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R. D. G. MILNER, F. N. LEACH, M. A. ASHWORTH, A. CSER, and P. M. B. JACK

SUMMARY

Insulin release was studied in vitro using pieces of pancreas from rabbits of between 24 days gestational age and 6 weeks postnatal age. When allowance was made for the fraction of pancreas which was endocrine, 16·5 mm-glucose caused increasing stimulation of insulin release as development advanced and 3·3 mm-glucose caused a similar rate of secretion at all ages. Secretion was not significantly influenced by insulin destruction in the incubation medium. Glucagon (5 μg/ml) did not stimulate insulin secretion from 24-day foetal pancreas but did so postnatally. Theophylline (1 mmol/l) stimulated insulin release at all ages and was equipotent on 24-day foetal pancreas in 3·3 or 16·5 mm-glucose. The stimulation of insulin release from 24-day foetal pancreas by 1 mm-theophylline occurred in the absence of extracellular glucose, pyruvate, fumarate and glutamate and in the presence of mannoheptulose and 2-deoxyglucose (each 3 mg/ml). Adrenaline (1 μmol/l) and diazoxide (250 μg/ml) abolished or attenuated the stimulation of insulin release by glucose, leucine plus arginine or theophylline from 24-day foetal, 1 day and 6 weeks postnatal pancreas. The stimulation of insulin release from 6-week-old pancreas by 1 mm-barium was blocked by adrenaline and diazoxide but the effect became less with increasing immaturity.

The experimental results illustrate some of the ways in which insulin secretion by the rabbit β cell changes as a function of development and draw attention to the importance of glucose and cyclic adenosine monophosphate in this process.

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F. HERTELENDY, H. TODD, and G. POUNDS

It has been reported that hypoglycin and hypoglycin-like compounds, including 4-pentenoic acid, inhibit fatty acid oxidation and gluconeogenesis as well as inducing profound hypoglycaemia (Bressler, Corredor & Brendel, 1969). A vinyl group separated by two carbon atoms from the carboxyl group is apparently a structural requirement for biological effects (Corredor, Brendel & Bressler, 1967), valeric acid, the saturated analogue of 4-pentenoic acid, being inactive. In the course of investigations on insulin secretion in ruminants we observed that valerate is a very potent insulin secretogogue (Horino, Machlin, Hertelendy & Kipnis, 1968). In this communication evidence is presented which shows that 4-pentenoic acid is also a potent stimulant of insulin secretion in the sheep and, contrary to observations in non-ruminants, it can induce hyperglycaemia and inhibit lipolysis.

Four castrated male sheep (35–50 kg) were infused through a polyethylene catheter inserted into a jugular vein after a 24-h fast. Two animals received I

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Rahman M Hafizur, Randa Babiker, Sakina Yagi, Sidra Chishti, Nurul Kabir, and M Iqbal Choudhary

between the effects of G. alata and Gb, it can be suggested that the mode of action of G. alata extract might be mediated by an enhanced insulin secretion. This assumption was confirmed by our biochemical examination, which revealed enhanced insulin

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F Bertuzzi, C Berra, C Socci, A M Davalli, G Calori, M Freschi, L Piemonti, P De Nittis, G Pozza, and A E Pontiroli

Abstract

It has been shown that peripheral glucagon secreting cells (A-cells) are lost during most of the isolation procedures employed for pig islets. Loss of A-cells decreases intra-islet glucagon levels and cAMP levels in B-cells and might reduce glucose-induced insulin release. This study was designed to test this hypothesis, by evaluating the effects of culture of porcine islets with exogenous glucagon on insulin secretion and on insulin and cAMP content in islets. Islets were isolated from adult 2-year old Large White pigs using an automated method. The number of A-cells was calculated by immunostaining for glucagon in islets before and after isolation and a significant decrease in A-cells was observed. After an overnight culture, islets were cultured for 48 h in a standard medium (CMRL 1066, 10% foetal calf serum, 1% antibiotics, 1% glutamine) alone or in the presence of glucagon at two different concentrations (1·0 and 10·0 μm); exposure to glucagon was either continuous or alternated with periods of incubation in CMRL 1066 alone. After the 48-h culture in standard medium, the islet glucagon response to arginine was almost negligible and significantly lower than that observed in human islets. After culture, islet insulin response to glucose, and islet insulin and cAMP content were evaluated; continuous exposure to glucagon did not produce any significant effect on either insulin secretion or insulin and cAMP content; in contrast, discontinuous exposure to glucagon induced a significant improvement in insulin release, proportional to glucagon concentrations (integrated insulin release: −13·8 ±20·12 pg/islet/20 min in control islets, 111·0±50·73 and 144·7± 47·54 pg/islet/20 min in islets exposed to 1·0 and 10·0 μg glucagon respectively; n=10, P=0·01). Intracellular insulin and cAMP content of islets cultured in different culture media were not different. In conclusion, discontinuous exposure of isolated pig islets to exogenous glucagon induced a significant increase in glucose-induced insulin release which was not associated with an increase in cAMP content. The fact that even in the presence of glucagon the secretory activity of pig islets was lower than the reported activity of human or rat islets suggests that glucagon is only one of the factors involved in the poor insulin responsiveness of pig islets.

