A Comparative Study on the Metabolism of Human Insulin and Porcine Proinsulin in Man

1973 ◽  
Vol 45 (5) ◽  
pp. 633-654 ◽  
Author(s):  
P. H. Sönksen ◽  
Christine V. Tompkins ◽  
M. C. Srivastava ◽  
J. D. N. Nabarro
Keyword(s):  
Human Insulin ◽  
Normal Subjects ◽  
Constant Infusion ◽  
Metabolic Clearance ◽  
Priming Dose ◽  
Metabolic Clearance Rate ◽  
Serum Growth Hormone ◽  
Biological Potency ◽  
Infusion Technique ◽  
Apparent Distribution

1. The metabolism of unlabelled monocomponent human insulin and porcine proinsulin was studied in ten normal subjects (five males and five females) by using a priming dose-constant-infusion technique. In each subject, the metabolic clearance rate (MCR) was measured at four separate steady-state hormone concentrations averaging 16–216 μunits/ml (insulin) and 4·2–42·8 ng/ml (proinsulin). 2. For insulin the MCR fell progressively from 34 ml kg−1 min−1 at a mean fasting insulin concentration of 3·8 μunits/ml to 11·4 ml kg−1 min−1 at the highest concentration achieved (280 μunits/ml); for proinsulin MCR averaged 3·7 ml kg−1 min−1 at a mean plasma concentration of 4·2 ng/ml and fell to 2·71 ml kg−1 min−1 at 10·7 ng/ml, remaining constant thereafter at concentrations up to 71 ng/ml. 3. The half-disappearance time (T½) from the plasma, after the end of the infusion, averaged 4·3 min for insulin and 25·6 min for proinsulin. 4. The apparent distribution space (DS) was similar for both hormones (83 ml/kg of insulin and 98·9 ml/kg of proinsulin). 5. There was a direct correlation between T½ and DS for both hormones. 6. Although the higher MCR of insulin was reflected in its shorter T½ there was, for each hormone, no relationship between MCR and T½. 7. The biological potency of porcine proinsulin, as judged by its effect on plasma glucose, was approximately 5% of that of insulin. 8. The responses of serum growth hormone and Cortisol were shown to be directly related to the degree of hypoglycaemia induced.

Changes induced by exercise in rates of turnover and oxidation of ketone bodies in fasting man

1978 ◽  
Vol 44 (1) ◽  
pp. 5-11 ◽  
Author(s):  
E. O. Balasse ◽  
F. Fery ◽  
M. A. Neef
Keyword(s):  
Steady State ◽  
Clearance Rate ◽  
Ketone Bodies ◽  
Normal Subjects ◽  
Bicycle Ergometer ◽  
Constant Infusion ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Maximal Aerobic Capacity ◽  
Energy Needs

Seven normal subjects fasted for 3 days were exercised for 30 min on a bicycle ergometer at 60 +/- 30% (mean +/- SE) of their maximal aerobic capacity. Rates of transport and oxidation of ketone bodies were determined at rest and during exercise using a primed constant infusion of [14C]acetoacetate. During the initial 7.5 min of exercise, ketone concentration abruptly decreased (-19.4 +/- 3.1%; P less than 0.001) as the result of a 22.2 +/- 7.0% reduction (P less than 0.05) in ketone production rate (Ra) and a 30.4 +/- 7.5% increase (P less than 0.01) in the rate of uptake (Rd) of ketones. As work progressed, blood ketones continued to fall slowly until the 15th min of exercise and thereafter plateaued at a level which was 21.9 +/- 4.1% lower (P less than 0.005) than resting values. During this apparent new steady state, both Ra and Rd were below control values but tended to be equal and to return simultaneously to their preexercise level. The metabolic clearance rate was increased throughout the entire period of exercise, the rise being more marked during the initial 7.5 min (+40.7 +/- 7.5%; P less than 0.01) than at later periods (+19.0 +/- 7.4%; P less than 0.05). Exercise greatly enhanced ketone oxidation which became virtually complete; despite this, the %CO2 derived from ketones, which averaged 17.6 +/- 1.6% at rest, decreased to 10.1 +/- 0.6% (P less than 0.01) after 30 min of work. This indicates that even during the hyperketonemia of fasting, the increased energy needs related to exercise are met primarily by fuels other than ketones.

