bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity of Circulating Human C-peptide
Authors: Kuzuya Hideshi , Blix Petra M , Horwitz David L , Rubenstein Arthur H , Steiner Donald F , Faber Ole K , Binder Christian 
Published: September 2013

Values reported for serum C-peptide immunoreactivity in healthy individuals vary considerably. To assess factors that contribute to this finding, three human C-peptide assay systems were developed utilizing three distinct antisera that react differently with various C-peptide fragments.
Preparations of natural pancreatic and synthetic human C-peptide standards were compared immunologically in these systems. The curves of the natural C-peptide and the synthetic preparations were not identical. The relative immunoreactivity of each standard varied, depending on the particular antiserum used.
Serum C-peptide concentrations varied when measured in the different assay systems. Furthermore, the results of dilution and recovery tests and stability of the C-peptide during storage showed differences among the three assays. Gel filtration of serum indicated heterogeneity within the major C-peptide peak, and, in addition, a smaller peak of lower molecular weight material was present in some samples. Although degradation of serum C-peptide may occur during storage, fragments of C-peptide may also be secreted or arise during in-vivo metabolism.
Thus, the present studies indicate the need for careful standardization and checking of each particular assay system before its use in clinical studies.
The Handling of Insulin, Proinsulin, and C-peptide by the Isolated Rat Kidney
Authors: Rabkin Ralph , Ross Brian D , Mako Mary E , Rubenstein Arthur H 
Published: September 2013

The renal handling of proinuslin, insulin, and C-peptide was studied in the isolated perfused rat kidney. At perfusate peptide concentrations below 12 ng./ml. (control value), the organ clearance of proinsulin (637 ± 74 μl. per minute) was significantly (P &lt; 0.001) lower than that of insulin (1,276 ± 48 μl. per minute) and C-peptide (1,618 ± 218 μl. per minute). There was a significant (P &lt; 0.001) inverse correlation between the organ clearance and the molecular size of the peptide (r = − 0.86). As the glomerular filtration rate was 53 per cent of the organ clearance of proinsulin, 16 per cent of the organ clearance of insulin, and 27 per cent of the organ clearance of C-peptide, it was evident that a mechanism for extracting these peptides from the peritubular circulation exists.
When kidneys were perfused with insulin in concentrations above 330 ng./ml., the organ clearance fell to approximately half the control value and its fractional urinary excretion increased several fold, indicating saturation of luminal absorption of filtered insulin. As the fall in organ clearance of insulin was larger than any decrease in the rate of insulin filtration that may have occurred, we conclude that at high insulin concentrations saturation of contraluminal uptake of insulin also occurs. Similarly, the organ clearance of C-peptide declined to 46 per cent of the control level at perfusate concentrations of 108 to 301 ng./ml. In contrast, despite perfusing kidneys with concentrations of proinsulin as high as 367 ng./ml., its organ clearance and fractional urinary excretion did not decline. There was no evidence of conversion of proinsulin to insulin or C-peptide.
Insulin Receptors on Monocytes from Patients with Ketosis-prone Diabetes Mellitus
Authors: Pedersen Oluf , Beck-Nielsen Henning , Heding Lise 
Published: September 2013

