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I.N.R.A. Theix, 63110 Beaumont, France, and *Department of Animal Physiology and Nutrition, The University of Leeds, Leeds, LS5 3HL, England
(Received 3 May 1974)
It has been demonstrated that histamine injections in guinea-pigs cause peptic ulceration and death from peritonitis secondary to perforation of the ulcer and that the thyroid gland of these animals contains a non-thyroxine factor which regulates gastric HCl secretion (Watman & Nasset, 1949, 1951) and which protects against gastric ulceration. Thus we have investigated the effect of porcine calcitonin (P-CT) given intragastrally on histamine-induced peptic ulcer and gastric HCl secretion in guinea-pigs.
In the first experiment 18 young black and white male (180–200 g) guinea-pigs were used. They were given food and water ad libitum throughout the experiment. Twelve of them were surgically thyroidectomized (TX) (with preservation of the parathyroid glands) 10 days before the beginning of the experiment. These animals were supplemented with thyroxine (T4)
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Even though several attempts have been made to attribute a physiological role to calcitonin (CT) during calcium stress (Gray & Munson, 1969), the role of CT in calcium homeostasis during normocalcaemia has not yet been defined.
The role of normocalcaemic secretion of CT in calcium homeostasis was investigated in young pigs of either sex weighing 20–26 kg. Pigs were anaesthetized with phencyclidine and pentobarbitone, after an overnight fast. A femoral artery and a vein were catheterized and the thyroid gland was isolated (Care, Cooper, Duncan & Orimo, 1968). After taking five to six control blood samples for calcium estimation, the thyroid gland was removed and the plasma calcium concentration measured every 10 min and corrected for variation in plasma total solids (Care, Duncan & Webster, 1967).
In all seven experiments, thyroidectomy produced a significant elevation of plasma calcium concentration over a period of 47–118 min after thyroidectomy (Fig. 1).
To
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SUMMARY
The influence of magnesium on calcitonin (CT) secretion rate has been studied in pigs by perfusion of porcine thyroid glands, isolated in situ, under controlled conditions of flow rate and blood electrolyte composition. At concentrations of 4·4–12·7 mequiv./l, magnesium stimulated CT secretion in the presence of a normal calcium concentration in the perfusate. The maximum effect was reached at a concentration of about 7 mequiv. Mg/l. At higher magnesium concentrations, the secretion rate of CT tended to revert towards that found with concentrations of calcium and magnesium within the normal range. When hypermagnesaemia was superimposed on hypercalcaemia there was a fall in the secretion rate of CT as the Mg: Ca ratio in the perfusing blood plasma approached 1. The stimulatory effect of hypermagnesaemia was usually less than that caused by an equimolar increase in plasma calcium concentration. The results suggest that changes in plasma magnesium concentration probably do not influence CT secretion under normal conditions.
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SUMMARY
A possible role of the adenyl cyclase system in calcitonin (CT) release has been investigated by measurement of the rate of CT secretion in isolated porcine thyroid glands perfused in situ. Dibutyryl cyclic AMP increased the rate of secretion of CT and this effect was enhanced by theophylline. Concentrations of glucagon as low as 1·4 nm (5 ng/ml) induced a significant increase in the rate of CT secretion when precautions were taken to prevent enzymic degradation of glucagon. This stimulatory effect of glucagon on CT secretion was also increased by theophylline. Significant stimulation of CT release was demonstrated with adrenaline in the presence of α-adrenergic blockade with phentolamine and could be inhibited by β-adrenergic blockade with propranolol. In contrast, thyrotrophin, tri-iodothyronine, serotonin, parathyroid hormone and cyclic guanosine monophosphate had no significant acute effects on CT secretion. It is suggested that the C-cells of the thyroid gland contain an adenyl cyclase system similar to that described in other tissues and that physiological concentrations of glucagon and catecholamines may influence the response of the C-cell to plasma calcium concentration.
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SUMMARY
The role of calcitonin (CT) in postprandial calcium homeostasis and the possibility of a gastroentero-thyroid C-cell system was studied in young pigs. When pigs were fasted for more than 36 h and then fed, the plasma calcium concentration decreased by 6·1% over a period of 60–120 min after a meal. Since in thyroidectomized pigs the plasma calcium concentration increased by 7·2% when they were fed after a fast of 36 h it is suggested that increased CT secretion assists in the control of postprandial hypercalcaemia. Direct measurement of CT in peripheral plasma supported this suggestion. Because the plasma calcium concentration in an intact pig on a normal feeding regime does not change after a meal, the possibility of the involvement of one or more humoral factors in the stimulation of thyroid C-cells was investigated. Exogenous gastrin and endogenous gastrin stimulated by meat extract were both previously shown by us to increase CT secretion rate. This observation has now been extended to include other stimuli to endogenous gastrin, e.g. glycine and gastric distension. Furthermore, partially purified enteroglucagon increased CT secretion rate from perfused thyroid glands, isolated in situ. Stimulation of endogenous entero-glucagon by the intraduodenal administration of glucose, and probable stimulation of endogenous pancreozymin by intraduodenal fat, were both associated with an increased CT secretion rate from the thyroid gland.