CRITICAL ANALYSIS OF METHODS FOR ESTIMATING PRODUCTION RATES OF FSH

1975 ◽  
Vol 80 (2) ◽  
pp. 275-283 ◽  
Author(s):  
Salvatore Raiti ◽  
Robert M. Blizzard ◽  
Robert Penny ◽  
Claude J. Migeon
Keyword(s):  
Urinary Excretion ◽  
Clearance Rate ◽  
Critical Analysis ◽  
Constant Infusion ◽  
Metabolic Clearance ◽  
Production Rates ◽  
Metabolic Clearance Rate ◽  
Normal Men ◽  
Infusion Technique ◽  
Normal Adults

ABSTRACT The urinary excretion method and the constant infusion technique were used to estimate hFSH production rates (PR) in three normal men (aged 25–40 years). Both studies were also done in a hypophysectomized nine year old boy. The PR of hFSH in the urinary excretion studies ranged from 20.0 to 45.7 IU/24 h, whereas the constant infusion studies yielded PR's of 68.7 to 107.8 IU/24 h. Possible reasons for the discrepancy of the results obtained by the two methods are discussed. In the hypophysectomized patient, the metabolic clearance rate (MCR) of infused hFSH was much lower (4.3 ml/min) than in the normal adults (7.8 to 12.0 ml/min) and was not affected by the dose of hFSH given.

Glucose and lactate kinetics after endotoxin administration in dogs.

1977 ◽  
Vol 232 (2) ◽  
pp. E180 ◽  
Author(s):  
R R Wolfe ◽  
D Elahi ◽  
J J Spitzer
Keyword(s):  
Lactate Concentration ◽  
Constant Infusion ◽  
Glucose Turnover ◽  
Metabolic Clearance ◽  
Plasma Lactate ◽  
Metabolic Clearance Rate ◽  
Metabolic Substrate ◽  
E Coli ◽  
Lactate Kinetics ◽  
Plasma Lactate Concentration

We studied the effects of E. coli endotoxin on the glucose and lactate kinetics in dogs by means of the primed constant infusion of [6(-3)H] glucose and Na-L-(+)-[U-14C] lactate. The infusion of endotoxin induced a transient hyperglycemic level, followed by a steady fall in plasma glucose to hypoglycemic levels. The rate of appearance (Ra) and the rate of disappearance (Rd) of glucose were both significantly elevated (P less than .05) for 150 min after endotoxin, after which neither differed from the preinfusion value. The metabolic clearance rate of glucose was significantly elevated at all times 30 min postendotoxin. By 30 min postendotoxin, Ra and Rd of lactate, plasma lactate concentration, and the percent of glucose turnover originating from lactate were significantly elevated and remained so for the duration of the experiment. We concluded that after endotoxin hypoglycemia developed because of an enhanced peripheral uptake of glucose and a failure of the liver to maintain an increased Ra of glucose. We also concluded that lactate became an important precursor for gluconeogenesis and an important metabolic substrate.

Distribution volume, metabolic clearance and plasma half disappearance time of exogenous luteinizing hormone releasing hormone in normal women and women with obesity and anorexia nervosa

1981 ◽  
Vol 96 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Kazumasa Chikamori ◽  
Fumie Suehiro ◽  
Toshiki Ogawa ◽  
Kei Sato ◽  
Hiroyoshi Mori ◽  
...  
Keyword(s):  
Body Weight ◽  
Anorexia Nervosa ◽  
Normal Subjects ◽  
Distribution Volume ◽  
Metabolic Clearance ◽  
Obese Patients ◽  
Metabolic Clearance Rate ◽  
Provocation Tests ◽  
Disappearance Time ◽  
Normal Women

Abstract. Synthetic LRH was infused into normal women and women with obesity and anorexia nervosa to determine the distribution volume (DV), metabolic clearance rate (MCR) and half disappearance time (t½) of plasma LRH. In normal women, the DV of LRH was 12.1 ± 0.9 (mean ± se) l, the MCR was 1478.9 ± 39.8 ml/min (28.5 ± 1.2 ml/min/kg body weight) and the initial t½ was 5.6 ± 0.4 min. In obese patients the DV (20.6 ± 1.5 l) was significantly higher than that in normal subjects (P < 0.005), but the MCR and t½ were not significantly different from those in normal subjects. In patients with anorexia nervosa the DV and MCR were 6.5 ± 1.1 l and 621.8 ± 110.5 ml/min (17.9 ± 2.4 ml/ min/kg body weight), respectively, which were both significantly lower than those in normal subjects (P < 0.02), while the t½ (7.3 ± 0.1 min) was longer than in normal subjects (P < 0.02). These data suggest that 1) the abnormal responses of some hormones to provocation tests observed in obese patients and patients with anorexia nervosa should be evaluated in consideration of changes in the DV and metabolic clearance of hormones in these conditions, and 2) in patients with anorexia nervosa changes in MCR and t½ may reflect low metabolism of LRH.