I-125-Insulin binding to its receptor on monocytes was measured in 30 young, insulin-treated diabetic outpatients and in 13 newly diagnosed, ketotic diabetic patients before and after insulin treatment.
In insulin-treated diabetic outpatients, insulin binding was similar on average to that of 25 age-matched normal subjects. A slight but statistically significant negative relationship was found between the insulin concentration required to displace specific binding of I-125-insulin by 50 per cent and the plasma concentration of ketone bodies (R = −0.46, p &lt; 0.02), indicating a positive correlation between apparent receptor affinity and the plasma concentration of ketone bodies. No correlation was found between insulin binding and total plasma insulin concentration.
Insulin binding to monocytes from newly diagnosed diabetic patients exhibited large variability. Based on the initial insulin binding values and the receptor response to insulin treatment, the patients could be divided into two groups. Group 1 comprised eight diabetic subjects who had had specific cell-binding fractions at an insulin tracer concentration above the median of normal subjects before therapy; after insulin treatment for 10 days, insulin binding was restored to normal. Group 2 consisted of five diabetic patients who had had specific cell-binding fractions at a tracer level below the median of normal subjects when admitted; insulin therapy caused no significant change in insulin binding. In both groups of newly diagnosed, diabetic patients, no correlation could be found between the cellular insulin binding and the plasma concentrations of insulin and ketone bodies.
We conclude that (1) insulin-treated diabetic outpatients have normal insulin binding to monocytes; (2) among newly diagnosed, ketotic diabetics with identical metabolic presentation, some may have a raised but reversible insulin binding initially, while others seem to have defective cellular insulin binding in addition to insulin deficiency; and (3) no consistent relationships exist between the plasma levels of insulin and ketone bodies and the insulin binding on monocytes from insulin-dependent diabetics.
Functional Alteration of Islet Cells After Jejunal or Ileal Resection in Dogs
Authors: Tamura Katsuhiro , Kajiwara Tatehiro , Suzuki Takashi , Tobe Takayoshi 
Published: September 2013

Functional alteration of the islet cells was investigated in dogs after the resection of different parts of the small intestine. Three weeks after jejunal or ileal resection, when the dogs might still have been in a catabolic state, insulin and pancreatic glucagon release in response to intravenously infused glucose and arginine was reduced. Three months after jejunal resection, both intravenous glucose tolerance and insulinogenic index in the intravenous glucose tolerance test were significantly below the preoperative values (P &lt; 0.001, P &lt; 0.05), while pancreatic glucagon release in response to arginine infusion showed almost normal levels in contrast to low response of insulin release. This functional alteration three months after jejunal resection was similar to that seen in diabetes meilitus. On the other hand, three months after ileal resection, insulin and pancreatic glucagon release was almost normal.
We conclude that the jejunum plays a more important role in the enteroinsular system than the ileum and that prolonged interruption of this enteroinsular axis can cause insular disorder and what could hypotheticaUy be called enterogenic chemical diabetes, in view of the altered glucose tolerance test and the alteration in insulin secretory response.
Disposition of 131I Proinsulin in the Rat Comparisons with 131I Insulin
Authors: Izzo Joseph L , Roncone Angela M , Helton Deirdre L , Izzo Mary Jane 
Published: September 2013

The patterns of disposition of intravenously injected doses of 131I proinsulin and 131I insulin were compared in the rat with respect to plasma clearance, uptake, and degradation in selected organs and tissues, and rates of accumulation of degraded products in plasma and urine. Small doses of 131I insulin (4 mμg.per 100 gm. rat body weight) were cleared from plasma approximately twice as rapidly as large doses (4 μg. per 100 gm. rat body weight) and three times as rapidly as equi molar small doses (6 mμg. per 100 gm. rat body weight) or large doses (6μg.per 100 gm. rat body weight) of 131I proinsulin. Conversely, the relative rate of accumulation of 13lI-labeled degradation products in plasma after injection of low doses of 13lI insulin was about twice as rapid as the rate of accumulation after large doses and about three times as rapid as the rate of accumulation after either small or large doses of 13lI proinsulin. Peak uptake and degradation in the liver at one minute was greatest after injection of low doses of 13lI insulin (28.8 ± 2.5 per cent of injected radioactivity), less after injection of large doses (15.1 ±1.5 per cent), and least after injection of low doses (5.5 ± 0.9 per cent) or high doses (4.6 ±0.6 per cent) of 131I proinsulin. In contrast, peak uptake and degradation in the kidneys at seven to eleven minutes was greatest after injection of low doses (24.7 ± 2.7 per cent) or high doses (27.5 ± 1.2 per cent of 13lI proinsulin), least after injection of low doses (9.6 ±0.6 per cent) of 13lI insulin, and intermediate after injection of high doses (17.5 ±2.6 per cent). No large differences were noted in patterns of uptake of radioactivity in muscle, fat, or skin compartments. Excretion of degraded products in urine was more delayed after 13lI proinsulin injections. An inverse relationship was noted between initial concentration of hormone in plasma and uptake by the liver. Compared to 131I insulin, the hypoglycemie effect of 13lI proinsulin was weaker (58 per cent) and more delayed in onset. No evidence of conversion of l3lI proinsulin to 131I insulin was noted.
The studies indicate that the differences in dose dependency in plasma clearance and degradation of 131I insulin and 131I proinsulin can be attributed to differences in relative uptakes and degradation by the liver and kidneys. The liver appeared to be the major organ involved in the removal and degradation of insulin, whereas the kidney appeared to be the major organ involved in the case of proinsulin. The hepatic process was rapid but relatively saturable, whereas the kidney process was slower but relatively unsaturable. The inverse relationship between initial concentration of hormone in plasma and uptake by liver suggests that the ratio may provide a sensitive index of the role of the liver in plasma hormone clearance.
Age-related Glucose Intolerance in Hyperthyroid Patients
Authors: Ikejiri Kenji , Yamada Takashi , Ogura Hajime 
Published: September 2013

