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The effect of alterations in catecholamine metabolism on arginine-induced insulin release was studied in the anaesthetized rat. Alpha-methyl-p-tyrosine, which inhibits catecholamine synthesis, guanethidine, which prevents catecholamine release, and reserpine, which depletes catecholamine stores, all enhanced the secretion of insulin and reduced the rise in blood glucose after the amino acid load. Adrenalectomy, with or without corticosterone replacement, had a similar effect. Adrenaline inhibited the insulin response to arginine. It was concluded that in the rat, adrenergic mechanisms modulate the insulin response to arginine.

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C. M. Gronda, G. B. Diaz, J. P. F. C. Rossi, and J. J. Gagliardino


Using medium with a low ionic strength, a low concentration of Ca2+ and Mg2+ and devoid of K+, we have measured Ca2+-ATPase activity in the homogenates of rat islets preincubated for 3 min with several hormones in the presence of 3·3 mmol glucose/l. Insulin secretion was also measured in islets incubated for 5 min under identical experimental conditions. Islets preincubated with glucose (3·3 mmol/l) and glucagon (1·4 μmol/l) plus theophylline (10 mmol/l), ACTH (0·11 nmol/l), bovine GH (0·46 μmol/l), prolactin (0·2 μmol/l) or tri-iodothyronine (1·0 nmol/l) have significantly lower Ca2+-ATPase activity than those preincubated with only 3·3 mmol glucose/l. All these hormones increased the release of insulin significantly.

Dexamethasone (0·1 μmol/l) and somatostatin (1·2 μmol/l) enhanced the Ca2+-ATPase activity while adrenaline (10 μmol/l) did not produce any significant effect on the activity of the enzyme. These hormones decreased the release of insulin significantly.

These results demonstrated that islet Ca2+-ATPase activity was modulated by the hormones tested. Their inhibitory or enhancing effect seemed to be related to their effect on insulin secretion; i.e. those which stimulated the secretion of insulin inhibited the activity of the enzyme and vice versa. Hence, their effect on insulin secretion may be due, in part, to their effect on enzyme activity and consequently on the concentration of cytosolic Ca2+. These results reinforce the assumption that Ca2+-ATPase activity participates in the physiological regulation of insulin secretion, being one of the cellular targets for several agents which affect this process.

Journal of Endocrinology (1992) 134, 221–225

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Foetal lambs (100–150 days' gestation) with indwelling vascular catheters were used to study the regulation of the insulin concentration in the plasma of foetal lambs in utero. Immediately after the implantation of the catheters the insulin concentration in foetal plasma was significantly correlated with the foetal glucose and fructose concentrations and with the maternal glucose concentration. On the next day the foetal insulin concentration was significantly correlated only with the maternal glucose concentration.

Both glucose and fructose, when infused i.v., increased the insulin concentration in foetal plasma, but the increases were slow and far less than those observed in newborn lambs infused with glucose or fructose. Intravenous infusion of isoprenaline or glucagon did not alter the plasma insulin concentration of foetal lambs, but both caused a rapid increase in the insulin concentration of newborn lambs. Glucagon did not potentiate the insulin response to glucose. Addition of aminophylline to a glucagon infusion failed to cause insulin secretion in foetal lambs. The results suggest the cyclic-3′,5′-AMP dependent part of the insulin secretory mechanism does not develop fully before the last week of gestation.

Gel filtration of foetal plasma on Sephadex indicated that the immunoreactive material present was insulin. No significant amounts of proinsulin were found.

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The influence of the pituitary gland of lean and genetically obese (ob/ob) mice on insulin secretion from microdissected pancreatic islets of lean and ob/ob mice has been studied by perifusing the pituitaries of these animals in series with the isolated islets and measuring insulin secretion at 5-min intervals over a period of 60 min.

It has been shown that the pituitary perifusate of both lean and obese mice stimulate insulin secretion from lean mouse islets but not from obese mouse islets. The maximum stimulation occurs in the first 10 min and with the lean mouse pituitaries returns to the basal level in about 20 min, whereas with the obese mouse pituitaries insulin secretion is about double that from the control islets even after 40 min.

A concentration of pure porcine ACTH equivalent to about three times the amount released from the pituitary gland under the experimental conditions used, caused only a small stimulation of insulin release. Possible interpretations of these findings and further lines of investigation are discussed.

