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C Gravena, PC Mathias, and SJ Ashcroft

Fatty acids have both stimulatory and inhibitory effects on insulin secretion. Long-term exposure to fatty acids results in impaired insulin secretion whilst acute exposure has generally been found to enhance insulin release. However, there are conflicting data in the literature as to the relative efficacy of various fatty acids and on the glucose dependency of the stimulatory effect. Moreover, there is little information on the responses of human islets in vitro to fatty acids. We have therefore studied the acute effects of a range of fatty acids on insulin secretion from rat and human islets of Langerhans at different glucose concentrations. Fatty acids (0.5 mM) acutely stimulated insulin release from rat islets of Langerhans in static incubations in a glucose-dependent manner. The greatest effect was seen at high glucose concentration (16.7 mM) and little or no response was elicited at 3.3 or 8.7 mM glucose. Long-chain fatty acids (palmitate and stearate) were more effective than medium-chain (octanoate). Saturated fatty acids (palmitate, stearate) were more effective than unsaturated (palmitoleate, linoleate, elaidate). Stimulation of insulin secretion by fatty acids was also studied in perifused rat islets. No effects were observed at 3.3 mM glucose but fatty acids markedly potentiated the effect of 16.7 mM glucose. The combination of fatty acid plus glucose was less effective when islets had been first challenged with glucose alone. The insulin secretory responses to fatty acids of human islets in static incubations were similar to those of rat islets. In order to examine whether the responses to glucose and to fatty acids could be varied independently we used an animal model in which lactating rats are fed a low-protein diet during early lactation. Islets from rats whose mothers had been malnourished during lactation were still able to respond effectively to fatty acids despite a lowered secretory response to glucose. These data emphasise the complex interrelationships between nutrients in the control of insulin release and support the view that fatty acids play an important role in glucose homeostasis during undernutrition.

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R. D. G. MILNER, A. J. BARSON, and M. A. ASHWORTH

SUMMARY

Pieces of human foetal pancreas were incubated under control conditions and in media containing different stimuli of insulin release. Insulin secretion was stimulated from the pancreases of foetuses (83–625 g body weight) which were of 16–24 weeks gestational age. Potassium (60 mmol/l), barium (2·54 mmol/l) and ouabain (10−5 mol/l) were effective stimuli in all experiments. Glucagon (5 μg/ml), theophylline (1 mmol/l) and dibutyryl 3′,5′-cyclic adenosine monophosphate (1 mmol/l) stimulated insulin secretion in media containing 0, 0·6 or 3·0 mg glucose/ml. Theophylline and dibutyryl 3′,5′-cyclic adenosine monophosphate were effective in all experients and glucagon stimulated insulin release in four out of six experiments. At all ages studied, histological examination of the pancreas after each experiment revealed islets of Langerhans containing β cells. In most cases the islets were of the mantle type but occasionally bipolar islets were seen. Cellular normality, as judged by light microscopy, was preserved after periods of incubation for up to 5½ h. Glycogen was demonstrable in the pancreatic acinar tissue but not in the islets.

The results of these experiments indicate that, between the 16th and 24th week of foetal life, the human β cell is capable of releasing insulin in vitro when stimulated appropriately.

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J. C. Escolar, R. Hoo-Paris, Ch. Castex, and B. Ch. J. Sutter

ABSTRACT

The direct effect of hypothermia on the inhibition of insulin secretion may result from inhibition of the availability of energetic substrates and/or the lack of metabolic signals. In order to verify this hypothesis, the insulin secretion and the main metabolic glucose pathways were measured during the incubation of rat islets. In the presence of 16·7 mmol glucose/l and at 37 °C, insulin secretion was 925 ± 119 μU/2 h per ten islets. With the same experimental conditions, glucose utilization, determined as the formation of 3H2O from [5-3H]glucose was 2225 ±184 pmol/2 h per ten islets, glucose oxidation measured as the formation of 14CO2 from [U-14C]glucose was 673 ± 51 pmol/2 h per ten islets, pentose cycle determined as the formation of 14CO2 from either [1-14C]glucose or [6-14C]glucose was 37 ± 5 pmol/2 h per ten islets; glucose oxidation by the tricarboxilic acid cycle, calculated to be the difference between glucose oxidation and pentose cycle values, was 636 pmol/2 h per ten islets.

Hypothermia highly inhibited glucose-induced insulin secretion and glucose utilization. Inhibition of insulin secretion was partial at 27 °C since it was 2·5 times lower than that at 37 °C, and it was complete at 17 °C. Glucose oxidation in the tricarboxilic acid cycle was markedly inhibited by hypothermia since the inhibition coefficient (Q10) between 37 and 27 °C was 5. In contrast, glucose oxidation in the pentose phosphate shunt was enhanced at 27 °C, reaching 92 ± 17 pmol/2 h per ten islets, and it was inhibited relatively little at 17 °C.