In an attempt to study age-related metabolic abnormalities, glucose intolerance and serum insulin were examined in normal subjects and hyperthyroid patients. For comparison, serum concentrations of thyroxine (T4), triiodothyronine (T3), and total cholesterol were also measured in normal subjects and hyperthyroid patients.
Although serum T4 concentration remained unchanged, serum T2 concentration decreased significantly in an elderly group of normal subjects. Similarly, serum T4 did not change with age and serum T2 decreased slightly but progressively with age in hyperthyroid patients. In addition, serum total cholesterol concentration increased progressively with age in normal subjects.
Oral glucose tolerance decreased with age in normal subjects despite the same timing, peak level attained, and total magnitude of insulin response for old and young subjects. Although the severity of hyperthyroidism decreases with age, age-related glucose intolerance was much more apparent in hyperthyroid patients because of the age-related decrease of basal concentration, the peak level attained, and the total magnitude of insulin response. It is suggested that age-related glucose intolerance is magnified by the hyperthyroid state.
Induction of Defective Insulin Secretion and Impaired Glucose Tolerance by Clonidine Selective Stimulation of Metabolic Alpha-adrenergic Pathways
Authors: Metz Stewart A , Halter Jeffrey B , Paul Robertson R 
Published: September 2013

Clonidine is an antihypertensive drug that markedly suppresses plasma catecholamine levels. In an attempt to investigate the effects of suppression of endogenous catecholamine secretion on glucose homeostasis and glucoregulatory hormones, we administered oral clonidine to 20 normal male subjects, two patients with transsections of the cervical spinal cord, and one patient with an insulinoma. Unexpectedly, after a single dose of 0.5 ing. given to normal subjects, insulin concentrations fell and plasma glucose rose 12 ± 1 mg./dl. (p &lt; 0.001; n = 6) without an increase in glucagon. After four days of clonidine treatment, plasma glucose again was elevated (Δ = +11 ± 3 mg./dl.; p &lt; 0.01), while basal plasma insulin and glucagon levels remained unchanged. The acute insulin response to an intravenous glucose injection of 5 gm. decreased from 33 ± 7 to 11 ± 2 μU./ml. (n = 8; p &lt; 0.01), and KG declined from 0.80 ± 0.13 to 0.53 ± 0.06 per cent per minute (p &lt; 0.01). Similar responses were seen in the paraplegic patients. In contrast, expected responses to clonidine were not observed in the insulinoma patient preoperatively; these normal responses were restored after resection of the tumor. All metabolic alterations induced by clonidine were reversed by infusion of phentolamine, an alpha-adrenergic blocking agent.
We conclude that clonidine causes hyperglycemia and inhibits insulin secretion through an alpha-adrenergic mechanism. Since plasma catecholamine concentrations and vascular tone were markedly reduced by clonidine, this drug appears to selectively stimulate metabolic adrenergic pathways different from those operative in vasomotor regulation.
Inhibition of Insulin Secretion by Exogenous Insulin in Normal Man as Demonstrated by C-peptide Assay
Authors: Liljenquist John E , Horwitz David L , Jennings Anthony S , Chiasson Jean-Louis , Keller Ulrich , Rubenstein Arthur H 
Published: September 2013