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HT Al-Majed, PM Jones, SJ Persaud, D Sugden, GC Huang, S Amiel, and BJ Whitehouse

It has previously been suggested that ACTH and ACTH-related peptides may act as paracrine modulators of insulin secretion in the islets of Langerhans. We have, therefore, examined the expression and function of the ACTH receptor (the melanocortin 2 receptor, MC2-R) in human and mouse primary islet tIssue and in the MIN6 mouse insulinoma cell line. Mouse MC2-R mRNA was detected in both MIN6 cells and mouse islet tIssue by PCR amplification of cDNA. In perifusion experiments with MIN6 pseudo-islets, a small, transient increase in insulin secretion was obtained when ACTH(1-24) (1 nM) was added to medium containing 2 mM glucose (control) but not when the medium glucose content was increased to 8 mM. Further investigations were performed using static incubations of MIN6 cell monolayers; ACTH(1-24) (1 pM-10 nM) provoked a concentration-dependent increase in insulin secretion from MIN6 monolayer cells that achieved statistical significance at concentrations of 1 and 10 nM (150 +/- 13.6% basal secretion; 187 +/- 14.9% basal secretion, P<0.01). Similar responses were obtained with ACTH(1-39). The phosphodiesterase inhibitor IBMX (100 microM) potentiated the responses to sub-maximal doses of ACTH(1-24). Two inhibitors of the protein kinase A (PKA) signaling pathway, Rp-cAMPS (500 microM) and H-89 (10 microM), abolished the insulin secretory response to ACTH(1-24) (0.5-10 nM). Treatment with 1 nM ACTH(1-24) caused a small, statistically significant increase in intracellular cAMP levels. Secretory responses of MIN6 cells to ACTH(1-24) were also influenced by changes in extracellular Ca2+ levels. Incubation in Ca2+-free buffer supplemented with 0.1 mM EGTA blocked the MIN6 cells' secretory response to 1 and 10 nM ACTH(1-24). Similar results were obtained when a Ca2+ channel blocker (nitrendipine, 10 microM) was added to the Ca2+-containing buffer. ACTH(1-24) also evoked an insulin secretory response from primary tIssues. The addition of ACTH(1-24) (0.5 nM) to perifusions of mouse islets induced a transient increase in insulin secretion at 8 mM glucose. Perifused human primary islets also showed a secretory response to ACTH(1-24) at basal glucose concentration (2 mM) with a rapid initial spike in insulin secretion followed by a decline to basal levels. Overall the results demonstrate that the MC2-R is expressed in beta-cells and suggest that activation of the receptor by ACTH initiates insulin secretion through the activation of PKA in association with Ca2+ influx into beta-cells.

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An inverse age-related pattern of GH secretion has been identified in immature ducks between 2 and 9 weeks of age, the plasma level of GH falling progressively from 30–40 ng/ml at 2 weeks of age to the adult level (< 10 ng/ml) by 9 weeks of age. This decrease in GH secretion was not accompanied by any age-related changes in the concentrations of plasma immunoreactive insulin or glucagon-like immunoreactivity or in plasma glucose or free fatty acid level.

In 4- to 6-week-old ducklings the intravenous infusion of insulin (2·5 or 10 mu./kg per min for 30 min) and glucagon (0·1 or 0·5 μg/kg per min for 30 min) induced some inhibition of GH secretion, independently of changes in blood glucose level. These results suggest that although insulin and especially glucagon have direct effects on GH secretion in the duck, maturational differences in pancreatic function are unlikely to be causally related to the decrease in GH secretion during growth.

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J. A. Charlton, C. J. Thompson, J. M. Palmer, S. Thornton, and P. H. Baylis


To investigate whether hyperglycaemic ketoacidotic diabetic rats continue to osmoregulate the secretion of arginine vasopressin (AVP), male Wistar rats were injected with streptozotocin (150 mg/kg body weight). Rats rendered diabetic were maintained on protamine–zinc insulin (PZI) for 11 days (insulin-treated rats; n = 35), after which PZI was withdrawn for 72 h in half the rats (insulin-withdrawn rats). Insulin-withdrawn and -treated rats were divided into two groups; one was injected i.p. with distilled water (20 ml/kg) and the other with hypertonic saline (500 mmol NaCl/l; 20 ml/kg), and killed 30 min after injection. Insulin-withdrawn rats (water loaded and osmotically stimulated) were hyperglycaemic (16·5 ± 0·8 and 16·5 ± 0·9 mmol glucose/l respectively) and ketotic (2077 ± 664 and 1474 ± 170 μmol acetoacetate/l respectively). Insulin-treated rats were euglycaemic and non-ketotic. Osmotic manipulation caused similar changes in plasma sodium in both insulin-withdrawn and -treated rats. Plasma AVP was low in the water-loaded rats (0·6 ± 0·1 and 4·5 ± 0·9 pmol/l in the insulin-treated and -withdrawn rats respectively) and increased in rats injected with hypertonic saline (1·2 ± 1·8 and 35·2 ± 17·9 pmol/l respectively). There was no evidence of hypotension and hypovolaemia in any group of rats. Linear regression analysis defined the functions: plasma AVP = 2·56 (plasma Na – 141), r = +0·63, P < 0·01 for hyperglycaemic ketotic rats; plasma AVP = 0·83 (plasma Na – 146), r = +0·78, P < 0·001 for insulin-treated animals. The slopes and abscissal intercepts were significantly (P < 0·05) different. We conclude that the hyperglycaemic ketotic diabetic rat retains the ability to osmoregulate AVP secretion.