These results support the concept of a gastroentero-thyroid C-cell system which serves to stimulate CT secretion and thus to protect the skeleton from excessive bone resorption during periods of dietary sufficiency.
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SUMMARY
Our earlier observation that pentagastrin is a calcitonin (CT) secretagogue was confirmed and extended to include both synthetic human gastrin I and pure porcine gastrin II. The latter hormone was shown to stimulate the secretion rate of CT from thyroid preparations perfused in situ in anaesthetized pigs at concentrations (0·5 nmol/l) similar to those found after stimulation of gastrin production by a meat extract placed in the stomach (0·2 nmol/1). These concentrations of plasma gastrin are considerably less than those found in man in both pernicious anaemia and the Zollinger—Ellison syndrome, whereas the mean fasting plasma gastrin concentrations in normal human beings and pigs are similar. It is suggested that the comparatively high incidence of parathyroid hyperactivity in association with the Zollinger—Ellison syndrome may be a consequence of an increased CT secretion rate induced by hypergastrinaemia. Furthermore, the existence of a gastrointestinal—thyroid C cell system is proposed as an integral part of postprandial calcium homeostasis.
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An antibody to porcine calcitonin (CT) was selected which cross-reacted completely to bovine CT in a radioimmunoassay using a synthetic porcine CT preparation (CT-s) labelled with 125I (Lequin, Hackeng, Schopman & Care, 1970). With this radioimmunoassay it has been possible to measure CT concentrations in samples of bovine peripheral and thyroid venous plasma. All concentrations of CT reported here are expressed in terms of immunologically active CT-s/ml. The standard error of the CT measurements was ± 50 pg CT-s/ml over the range of concentration 250–2000 pg/ml.
One lobe of the thyroid gland was isolated in situ in each of three calves (33–38 kg body wt) and in one adult Jersey cow (300 kg body wt). The glands were perfused with blood which contained various concentrations of calcium. Glucagon and the kallikrein inhibitor (KI) aprotinin (Zymofren) were also added in an experiment with the cow to give perfusing concentrations of
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SUMMARY
Hypocalcaemia was produced by i.v. infusion of EDTA into pigs from which the thyroid venous effluent could be quantitatively collected. Calcitonin in the effluent was measured by radioimmunoassay. Reduction of plasma calcium concentration rapidly suppressed the secretion of calcitonin. In contrast, as plasma calcium was raised slowly from hypocalcaemic levels by infusion of CaCl2, calcitonin secretion quickly returned and increased rapidly. The secretion rate observed when the plasma calcium concentration had been raised from hypocalcaemia to the initial normocalcaemic level was 3½–10 times greater than that observed during the normocalcaemia which pertained at the start of each experiment. A previous period of hypocalcaemia also produced an exaggerated response to a subsequent hypercalcaemic stimulus. It is suggested that the preconditioned response of calcitonin secretion increases the efficiency of the role of calcitonin in calcium homeostasis.
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Abstract
Transgenic mice were made by introducing extra copies of the mouse insulin-like growth factor-II (IGF-II) gene driven by the bovine keratin 10 promoter (BKVI). The adult plasma IGF-II levels were elevated at least three times in one line. In this line, there was a lower lipid content of both brown and white adipose depots at 2–4 months of age, and 40% less fat in the carcass at 7–9 months. The low lipid phenotype was not detected in the carcass at 2 weeks after birth. The lean characteristic was attributed to circulating IGF-II because the transgene was not expressed in fat. At 2–4 months of age, the transgenes oxidized more oral lipid, and less of this lipid was incorporated into the whole body and the epididymal fat. In contrast, the interscapular brown adipose tissue maintained lipid incorporation and lipoprotein lipase activity despite its reduced size. The altered activity of the brown adipose tissue may account for the gradual onset and persistence of the lean feature of the transgenic mice. There were no substantial changes in lipogenesis which could account for the low fat content. The plasma levels of IGF-I, insulin, glycerol, non-esterified fatty acids, triacylglycerols and glucose were not greatly changed and the pituitary GH content was within the normal range.
Journal of Endocrinology (1994) 143, 433–439
