basement membrane thickening is a very constant finding among overtly diabetic patients, in that approximately 98% of individual diabetic subjects demonstrated this lesion. The degree of basement membrane thickening in diabetic patients is, however, unrelated to age, weight, severity, or duration of diabetes. Second, capillary basement membrane hypertrophy has been found in approximately 50% of patients who are genetically prediabetic but who have not yet demonstrated evidence of the manifest carbohydrate disturbances of diabetes mellitus. Third, in contrast to the results obtained in genetically diabetic patients, subjects with severe hyperglycemia due to causes other than genetic diabetes only infrequently show basement membrane hypertrophy.

Authors

M. D. Siperstein, R. H. Unger, L. L. Madison

Studies of peripheral thyroxine distribution in thyrotoxicosis and hypothyroidism

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Compartmental analysis of the peripheral distribution of labeled thyroxine was applied to various groups of subjects with thyrotoxicosis and hypothyroidism. It was observed that the hepatic incorporation of thyroxine was augmented in subjects with Graves' disease when compared to non-Graves' disease control groups at all levels of thyroid function. Decreased values of hepatic incorporation occurred in primary hypothyroid subjects. These lowered values were not acutely corrected by elevation of the serum thyroxine level, but were observed to be rectified after several months' therapy with exogenous thyroid hormone. These alterations of the hepatic thyroxine-131I incorporation were independently verified by direct quantitative liver scintiscan determinations.

Authors

John T. Nicoloff, J. Thomas Dowling

Control of fluid absorption in the renal proximal tubule

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Glomerulotubular balance was investigated in isolated, perfused rabbit proximal tubules in vitro in order to evaluate some of the mechanisms proposed to account for the proportionate relationship between glomerular filtration rate and fluid absorption generally observed in vivo. The rate of fluid transport from lumen to bath in proximal convoluted tubules in vitro was approximately equal to the estimated normal rate in vivo. The absorption rate in proximal straight tubules however was approximately one-half as great. If the mechanism responsible for maintenance of glomerulotubular balance is intrinsic to the proximal tubule, as has been proposed on the basis of micropuncture studies, the rate of fluid absorption in vitro should be directly related to the perfusion rate and/or tubule volume. In the present studies absorption rate was only minimally affected when perfusion rate was increased or the tubule distended. Thus, glomerulotubular balance is not mediated by changes in velocity of flow of the tubular fluid or tubular diameter and therefore is not an intrinsic property of the proximal tubule. It has also been proposed that glomerulotubular balance results from a humoral feedback mechanism in which angiotensin directly inhibits fluid absorption by the proximal convoluted tubule. In the present experiments, angiotensin was found to have no significant effect on absorption rate.

Authors

Maurice B. Burg, Jack Orloff

Retinol-binding protein: the transport protein for vitamin A in human plasma

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Vitamin A circulates in human plasma as retinol bound to a specific transport protein. This protein differs from the known low and high density plasma lipoproteins and has a hydrated density greater than 1.21. In order to study this protein, volunteers were injected intravenously with retinol-15-14C. Plasma was collected 1-3 days later, and the purification of retinol-binding protein (RBP) was monitored by assaying for 14C and also by following the fluorescence of the protein-bound retinol. Purification of RBP was effected by the sequence: Cohn fractionation, chromatography on columns of Sephadex G-200 and diethylaminoethyl (DEAE)-Sephadex, preparative polyacrylamide gel electrophoresis, and finally chromatography on Sephadex G-100. These procedures resulted in a preparation of RBP which was at least 98% pure and which had been purified more than 1500-fold. Purified RBP has α1 mobility on electrophoresis and has a molecular weight of approximately 21,000-22,000. There appears to be one binding site for retinol per molecule of RBP. Solutions of RBP are fluorescent (characteristic of retinol) and have ultraviolet absorption spectra with peaks at 330 mμ (resulting from the bound retinol) and at 280 mμ. There are no fatty acid or fatty acyl chains present in purified RBP. The usual concentration of RBP in plasma is of the order of 3-4 mg/100 ml. In plasma, RBP apparently circulates as a complex, together with another, larger protein with prealbumin mobility on electrophoresis. The RBP-prealbumin complex remains intact during Cohn fractionation and during chromatography on Sephadex and on DEAE-Sephadex columns. The complex dissociates during gel electrophoresis, permitting the isolation and subsequent purification of each of the components. The complex is again formed by mixing together solutions of the separated RBP and of prealbumin. Retinol transport in plasma thus appears to involve both a lipid-protein (retinol-RBP) interaction and a protein-protein (RBP-prealbumin) interaction.