Journal of Endocrinology (1995) 147, 87–93

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MC Sugden and MJ Holness

Insulin secretion and glucose tolerance were studied in 20-week-old male and female offspring of rat dams maintained on an isocaloric 20% or 8% protein diet during pregnancy and lactation after transfer to the same diet at weaning. Protein-restricted male and female offspring were also weaned onto a 20% protein diet. In males, post-absorptive insulin concentrations were suppressed by protein restriction from conception to adulthood (by 41%; P<0.001); however, basal insulin levels were 2.6-fold higher (P<0.001) if protein restriction was limited to gestation and lactation. Post-absorptive insulinaemia in females was unaffected by early or sustained protein restriction, but was lower than for males in the control group and the group exposed to protein restriction during early life alone (by 40% (P<0.001) and 52% (P<0.001) respectively). Plasma insulin/blood glucose ratios were higher in males compared with females in both control and early protein-restricted groups (1.6-fold (P<0.05) and 2.3-fold (P<0.001) respectively). A positive linear relationship existed between mean ambient insulin and glucose concentrations in males (r=1.0) and females (r=0.9), but the gradient was 12.4-fold greater (P<0.01) in males. beta-Cell function was evaluated after intravenous glucose challenge. In males, the acute insulin response and the suprabasal 30-min area under the insulin curve were dramatically higher in rats exposed to protein restriction during gestation and lactation alone (2.6- and 2.8-fold respectively; P<0.001). In contrast, these parameters were lowered by extending the exposure to protein restriction to adulthood in males, and by either early or prolonged exposure to protein restriction in females. The insulin resistance index was increased (2.5-fold; P<0.001) in male, but not female, rats exposed to protein restriction during gestation and lactation alone, and was not increased by extending the period of protein restriction to adulthood in either sex. Thus the data have demonstrated gender-specific lowering of insulin sensitivity due to protein restriction during early life only. The insulinogenic index (insulin response in relation to prevailing glycaemia) was increased in male, but not female, rats exposed to protein restriction during gestation and lactation alone (3.0-fold; P<0.001). A modest decline in insulin secretion in the female groups exposed to protein restriction until either the end of lactation or adulthood was compensated by increased insulin sensitivity, as demonstrated by significant decreases in the insulin resistance index in both groups (by 48% and 52% respectively; P<0.05). Glucose disappearance rates did not differ between the male and female control or early protein-restricted groups but were higher in both male (31%; P<0.05) and female groups (46%; P<0.001) exposed to protein restriction from conception to adulthood. Marked gender differences in glucose-stimulated insulin secretion were not associated with gender differences with respect to glucose tolerance. Our data therefore demonstrated that exposure to protein restriction during early life alone leads to relative insulin resistance and hyperinsulinaemia in adulthood, but this relationship is gender specific, observed only in males, and glucose tolerance is maintained.

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S B Richardson, T Laya, and M VanOoy

Abstract

Arginine vasopressin (VP) activates phospholipase C (PLC) and stimulates insulin secretion and inositol phosphate (insP) production in mouse islets and clonal hamster beta cells (HIT). The insulin response to VP is reportedly dependent on extracellular glucose and there is evidence that glucose also activates PLC. The interactions of VP and glucose have been further examined in HIT cells. Glucose stimulated insulin secretion but not insP production and VP stimulated both insulin secretion and insP production in the absence of extracellular glucose. However, in the presence of glucose the insulin and insP responses to VP were potentiated. The phorbol ester, tetradecanoylphorbol acetate (TPA), which activates protein kinase C (PKC), stimulated basal insulin secretion but inhibited insP production. In the presence of submaximal concentrations of VP, 100 nmol/l TPA inhibited VP-stimulated inositol monophosphate production and there was no additivity of stimulated insulin secretion. With a maximal (10 nmol/l) concentration of VP, TPA caused additive insulin secretion and insP levels were stimulated above baseline. Twenty-four hour preincubation with TPA to down-regulate PKC did not inhibit the insulin response to VP. We conclude that extracellular glucose does not activate PLC and is not required for VP-stimulated insulin secretion although it potentiates VP-stimulated insulin secretion and insP production.