Production rate, metabolic clearance rate and blood concentration of progesterone in conscious and anaesthetized pregnant rats

1984 ◽  
Vol 102 (3) ◽  
pp. 357-363 ◽  
Author(s):  
B. J. Waddell ◽  
N. W. Bruce
Keyword(s):  
Production Rate ◽  
Clearance Rate ◽  
Blood Concentration ◽  
Constant Infusion ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Short Term ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Anaesthetized Rats

ABSTRACT Both production rate and metabolic clearance rate (MCR) of progesterone may vary rapidly and so effect short-term changes in blood concentration of the hormone. Here, a constant infusion and sampling technique was used to estimate these three characteristics of progesterone metabolism in seven conscious and ten anaesthetized rats on day 16 of pregnancy. After steady state was achieved, four samples were collected during a 1-h period from each rat. Mean values for production rate and MCR of progesterone in conscious rats were 14·0 ±1·4 μmol/day and 63·2 ± 6·2 litres/day respectively. Both values were substantially reduced in anaesthetized rats (8.6 ±0·8 μmol/ day and 39·4± 3·4 litres/day respectively) and so blood concentration was unchanged. The production rate was positively related to the total mass of luteal tissue (common correlation coefficient, r = 0·61, P <0·05). There were no consistent changes in the three characteristics with time but variation within rats was high. The estimated coefficients of variation for production rate, MCR and blood concentration within rats were 26, 18 and 17% in conscious and 27, 20 and 23% in anaesthetized rats respectively. Short-term changes in production rate and MCR generally were in the same direction (P <0·05). This reduced variation in blood concentration which would otherwise have occurred if production rate and MCR were unrelated. The pregnant rat is clearly capable of rapid shifts in production rate, MCR and blood concentration of progesterone and the positive relationship between production rate and MCR has a homeostatic effect on blood concentration. J. Endocr. (1984) 102, 357–363

Increased clearance of lactate after short-term training in men

1995 ◽  
Vol 79 (6) ◽  
pp. 1862-1869 ◽  
Author(s):  
S. M. Phillips ◽  
H. J. Green ◽  
M. A. Tarnopolsky ◽  
S. M. Grant
Keyword(s):  
Blood Lactate ◽  
Clearance Rate ◽  
Maximal Oxygen Consumption ◽  
Lactate Concentration ◽  
Blood Lactate Concentration ◽  
Constant Infusion ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Short Term ◽  
Mitochondrial Potential

A short-term training model previously shown to result in a tighter metabolic control in working muscle in the absence of an increase in mitochondrial potential was used to examine changes in lactate turnover. Lactate flux was studied before and after 10 days of cycle training [2 h/day at 59% maximal oxygen consumption (VO2max)] in untrained men [VO2max = 45.5 +/- 2.4 (SE) ml.kg-1.min-1). A primed constant infusion of L-[1–13C]lactate was used to examine lactate kinetics during a prolonged exercise protocol (90 min at 59% VO2max). Rate of appearance of lactate increased with exercise (P < 0.01), both pretraining (rest = 30.3 +/- 4.9 ml.kg-1.min-1, exercise = 115 +/- 14 ml.kg-1.min-1) and posttraining (rest = 28.4 +/- 4.7 ml.kg-1.min-1, exercise = 112 +/- 13 ml.kg-1.min-1). Despite a lower blood lactate concentration (P < 0.05) during exercise after training, there was no difference in the rate of appearance of lactate. Training increased (P < 0.05) the metabolic clearance rate of lactate during exercise from 36.8 +/- 4.8 to 51.4 +/- 6.8 ml.kg-1.min-1. These findings indicate that at least part of the lower exercising blood lactate observed after training is due to an increase in metabolic clearance rate. In addition, the lower intramuscular lactate levels suggest a decreased recruitment of glycolysis particularly early in exercise.

In Vivo Catabolism of Human Fibrinogen Fragment D in Normal Subjects and Patients with Liver Cirrhosis

1979 ◽  
Author(s):  
N. Ardaillou ◽  
J. Yvart ◽  
M.J. Larrieu
Keyword(s):  
Liver Cirrhosis ◽  
Polyacrylamide Gel Electrophoresis ◽  
Normal Subjects ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Compartment System ◽  
Human Fibrinogen ◽  
Chloramine T ◽  
Disappearance Curve