Authors

Masamitsu Kanai, Amiram Raz, DeWitt S. Goodman

Evaluation of the forced oscillation technique for the determination of resistance to breathing

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Total respiratory resistance (RT) was measured by the application of a sine wave of airflow to the mouth at the resonant frequency of the respiratory system. The mean respiratory resistance of 42 normal subjects, measured at a mean functional residual capacity of 3.3 liters, was 2.3, SD ± 0.5, cm H2O/liter per sec, and the resonant frequency was between 5 and 8 cycle/sec. The airway resistance measured in these same subjects with the body plethysmograph at a mean panting thoracic gas volume of 3.5 liters was 1.3, SD ± 0.3, cm H2O/liter per sec. Total respiratory resistance was found to vary inversely with lung volume (V) measured plethysmographically; prediction formulae for normal subjects based on this relationship are: RT (mean) = 7.1/V, RT (range) = 4.0/V to 11.6/V where V is in liters and RT is in cm H2O/liter per sec. When these criteria were applied to subjects with thoracic disease the following results were obtained: 17 subjects with obstructive lung disease all had elevated total respiratory resistance; 9 subjects with diffuse lung disease without airway obstruction all had normal respiratory resistance; all but 1 of 5 obese subjects and all but 2 of a heterogeneous group of 9 subjects without airway obstruction had normal respiratory resistance. Failure to take lung volume into account resulted in a considerable decrease in the ability to discriminate between obstructive and nonobstructive lung disease on the basis of the forced oscillation test. The resonant frequency of the respiratory system of patients with obesity or nonobstructive lung disease was similar to that obtained in the normal group; accurate evaluation of resonant frequency in subjects with obstructive lung disease was frequently not possible. The combined resistances of lung, thoracic wall and abdominal tissues were found to account for less than 43% of the total respiratory resistance in normal subjects and were only slightly increased by the presence of obesity, restrictive diseases of the thoracic wall, and hyperinflation of the thorax. The forced oscillation method is potentially of value in the study of resistance to breathing of patients who cannot undergo body plethysmography, such as acutely ill, anesthetized, or unconscious subjects. Accurate evaluation of RT requires an independent measure of lung volume as well as careful attention during measurements to the airflow rate, phase of respiration, and the adequacy of cheek compression and laryngeal relaxation.

Authors

Aron B. Fisher, Arthur B. DuBois, Richard W. Hyde

Iron metabolism in copper-deficient swine

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The way in which iron is handled by the duodenal mucosa, the reticuloendothelial system, the hepatic parenchymal cell, and the normoblast was investigated in copper-deficient swine.

Authors

G. Richard Lee, Sergio Nacht, John N. Lukens, G. E. Cartwright

Absorption of bile acids from the large bowel in man

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The absorption of bile acids from the human large bowel was studied in eight patients. All patients had cholecystitis and cholelithiasis and had to undergo cholecystectomy. Cholic acid-14C was injected during surgery into the lumen of the cecum, hepatic flexure of the colon, or transverse colon in six patients, under the visual control of the surgeon. Common duct bile was collected by T tube daily for 5 days, and bile acids were extracted. Significant amounts of radioactivity appeared in T tube bile in each patient. T tube bile acids contained a total of 43.6-84.6% of the administered radioactivity; the average for the six patients was 58.9%. The majority of the tracer was excreted during the first 24 hr. In an additional patient cholic acid-14C was given in the form of an enema 5 days postoperatively. In this subject 30.8% of the retained radioactivity was excreted through the T-tube in 48 hr. The labeled cholic acid was recovered as both cholic and deoxycholic acid from T tube bile. Thin-layer chromatographic analysis of the bile acid samples indicated that the fraction of radioactivity recovered as deoxycholate increased with time during the postoperative period. Gas-liquid chromatographic analysis showed that the daily total quantity of excreted bile acids increased significantly from the 1st-5th days of the experiment. The amount of cholate excreted in T tube bile increased markedly with time, that of chenodeoxycholate increased moderately, and that of deoxycholate decreased sharply during the 5 days of the experiment. In three patients, injection of radiopaque material mixed with the tracer showed no evidence of regurgitation into the small bowel by serial X-rays. In an additional patient, tube aspirate from the terminal ileum contained no radioactivity. The results indicate that cholic acid is converted to deoxycholic acid in the human colon, and both of these bile acids are absorbed from the human large bowel in significant amounts. These data establish the previously unproved concept that significant absorption of bile acids takes place from the large bowel of man.