To investigate whether insulin exerts feedback regulation of its own secretion, paired studies were performed in normal men in two separate protocols. In the first protocol, four men were studied on two occasions. On one occasion, insulin was infused at 5 μU. per kilogram per minute for 120 minutes, achieving arterial insulin levels of 600 to 700 μU./ml. With use of a variable glucose infusion, the plasma glucose concentration was maintained at fasting levels for 60 minutes and then raised abruptly to 165 mg./dl. and was maintained at that level for the remaining 60 minutes. On a second occasion, the study was repeated except that saline was infused instead of insulin. The plasma glucose concentration remained at fasting levels until the last 60 minutes, when it was similarly raised to 165 mg./dl. and maintained at that level until the end of the study. Connecting peptide reactivity (CPR) was measured as an index of endogenous insulin secretion in the presence of exogenous insulin. During the initial 60 minutes of the study, with euglycemia maintained, there was a significant (46 per cent) decline (p &lt; 0.01) in the levels of CPR in the insulin-treated subjects. At 60 minutes, when hyperglycemia was induced, CPR rose in both groups. The rise of CPR in the insulin-treated group, however, was significantlyless (p &lt; 0.01) than in the saline control group.
To investigate whether insulin inhibition of insulin secretion during hyperglycemia would occur without prolonged insulin pretreatment, paired studies were performed in three additional men. In this protocol, insulin (5 mU. per kilogram per minute) or saline was infused for 70 minutes. Euglycemia was maintained for just 10 minutes. Thereafter, the plasma glucose concentration was. raised to 170 mg./dl. in both groups. This acute induction of hyperglycemia without prolonged insulin pretreatment resulted in similar increases in CPR in both insulin- and saline-treated groups.
From these data we conclude that (1) exogenous insulin administration, with maintenance of euglycemia, results in significant inhibition of basal insulin secretion; (2) the administration of exogenous insulin for 60 minutes before and for 60 minutes after the acute induction of hyperglycemia results in significant inhibition of glucose-stimulated insulin secretion; and (3) exogenous insulin administered for just 10 minutes before and during the acute induction of hyperglycemia, however, does not result in inhibition of the insulin response to the hyperglycemic stimulus.
Antiketogenic Action of Fructose in Man
Authors: Dietze Günther , Wicklmayr Matthias , Mehnert Hellmut 
Published: September 2013

The effect of fructose infusion (10 gm. every five minutes as a bolus followed by 0.5 gm. per kilogram × hours) on arterial concentrations and hepatic balances of ketones was studied in four juvenile diabetics 24 hours after the withdrawal of insulin. Arterial and hepatic venous concentrations of β-hydroxybutyrate, acetoacetate, free fatty acids, fructose, and oxygen were measured. Hepatic blood flow was also determined.
At constant rates of splanchnic fructose extraction, an 82 per cent diminution of the arterial hepatic venous concentration difference of the ketones was observed but the arteriovenous difference of free fatty acis rose moderately. Since hepatic blood flow was only slightly increased (17 per cent) there was no doubt that total hepatic ketone body formation was reduced. The magnitude of this antiketogenic action became apparent from the continuous fall of the arterial ketone concentrations. Since splanchnic oxygen uptake rose 40 per cent, it is suggested that the antiketogenic effect of fructose was due not only to enhanced re-esterification but also to accelerated oxidation of free fatty acids.
Reproducibility and Comparative Analysis of Repeated Intravenous and Oral Glucose Tolerance Tests
Authors: Ganda O P , Day J L , Soeldner J S , Connon J J , Gleason R E 
Published: September 2013

