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C.S.T. Hii and S.L. Howell

ABSTRACT

The effects of some flavonoids, a group of naturally occurring pigments one of which has been claimed to possess antidiabetic activities, on insulin release and 45Ca2+ handling have been studied in isolated rat islets of Langerhans. Insulin release was enhanced by approximately 44–70% when islets were exposed to either (−)epicatechin (0·8 mmol/l) or quercetin (0·01–0·1 mmol/l); others such as naringenin (0·1 mmol/l) and chrysin (0·08 mmol/l) inhibited hormone release by approximately 40–60%. These effects were observed only in the presence of 20 mmol glucose/l. Quercetin (0·01 mmol/l) and (−)epicatechin (0·8 mmol/l) both inhibited 45Ca2+ efflux in the presence and absence of extracellular Ca2+. In the presence of 20 mmol glucose/l both the short-term (5 min) and steady-state (30 min) uptake of 45Ca2+ were significantly increased by either quercetin or (−)epicatechin. These results suggest that the stimulatory compounds such as quercetin and (−)epicatechin may, at least in part, exert their effects on insulin release via changes in Ca2+ metabolism.

J. Endocr. (1985) 107, 1–8

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S. L. HOWELL and K. W. TAYLOR

SUMMARY

The origin of the pronounced hypoglycaemic phase during the onset of alloxan diabetes in the rabbit has been investigated.

Blood sugar and serum insulin levels were recorded 6, 12 and 24 hr. after alloxan administration and were related to changes in the insulin content of the pancreas and to the rate of insulin release from pancreas slices in vitro at similar time intervals. During the phase of hypoglycaemia, serum insulin levels were elevated, and insulin release from the pancreas slices was markedly increased, but a decrease in the quantity of insulin extractable from the pancreas occurred during the same 6 hr. period.

These results indicate that the hypoglycaemia may result from an unregulated release of preformed insulin from the β cells, during their destruction after the administration of alloxan.

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Marianne Hall, S. L. Howell, D. Schulster, and M. Wallis

We have used fractionation on density gradients of Percoll to separate the cell types in the rat anterior pituitary gland and to produce a purified preparation of somatotrophs. The method differs from those described previously which used, for example, albumin or Ficoll gradients, in being more rapid and avoiding low temperatures, and therefore gives cells with improved viability. Anterior pituitary glands from male rats were dispersed with trypsin to produce 1·5 × 106–2·0 × 106 cells/gland. These were fractionated on hyperbolic density gradients of Percoll. Two bands of cells containing somatotrophs were detected, one of which (band A; density 1·075–1·082 g/cm3) contained approximately 90% somatotrophs, whereas the other (band B; density 1·055–1·068 g/cm3) contained about 70% somatotrophs mixed with other cells, especially lactotrophs. Cells in band A appeared more responsive to secretagogues than those in band B; growth hormone secretion was stimulated markedly by cyclic AMP derivatives and prostaglandin E2, and inhibited by somatostatin. Such purified somatotrophs are well suited to biochemical studies on the mechanism of the control of growth hormone secretion.

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J. M. Fyles, M. A. Cawthorne, and S. L. Howell

ABSTRACT

The sympathetic nervous system is believed to play a part in the control of insulin release from the pancreatic islets of Langerhans. Stimulation of α-adrenoceptors is thought to inhibit the release of insulin whereas stimulation of β-adrenoceptors enhances insulin release. The present experiments were conducted to establish the existence of β-adrenergic receptors on guinea-pig and rat islet cells and to quantify them using the selective β-adrenergic ligands [3H]dihydroalprenolol (DHA) and [125I]cyanoiodopindolol (CYP).

Guinea-pig islets had 62 fmol β-adrenoceptors/mg protein using [3H]DHA, corresponding to 43 700 binding sites/cell and 25 fmol β-adrenoceptors/mg protein using [125I]CYP, corresponding to 17 400 sites/cell. Rat islet cells were found to have 4·6 fmol β-adrenoceptors/mg protein using [125I]CYP, corresponding to 7200 sites/cell. Adenylate cyclase activation exhibited a positive dose–response relationship when exposed to the β-adrenoceptor agonist isoprenaline, with a maximum response (190 ± 21% above basal) at 10 μmol isoprenaline/l. This response was abolished with 1 μmol/l of the β-adrenergic antagonist 1-alprenolol. Insulin secretion in the presence of 10 mmol glucose/l, but in the absence of the α-adrenoceptor blocker phentolamine, was not affected by 10 μmol isoprenaline/l. However, perifusion experiments showed that secretion of insulin from isolated rat islets in the presence of 10 mmol glucose/l was significantly increased (332%) by 10 μmol isoprenaline/l in the presence of 10 μmol phentolamine/l.