Journal of Endocrinology (1989) 123, 413–419

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H Cherif, B Reusens, S Dahri, C Remacle, and J-J Hoet


Islets of rat fetuses born to mothers fed a low protein diet (LP) have a depressed insulin secretion in vitro in response to secretagogues. These fetuses have lower plasma levels of taurine than controls. The aim of this study was to analyze the effect of taurine on fetal islets insulin secretion. After 5 days of culture in serum containing standard RPMI medium, islets were cultured for 2 days in serum-free DME/F12 medium with 8·2 or 16·7 mm glucose alone or with taurine at 0·3 or 3 mm. They were then incubated for 120 min in Krebs Ringer solution with glucose alone (5·6 or 16·7 mm) or glucose (5·6 mm) added to leucine or arginine (both at 10 mm). In both concentrations of glucose, taurine increased the fractional insulin release by islets stimulated with secretagogues tested during the incubation. The effect did not seem to be mediated by changes in cAMP content. In a second set of experiments, islets cultured in RPMI medium for 7 days were incubated in the presence of Krebs Ringer solution with leucine (10 mm) or with sulfur amino acids (taurine at 10 mm, methionine or cysteine at 5 mm) for 120 min. Taurine and methionine stimulated insulin release at the same magnitude as leucine, whereas cysteine had no effect. In conclusion, taurine enhances insulin secretion by fetal islets, at least in vitro. Low taurine levels in fetuses from LP mothers might be implicated in their depressed insulin secretion.

Journal of Endocrinology (1996) 151, 501–506

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P. M. B. JACK and R. D. G. MILNER


Foetal rabbits were injected with adrenocorticotrophin (ACTH), decapitated, or decapitated and injected simultaneously with ACTH or cortisol in utero on day 24 of gestation. The foetuses were killed after Caesarian section on day 29, and blood was collected for measurement of plasma insulin concentration and pancreatic tissue was obtained for incubation in physiological buffer. Insulin release from the pancreatic tissue of decapitated foetuses was significantly greater than that from the pancreas of control litter-mates when incubated in media containing 3·3 mm-glucose, 16·5 mm-glucose or 16·5 mm-glucose plus 5 μg glucagon/ml, but was similar when the incubation medium contained 3·3 or 16·5 mm-glucose plus 1 mm-theophylline or 3·3 mm-glucose plus 60 mm-potassium. The pancreata of decapitated or intact foetuses injected with ACTH did not differ significantly from control foetuses in terms of insulin release in response to glucose in vitro. The plasma insulin concentration of decapitated foetuses and decapitated foetuses injected with ACTH was raised, whereas that of intact foetuses injected with ACTH was similar to that of the control foetuses. Cortisol injection at the time of decapitation resulted in a high rate of foetal mortality.

The results indicate that foetal ACTH or foetal adrenocortical secretion influences the normal development of glucose-mediated insulin secretion in the rabbit and that exogenous ACTH corrects the effect of decapitation on β cell function in vitro but not on plasma insulin concentration.

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R. J. Lacey, H. C. Cable, R. F. L. James, N. J. M. London, J. H. B. Scarpello, and N. G. Morgan


The effects of the mixed α/β-agonist adrenaline on insulin secretion from isolated human islets of Langerhans were studied. In static incubation experiments, adrenaline (0·1 nmol/l to 10 μmol/l) caused a concentration-dependent inhibition of glucose-induced insulin secretion from isolated human islets. However, perifusion experiments revealed that the time-course of the secretory changes induced by adrenaline was complex. When employed at a high concentration (1 μmol/l), adrenaline caused a sustained inhibition of glucose-induced insulin secretion, which could be relieved by the addition of the α2-antagonist yohimbine (10 μmol/l). By contrast, infusion of adrenaline at a lower concentration (10 nmol/l), produced a large initial potentiation of glucose-induced insulin secretion. This response was, however, short-lived and followed by sustained inhibition of secretion, which could be relieved by yohimbine (10 μmol/l). The initial stimulation of insulin secretion provoked by 10 nmol adrenaline/l was abolished when islets were incubated in the presence of the β-antagonist, propranolol (1 μmol/l), consistent with activation of β-adrenoceptors. In support of this, treatment of human islets with the selective β2-agonist clenbuterol, was also associated with marked stimulation of insulin secretion. By contrast, each of two selective β3-agonists tested failed to alter insulin secretion from human islets. The results indicate that human pancreatic B-cells are equipped with both α2-and β2-adrenoceptors which can affect insulin secretion. Adrenaline interacts with both of these but the α2-response is predominant and can overcome the tendency of β2-adrenoceptors to potentiate insulin release.

Journal of Endocrinology (1993) 138, 555–563