We have developed a methodology for measuring the reproducibility of the oral glucose tolerance test (OGTT) and the intravenous glucose tolerance test (IVGTT) in normal subjects and in offspring of conjugal diabetic parents.
Both groups of subjects revealed more striking correlations of several parameters of blood glucose and insulin secretion between two IVGTTs than between two OGTTs. Employing arbitrary criteria, we calculated a “reproducibility index” as a quantitative measure of blood glucose variability in each subject. No significant difference was found in the reproducibility of OGTT versus IVGTT, nor in normals versus the offspring. Only about 50 per cent of the tests in normals and in the offspring could be considered to be “reproducible.”
The offspring revealed greater correlations of several parameters, particularly insulin secretion, between the two IVGTTs and between the two OGTTs as compared with the normal group. However, the blood glucose variations tended to be considerably greater in the offspring from one to the other test.
The Acute Effect of Insulin on Capillary Endothelial Cells
Authors: Østerby R , Gundersen H J G , Christensen N J 
Published: September 2013

A quantitative morphologic study of the capillary endothelium of striated muscle was performed in diabetic rats one hour after injection of insulin. Diabetic and nondiabetic rats injected with saline constituted the reference groups. In a randomized sample of capillary profiles, morphometric data on micropinocytotic vesicles (MPV) and on various capillary characteristics were collected.
The numeric density of MPV was higher in diabetic rats injected with insulin than in diabetic rats injected with saline (44.2 ± 8.5 versus 34.0 ± 4.5 MPV/μ2 endothelial cytoplasm (mean ± S.D.), 2p = 0.045), thereby approaching the control value of 48.0 ± 7.3, 2p = 0.51. The insulin-injected animals, furthermore, differed markedly from the diabetic reference group as regards the ratio of free-to-attached vesicles, since they showed a large increase in the numeric density of free MPV (1.40 ± 0.18 versus 1.00 ± 0.23/μ circumference, 2p = 0.015, control value 1.59 ± 0.20) and a small decrease in the density of attached MPV (0.19 ± 0.03 versus 0.23 ± 0.02/μ circumference, 2p = 0.022; controls: 0.15 ± 0.04). Both the height of the endothelial cytoplasm and the size of the MPV were similar in all groups.
These findings may be the morphologic counterpart of the clinically demonstrated decrease in plasma volume and in the intravascular pool of albumin in diabetic patients after insulin injection. The present results demonstrate that insulin has an acute effect on the endothelial cells, including a change in the kinetics of the vesicular transport pathway
The Regulation of Plasma Ketone Body Concentration by Counter-regulatory Hormones in Man: II. Effects of Growth Hormone in Diabetic Man
Authors: Schade David S , Eaton R Philip , Peake Glenn T 
Published: September 2013

Growth hormone has classically been considered to be a diabetogenic hormone. However, in insulin-dependent diabetic man the mechanism of its ketogenic activity has not been resolved. Therefore, this study was designed to examine three aspects of growth hormone's ketogenic activity: first, whether growth hormone's ketogenic activity can be entirely accounted for by its lipolytic effect; second, whether growth hormone's ketogenic activity is rapid or delayed in onset; and third, whether growth hormone may exert ketogenic activity indirectly by altering the plasma concentration of other ketone body-regulatory hormones (i.e. insulin, glucagon, and cortisol). In order to obtain data relative to these three questions, growth hormone was administered to six insulin dependent, ketosis-prone diabetic subjects. Both acute and prolonged growth hormone exposure studies were performed in all subjects and compared with a control study. Plasma free-fatty-acid concentration was elevated in all studies by heparin administration to assess growth hormone's ketogenic activity independent of its lipolytic effect.
Our results suggest that, in insulin-dependent diabetic man, growth hormone exerts profound ketogenic activity that is delayed at least 60 minutes. Although this ketogenic activity may be a direct effect of the hormone, our results indicate that at least two indirect mechanisms may participate in raising plasma ketone body concentration. First, growth hormone may exert ketogenic activity indirectly by elevating plasma free-fatty-acid substrate concentration. Second, growth hormone administration results in a significant reduction in circulating plasma free–insulin concentration, an observation that has not been previously reported. Since the diabetics in this study were given a fixed dose of exogenous insulin, these results suggest that growth hormone alters either the absorption and/or degradation of injected insulin in diabetic man. This latter mechanism may account for our observation that growth hormone exerts ketogenic activity independent of its lipolytic effect.