Authors

Paul Samuel, George M. Saypol, Edward Meilman, Erwin H. Mosbach, Mohsen Chafizadeh

Growth hormone secretion during sleep

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Plasma growth hormone (GH), insulin, cortisol, and glucose were measured during sleep on 38 nights in eight young adults. Blood was drawn from an indwelling catheter at 30-min intervals; EEG and electrooculogram were recorded throughout the night. In seven subjects, a plasma GH peak (13-72 mμg/ml) lasting 1.5-3.5 hr appeared with the onset of deep sleep. Smaller GH peaks (6-14 mμg/ml) occasionally appeared during subsequent deep sleep phases. Peak GH secretion was delayed if the onset of sleep was delayed. Subjects who were awakened for 2-3 hr and allowed to return to sleep exhibited another peak of GH secretion (14-46 mμg/ml). Peak GH secretion was not correlated with changes in plasma glucose, insulin, and cortisol. The effects of 6-CNS-active drugs on sleep-related GH secretion were investigated. Imipramine (50 mg) completely abolished GH peaks in two of four subjects, whereas chlorpromazine (30 mg), phenobarbital (97 mg), diphenylhydantoin (90 mg), chlordiazepoxide (20 mg), and isocarboxazid (30 mg) did not inhibit GH peaks. Altered hypothalamic activity associated with initiation of sleep results in a major peak of growth hormone secretion unrelated to hypoglycemia or changes in cortisol and insulin secretion.

Authors

Y. Takahashi, D. M. Kipnis, W. H. Daughaday

Effect of early nutrition on the development of rat epididymal fat pads: cellularity and metabolism

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The effect of infantile nutritional levels on adipose tissue cellularity and metabolism was studied in two groups of Sprague-Dawley rats. Caloric intake was varied during the suckling period by manipulating litter size immediately after birth; however, all animals had free access to food after weaning. The epididymal fat pads of animals raised in small litters were heavier than those of their paired siblings raised in large litters. Initially, the differences in pad weight were accounted for primarily by differences in total cell number; however, at 20 wk both cell number and cell size contributed equally. The rate of glucose incorporation into CO2 and triglyceride during in vitro incubations was the same for both groups if expressed on a per cell basis; therefore total tissue incorporation was greater in animals with more cells. The results support the hypothesis that early nutritional experiences can effect permanent changes in the cell number and size of the epididymal fat depot and that total cell number is important in the total metabolism of this organ. These findings and the fact that extreme human obesity is accompanied by similar alterations in cellularity and metabolism indicate that early nutritional experiences should be studied further as a guide to the etiology of obesity in man.

Authors

Jerome L. Knittle, Jules Hirsch

Transsulfuration in mammals: fetal and early development of methionine-activating enzyme and its relation to hormonal influences

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The development of activity of methionine-activating enzyme was studied in four organs of the rat. Three different patterns were observed: (a) in the liver, specific activity began to increase in late fetal life and reached a maximum 2 days after birth; (b) in the small intestine, specific activity began to rise in the 2nd wk after birth and reached a maximum at age 18 days; and (c) in the brain and kidney, specific activity did not change markedly from the earliest stage of fetal development studied to adult life. Hydrocortisone increased hepatic methionine-activating enzyme activity as much as 55% in the young rat. However, adrenalectomy in the newborn rat did not prevent the postnatal rise in hepatic methionine-activating enzyme activity, nor did adrenalectomy at age 10 days prevent the developmental rise of intestinal activity at age 18 days. Conjugated estrogens partially inhibited both the neonatal rise in hepatic methionine-activating enzyme activity and the rise in activity after adrenal steroid injection. Injection of L-methionine did not increase hepatic methionine-activating enzyme activity in the developing or adult rat.