Journal of Endocrinology (1995) 145, 221–226

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P. M. Jones and F. M. Mann

ABSTRACT

Burmese Russell's viper venom (RVV) caused a dose-and temperature-dependent stimulation of insulin secretion from islets of Langerhans isolated from rat pancreas by collagenase digestion. RVV stimulated both basal and glucose-induced insulin secretion at concentrations which did not compromise islet cell viability as assessed by exclusion of trypan blue dye. The effects of RVV on insulin secretion could not be attributed to the activation of protein kinase C (PKC), since down-regulation of PKC by prolonged exposure to a tumour-promoting phorbol ester did not abolish subsequent secretory responses to RVV. However, RVV-induced insulin secretion was inhibited in the absence of extracellular Ca2 +, and RVV did not stimulate insulin secretion from Ca2+-clamped electrically permeabilized islets at either substimulatory (50 nmol/l) or stimulatory (10 μmol/l) concentrations of Ca2 +, suggesting that changes in cytosolic Ca2+ are important in the stimulation of insulin secretion by RVV. The phospholipase A2 (PLA2) inhibitor quinacrine caused a dose-dependent inhibition of RVV-induced insulin secretion, suggesting that the activation of PLA2, perhaps in response to Ca2+ influx, may be partially responsible for RVV-induced insulin secretion.

Journal of Endocrinology (1993) 136, 27–33

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H. P. T. Ammon, C. Reiber, and E. J. Verspohl

ABSTRACT

Feedback inhibition of glucose-mediated insulin release has repeatedly been demonstrated in isolated pancreatic islets and in the perfused pancreas. It was the aim of the present study to determine whether inhibition occurs through a long-loop (plasma concentration of insulin) or a short-loop (local concentration) action of insulin. The perfused rat pancreas was used, with different perfusion rates and different insulin concentrations in the medium. Increasing the flow rate from 1 to either 3 or 6 ml/min gradually decreased the insulin concentration in the effluent, at stimulatory concentrations of glucose (11·1 and 16·7 mmol/l). Under the same conditions, however, the integrated amount of insulin released over a period of 30 min was significantly enhanced. When exogenous insulin (2·7 and 5·4 μmol/l) was added to the perfusion medium, insulin secretion in the presence of 11·1 or 16·7 mmol glucose/l at flow rates of 3 and 6 ml/min was diminished. This effect was most prominent with 1 1·1 mmol glucose/l and 2·7 μmol exogenous insulin/l at all flow rates (except 1 ml/min), as well as at the high perfusion flow rates with other glucose concentrations. Insulin secretion was not affected by 5·4 μmol exogenous insulin/l at 1 ml/min or by 2·7 μmol exogenous insulin/l at 3 ml/min. The data support a negative feedback inhibition of insulin secretion by secreted insulin, since insulin secretion was decreased by either adding exogenous insulin or by lowering endogenous insulin as the consequence of increased flow rates. They also suggest that the local extracellular concentration of insulin is of more importance than the plasma concentration, consistent with the concept of a short-loop feedback as already claimed for other hormones and/or neurotransmitters.

Journal of Endocrinology (1991) 128, 27–34

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K Ohtani, H Shimizu, Y Tanaka, N Sato, and M Mori

Abstract

Pioglitazone hydrochloride (AD-4833), one of the thiazolidinedione analogs, is a new anti-diabetic agent which improves peripheral insulin resistance in diabetic patients. We determined the direct effect of AD-4833 on insulin secretion in HIT-T 15 cells. The effects of AD-4833 (10−7 m to 10−5 m) on insulin secretion were examined in 3 and 7 mm glucose-containing F-12 K media. The addition of 10−5 m AD-4833 significantly increased insulin secretion in both media, but its stimulatory effect was more potent in the medium containing 7 mm glucose. The addition of 10−5 m AD-4833 caused an immediate, significant increase in cytosolic free Ca2+ concentration ([Ca2+]i). Nifedipine at all concentrations from 10 to 1000 nm significantly attenuated insulin secretion by 10−5 m AD-4833. In addition, 10−5 m AD-4833 failed to stimulate insulin secretion in the Ca2+-free Kreb's-Ringer bicarbonate buffer. These data indicated that AD-4833 stimulates in vitro insulin secretion in HIT-T 15 cells, perhaps by inducing Ca2+ influx.

Journal of Endocrinology (1996) 150, 107–111

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ERIK GYLFE

SUMMARY

The efflux of radioactivity after loading with trace amounts of tritiated 5-hydroxytryptamine ([3H]5-HT) or 5-hydroxytryptophan ([3H]5-HTP) was studied in perifused β-cellrich pancreatic islets from ob/ob mice. Analysis of the effluent revealed that more than 90% of the radioactivity was released as [3H]5-HT after loading with [3H]5-HTP. Increasing the concentration of glucose in the perifusion medium from 3 to 20 mmol/l enhanced the efflux when islets from fed mice were used and this effect was potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Whereas 20 mm-glucose alone did not stimulate the efflux of 5-HT from islets isolated from mice starved for 3 days, a stimulatory effect was observed in the presence of IBMX. Stimulation of the efflux of radioactivity by glucose was inhibited if calcium was omitted from or adrenaline added to the medium. The results are consistent with the concept of exocytotic release of 5-HT occurring in response to stimulation of insulin secretion, although basal non-exocytotic transport must also be occurring across the β-cell membrane.