The in vivo catabolism of purified 131-I-fragment D (Fg D) was studied in comparison with that of 125-I-Fibrinogen (Fg) simultaneously injected in 6 controls and 8 patients with liver cirrhosis. Fg D, M.W. 85,000, was obtained following prolonged (24 hours) plasmin digestion of human Fg. Labelling was performed using the chloramine T method. Linlabelled and labelled Fg and Fg D were characterized hy immunoelectrophoresis and SDS Polyacrylamide gel electrophoresis. Radioactivity was measured in thrombin-clottable (Fg) and TCA-precipitable (Fg D) proteins from plasma. Labelled Fg D present in plasma samples 1, 6 and 12 hours following injection eluted from Sephadex G 2D0 at the same position as native Fg D. A two compartment system was derived from the corresponding plasma disappearance curves for both Fg and Fg D in controls and patients. In controls, the first component of Fg D disappearance curve represented 54.1±13.4% of the total clearance with T 1/2 of 2.5±0.9 hours. The T 1/2 of the second component was 3.9±1.0 hours, Fg D disappeared more rapidly from plasma than Fg, and the ratio of Fg D to Fg was 0.11-0,02. In patients with liver cirrhosis, there was a significant (p<0.005) increase of T 1/2 of the second component (13.6±2.6 hours), whereas the in vivo survival of Fg was normal (4 cases) or decreased (2 cases). These results suggest that the liver interfers with the metabolic clearance rate of Fg D.

Circulating galanin: origin, metabolism, and pharmacokinetics in anesthetized pigs

1992 ◽  
Vol 262 (1) ◽  
pp. E52-E57
Author(s):  
H. Harling ◽  
J. J. Holst
Keyword(s):  
Gastrointestinal Tract ◽  
Metabolic Clearance ◽  
Distribution Space ◽  
Metabolic Clearance Rate ◽  
Concentration Difference ◽  
Arterial Plasma ◽  
The Brain ◽  
Apparent Distribution ◽  
Negative Gradient

The concentration of galanin-like immunoreactivity (GAL-LI) was 12.9 +/- 0.9 pmol/l in porcine arterial plasma (n = 9) and ranged from 1 to 14 pmol/g in extracts of porcine gastrointestinal tract (n = 5), the colon being the richest gut segment. A significant (P less than 0.05) arteriovenous concentration difference of circulating endogenous GAL-LI occurred across the kidney (15.1 +/- 2.3 vs. 6.2 +/- 0.5 pmol/l) and a hind leg (15.7 +/- 2.5 vs. 10.2 +/- 1.0 pmol/l), whereas a negative gradient was observed across the intestine (12.5 +/- 2.0 vs. 17.7 +/- 3.3 pmol/l) of anesthetized pigs. Passage through the brain, liver, or lungs did not change the concentration of endogenous GAL-LI significantly. During basal circumstances, the major source of circulating GAL-LI is therefore the gut. During infusion of 20 pmol.kg-1.min-1 of synthetic porcine galanin, a significant extraction occurred across the kidney (64.8 +/- 4.3%), hind leg (20.3 +/- 3.8%), and liver (19.7 +/- 4.3%). The overall metabolic clearance rate was 37.8 +/- 3.7 ml.min-1.kg-1. The half-life of galanin in plasma was 4.6 +/- 0.3 min, and the apparent distribution space was 255.6 +/- 31.4 ml/kg. Incubation studies in vitro showed that the concentration of galanin, added to blood and plasma at 37 degrees C, was halved in 1 h, unless stabilized with EDTA and aprotinin.

A primed-infusion technique for rapid estimation of the metabolic clearance rate of 1,25(OH)2D3

1987 ◽  
Vol 253 (3) ◽  
pp. E246-E250
Author(s):  
R. Eastell ◽  
B. L. Riggs ◽  
R. Kumar
Keyword(s):  
Production Rate ◽  
Clearance Rate ◽  
Human Subjects ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Study Interval ◽  
Normal Women ◽  
Infusion Technique

We have developed a rapid primed-infusion technique for the measurement of the metabolic clearance and production rate of 1,25-dihydroxyvitamin D3 in normal human subjects and experimental animals. With this method, an estimate of the metabolic clearance rate of 1,25-dihydroxyvitamin D3 can generally be made within 3 to 4 h. Initial studies in five dogs using 1,25-[3H]-dihydroxyvitamin D3 (180 Ci/mmol) allowed us to determine the optimal ratio of loading dose to infusion rate that resulted in the most rapid attainment of steady-state levels of plasma radioactivity. By use of this technique we found that the metabolic clearance rate of 1,25-dihydroxyvitamin D3 in dogs was 6.3 +/- 1.2 ml/min (mean +/- SD); the production rate of the hormone was 0.40 +/- 0.25 microgram/day (20.4 +/- 14.4 ng . kg-1 . day-1). In eight normal women, aged 28-51 yr, the metabolic clearance rate for 1,25-dihydroxyvitamin D3 was 25.9 +/- 4.7 ml/min; the production rate was 1.38 +/- 0.45 microgram/day (20.7 ng . kg-1 . day-1). The advantages of this method relative to ones used in the past are that it can be performed quickly (generally within 3-4 h) with the use of only tracer amounts of this hormone (equivalent to 1.1% of the production rate). With this method, no assumptions about the most appropriate model to which to fit the data need to be made. Because of its rapidity, no metabolites of the injected 1,25-dihydroxyvitamin D3 are formed during the study interval.

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