Authors

H. Peter Chase, Joseph J. Volpe, Leonard Laster

Testosterone-binding globulins in human plasma: studies on sex distribution and specificity

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When human plasma is mixed with testosterone-3H and subjected to electrophoresis on paper in glycine acetate buffer at pH 8.6, at least two proteins other than albumin bind the testosterone. In normal women 80.5 ± 1.9% (SEM) of the recovered radioactivity migrates with the β-globulins, 7.3 ± 0.80% with the inter-α-globulins, and 4.3 ± 0.40% with albumin. In normal men the percentages are 69.3 ± 3.0%, 14.3 ± 1.6%, and 6.2 ± 1.1%, respectively. These differences between men and women in binding among the β-globulins and inter-α-globulins are statistically significant (P < 0.001). The highest percentages of radioactivity associated with the β-globulins are seen in infants of both sexes, men receiving diethylstillbestrol, and pregnant women. These same subjects have the lowest percentages of radioactivity associated with the inter-α-globulins. Experiments with carrier testosterone indicate that at least some of the differences between the normal men and women and infants can be explained by differences in the concentration of endogenous testosterone. This factor alone, however, cannot explain the increased binding among the β-globulins in the men receiving diethylstilbestrol or in the pregnant females. In this system estrone, estradiol, dehydroisoandrosterone, androsterone, 17α-hydroxyprogesterone, and 19-nortestosterone compete with testosterone for binding sites on the proteins. None is as potent as testosterone itself.

Authors

William Rosner, Susan M. Deakins

Renal excretion of urobilinogen in the dog

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The renal excretion of urobilinogen was studied in dogs by standard clearance techniques. The use of radiochemically pure tritiated mesobilirubinogen as a representative urobilinogen afforded much greater analytical precision than can be obtained with the usual colorimetric and fluorimetric techniques which are only semiquantitative. With constant plasma levels of urobilinogen, raising urinary pH from 5 to 8 increased urobilinogen excretion from about 30% to up to 200% of the filtered load. When urinary pH was kept constant, changes in blood pH had no effect on urobilinogen excretion. Increases in urinary flow had no effect on urobilinogen excretion when the urine was alkaline but increased excretion markedly during aciduria. Probenecid did not influence urobilinogen excretion by the kidney. It is concluded that urobilinogen is excreted by a three-component system of glomerular filtration, active secretion, and pH-dependent nonionic diffusion in the distal nephron. Urobilinogen is a weak acid, and this mode of excretion is similar to that of other weak, organic acids, such as salicylates. These results indicate that urinary pH and flow must be considered in the clinical interpretation of measurements of urinary urobilinogen.

Authors

Mortimer Levy, Roger Lester, Norman G. Levinsky

Regional distribution of acid mucopolysaccharides in the kidney

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Kidneys from 20 dogs were dissected into cortical and medullary components and analysed for acid mucopolysaccharide content. Heparitin sulfate accounted for approximately 80% of cortical acid mucopolysaccharide, 10% was chondroitin sulfate B, and 10% was low molecular weight hyaluronic acid. Medullary tissue exhibited a 4- to 5-fold higher concentration of acid mucopolysaccharide than did cortical tissue, and the dominant compound was moderately highly polymerized hyaluronic acid. While chondroitin sulfates A and (or) C were not detected in this study, the presence of minor amounts of these substances could not be excluded. A model experiment indicated that hyaluronic acid retards sodium diffusion, apparently due to its viscous properties rather than its electronegativity.

Authors

C. W. Castor, J. A. Greene

Brain metabolism in uremic and adenosine-infused rats

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Analyses of nucleotides and glycolytic intermediates were performed on perchlorate extracts of blood and quick-frozen brain from rats nephrectomized 48 hr previously, and from rats infused for 6 hr with adenosine or AMP. Blood nucleotides of acutely uremic rats were normal. Uremic brain showed an increase of creatine phosphate (CP), ATP, and glucose with a corresponding decrease in creatine, ADP, AMP, and lactate. Other nucleotide triphosphates were increased, but total adenine nucleotide in brain was unchanged. Uremic brain failed to use ATP or produce ADP, AMP, and lactate at normal rates when subjected to the stress of ischemic anoxia. Although levels of cation responsive ATPase in extracts of uremic brain were normal, the inhibition of glycolysis in the intact brain appeared to be due to a failure of ATP hydrolysis (a diminished ATPase activity). Adenosine infusion produced mild azotemia, marked hyperglycemia, an increase in blood ATP, and an increase in total blood adenine nucleotide. Brain from rats infused with adenosine or AMP also had high levels of ATP, creatine phosphate, and glucose, whereas levels of ADP, AMP, and lactate were low. However these brains responded with normal use of ATP and normal production of lactate when stimulated by ischemic anoxia.