These results suggest that binding of selective radio-labelled ligands occurs to β-adrenergic receptors on the B cell surface of the islets of Langerhans, and that these receptors are functionally coupled to insulin secretion through modulation of adenylate cyclase activity.

J. Endocr. (1986) 111, 263–270

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D. L. Economides, R. J. S. Howell, I. Gilbert, L. A. Perry, and T. Chard

ABSTRACT

Blood was taken from three healthy female and three healthy male volunteers every 20 s for 15 min. The serum level of oestradiol was measured and the pattern of variation assessed by a cusum plot of the sequential data, by autocorrelation of the detrended serial data, and by looking for pulses. In two cases the variation in oestradiol values was greater than that which could be attributed to variation in the assay. Both these subjects showed a significant overall change in values during the sampling period (an increase and a decrease). There was no trend in the remaining four subjects. In two of the six subjects there was significant autocorrelation of detrended sequential levels. Defining a 'pulse' as three times the assay coefficient of variation no more pulses were identified than was expected from random fluctuations. By frequency analysis the two subjects with significant autocorrelation showed periodic fluctuations of approximately 70/h and 9/h respectively. It is apparent that both the rate of sampling and the method of analysis greatly influence the evaluation of pulsatile release of oestradiol.

J. Endocr. (1988) 118, 161–165

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I. C. GREEN, S. EL SEIFI, D. PERRIN, and S. L. HOWELL

It was possible to vary the replication rate of cells in the islets of Langerhans of adult rats. The rate of incorporation of [3H]thymidine into islet DNA was increased at 12 days of pregnancy to 2·3-fold and at 19 days of pregnancy to 1·3-fold that in control rats. Ovariectomy, which leads to lowered plasma levels of ovarian steroids, induced a significant and unexpected increase in the rate of thymidine incorporation into islets; treatment of ovariectomized rats with 2 μg oestradiol/rat per day for 3 days reversed this upward trend. When islets from normal rats were cultured with certain combinations of steroid hormones including progesterone and oestradiol or with insulin secretagogues, with the exception of glucose, a decreased rate of DNA synthesis was usually found compared with that in control rats.

Since treatment with steroid hormones inhibited incorporation of [3H]thymidine into islets from ovariectomized rats and directly reduced incorporation into tissue-cultured islets from normal rats in vitro, it was concluded that increased levels of steroid hormones were not responsible for the higher rate of regeneration of islet cells in pregnant rats. However, a striking correlation between levels of blood glucose in vivo and DNA synthesis in islets in vitro has been observed.

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A. J. BONE, R. W. GUMPERT, S. L. HOWELL, J. SHELDON, M. TELLEZ-YUDILEVICH, M. TYHURST, P. G. WHITTAKER, and F. ZAHEER

The regulation of insulin biosynthesis, and insulin and glucagon secretion have been investigated in a human islet cell adenoma, by incubation of tumour fragments.

Both biosynthesis and secretion of insulin were strongly stimulated by incubation of islet tumour cells in the presence of increasing glucose concentrations in the range 2–8 mmol/l. However, 20 mm-glucose or 20 mm-glucose plus isobutyl methylxanthine (IBMX), both of which provide potent secretagogues for normal B cells, failed to stimulate proinsulin biosynthesis and secretion from the tumour cells. Overall rates of secretion, expressed as a proportion of total insulin content, were up to 20-fold higher than those expected for normal pancreatic tissue.

Glucagon secretion from the tumour was stimulated by low glucose concentrations; normal A cells also respond in this way under these conditions. However, no stimulation of glucagon secretion occurred in the presence of IBMX. There was therefore a major alteration in the regulation both of insulin and glucagon secretion, in that release of neither hormone was stimulated by cyclic AMP.

Ultrastructural examination showed the tumour to be rather heterogeneous. A and B cells with normal storage granule content and structure were seen, as well as a rather larger number of B cells containing some granules of atypical appearance. The insulin content of the tumour (13 i.u./g wet wt) was consistent with 6–8% of the tumour cells being B cells.