These results suggest that hypothermia markedly inhibits glucose metabolism with the exception of the pentose pathway which could play an important role by inducing the insulin secretion at 27 °C.

Journal of Endocrinology (1990) 125, 45–51

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L M McShane, N Irwin, D O’Flynn, Z J Franklin, C M Hewage, and F P M O’Harte

Introduction Through advances in our understanding of the pathways involved in glucose homeostasis, and an appreciation that type 2 diabetes (T2DM) is a bihormonal disorder, it is clear that abnormalities of insulin secretion and action in T2

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WS Zawalich and KC Zawalich

Islets from fed and 24-h-fasted rats were studied immediately after collagenase isolation. (1) After a 24-h fast, the insulin secretory responses to 8 mM glucose measured during perifusion were reduced by more than 90% from islets of fasted donors. (2) Increasing glucose to 11 or 27.5 mM resulted in enhanced insulin secretion from islets of fasted animals. (3) Fasting did not reduce islet insulin content. (4) Responses to 8 or 27.5 mM glucose were not affected if fatty acid-free albumin was used during the perifusion. (5) Inclusion of alpha-ketoisocaproate (5 mM), monomethyl succinate (10 mM) or carbachol (10 microM) significantly amplified insulin release from fasted islets in the simultaneous presence of 8 mM glucose. (6) Phospholipase C activation by glucose, carbachol or their combination was not adversely affected by fasting. (7) The response to the protein kinase C activator, phorbol 12-myristate 13-acetate (500 nM), was reduced by about 60% after fasting. (8) Extending the fast to 48 h resulted in a severe decline in response to 11 mM glucose; however, the further addition of 10 microM carbachol still enhanced release from these islets. The results confirm that caloric restriction impairs islet sensitivity to glucose stimulation and that protein kinase C may be involved in the reduction of glucose-induced insulin release from these islets. The activation of phospholipase C by cholinergic stimulation may contribute to the maintenance of insulin secretion from calorically restricted animals. These results also demonstrate that free fatty acids are not essential for glucose to evoke secretion from isolated islets of fasted donors.

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J C Parker, K S Lavery, N Irwin, B D Green, B Greer, P Harriott, F P M O’Harte, V A Gault, and P R Flatt

actions of the native hormones. Therefore, this study examined the effects of daily administration of GIP(3–42) and GLP-1(9–36)amide on metabolic parameters associated with glucose homeostasis and insulin secretion in obese diabetic ob / ob mice

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J. M. BASSETT and G. D. THORBURN

SUMMARY

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

SUMMARY

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

SUMMARY

One rabbit foetus in a litter was decapitated on day 24 of gestation. On day 29 the litter was killed and blood was collected from all foetuses for the measurement of plasma insulin concentration. The pancreas of the decapitated foetus and that of the control litter-mate with the nearest headless body weight were cut into pieces and incubated in a physiological buffer containing 0·6 or 3·0 mg glucose/ml. The pancreas of the decapitated foetus secreted significantly more insulin than that of the control foetus in either concentration of glucose in the medium. Higher insulin secretion from the decapitated foetus persisted for 4·5 h of incubation and was demonstrable in both the first 5 and subsequent 25 min of incubation when the pancreas was initially transferred to incubation medium containing 3·0 mg glucose/ml. The mean plasma insulin concentration of the foetuses decapitated on day 24 was higher on day 29 than that of the control foetuses but there was no significant difference between the concentration of insulin in the pancreas of the two groups of animals. The results indicate that removal of the foetal head influences the intrauterine development of the rabbit β-cell.

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A Martinez, R Pio, J Lopez, and F Cuttitta

Adrenomedullin (AM) is a ubiquitous peptide hormone which, among other functional roles, reduces insulin secretion in the pancreas. Recently we have described the interaction between AM and the complement regulator protein factor H, which results in mutual modulation of their respective functions. Here we identify the expression of factor H in the beta cells of the rat pancreatic islets by immunohistochemistry and multiple immunofluorescence followed by confocal microscopy. In addition, double immunogold staining under the electron microscope showed coexistence of insulin and factor H immunoreactivities within the same secretory granules; interestingly, factor H staining was found in the electron-lucent haloes whereas the insulin antibody labeled preferentially the dense cores. The existence of factor H mRNA in the pancreas was confirmed by RT-PCR and in situ hybridization. The function of factor H in the pancreas was investigated with an insulin secretion assay. Addition of factor H to freshly isolated islets in the presence of AM resulted in a further reduction in insulin secretion with a concomitant elevation of cAMP, suggesting that factor H increases AM function in glucose homeostasis. The expression of factor H in the pancreas may play other important roles such as protection against complement-mediated cell lysis.