Authors

Stanley Van Den Noort, Robert E. Eckel, Katherine Brine, Jeffry T. Hrdlicka

The regulation of antidiuretic hormone release in man: I. Effects of change in position and ambient temperature on blood ADH levels

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It has been postulated that alterations in the intravascular distribution of blood affect antidiuretic hormone (ADH) secretion in man. The studies reported here were designed to alter blood distribution by thermal and by positional change to test this thesis.

Authors

William E. Segar, Ward W. Moore

Attempt to transfer contact hypersensitivity in man with dialysate of peripheral leukocytes

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In humans delayed hypersensitivity to tuberculin and coccidiodin can be transferred from a skin-test positive donor to a previously nonreactive recipient with a dialyzable fraction of donor peripheral leukocytes. The mechanism by which transfer is effected by this relatively low molecular weight material is unknown. Should transfer with dialysate be accomplished with hypersensitivity to low molecular weight artificial antigens, further characterization of “transfer factor” might be facilitated.

Authors

Michael W. Brandriss

Biochemical energetics of simulated platelet plug formation: Effect of thrombin, adenosine diphosphate, and epinephrine on intra- and extracellular adenine nucleotide kinetics

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Washed human platelets were incubated in a modified Ringer's solution, pH 7.1, at 37°C for 1 hr. Intracellular basal levels for glycogen, adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and orthophosphate were 31.1, 2.52, 1.39, 0.36, and 1.2 μmoles/ml of platelets, respectively. Extracellular ATP, ADP, and AMP remained fairly constant and represented 4, 2, and 4% of total adenine nucleotide content. Total adenine nucleotide content remained unchanged during the period of control incubation. Glycogen depletion was 17.8 μmoles/ml at the end of 1 hr; lactate production was 20.7 μmoles/ml per hr. In the presence of glucose, lactate production increased 100%, and glycogen depletion was spared 13%. Approximately 55% of glucose or glycogen fuel was converted to lactate.

Authors

Simon Karpatkin, Richard M. Langer

The effect of salicylates on the hemostatic properties of platelets in man

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Ingestion of 1.5 g of aspirin, but not of sodium salicylate, produced a significant prolongation of the bleeding time in six normal male subjects when compared with the effects of a placebo. Similar differences in the effect of the two drugs on platelets was also observed. Aspirin ingestion resulted in impaired platelet aggregation by connective tissue and was associated with a decreased release of platelet adenosine diphosphate (ADP); sodium salicylate had no effect on these values. In vitro, incubation of platelet-rich plasma with an optimum aspirin concentration of 0.50 mmole/liter (0.045 mg/ml) inhibited both the adhesion of platelets to connective tissue and the release of ADP as well as the secondary wave of platelet aggregation produced with ADP or epinephrine; sodium salicylate had no effect on these reactions, which were also normal in patients with von Willebrand's disease. The inhibitory effect produced by ingesting a single 1.8 g dose of aspirin was detectable for 4-7 days at which time salicylate was no longer detectable in the blood, which suggested an irreversible effect on the platelet. Aspirin also inhibited the release of platelet adenosine triphosphate (ATP), but had no effect on the platelet surface charge, available platelet ATP or ADP, or the destruction of ADP by plasma ADPase. These studies lend further support to the hypothesis that ingestion of aspirin, in contrast to sodium salicylate, prolongs the bleeding time by inhibiting the release of platelet ADP, perhaps reflecting the findings in other cell systems which suggest that aspirin alters membrane permeability.

Authors

Harvey J. Weiss, Louis M. Aledort, Shaul Kochwa

Genetic polymorphism of the third component of human complement (C′3)

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Polymorphism of human C′3 has been defined by prolonged agarose electrophoresis of fresh serum. At least four, and probably five, alleles have been identified by the electrophoretic mobilities of gene products. Inheritance of three alleles, F1 F, and S, is consistent with the autosomal condominant type. The inheritance of S1 is probably codominant and that of F0·8 is not known. Of the 15 phenotypes predicted by these alleles, eight have been observed.

Authors

Chester A. Alper, Richard P. Propp

Functional Correlates of Compensatory Renal Hypertrophy

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Abstract

Authors