Bulletin et mémoires de l'Académie royale de médecine de Belgique, 1996
Na/Ca exchange is an important regulatory mechanism of the cytosolic free Ca2+ concentration in m... more Na/Ca exchange is an important regulatory mechanism of the cytosolic free Ca2+ concentration in most cells. This transporter, localized at the level of the plasma membrane, represents with the plasma membrane Ca2+ ATPase, one of the two systems allowing active Ca2+ extrusion from the cells. Renewed interest for this system comes from recent advances in the molecular biology of the exchanger and the identification of the major role played by the exchanger in Ca2+ extrusion from cardiac cells. These recent progresses may allow a better understanding of the role played by Na/Ca in Physiology and in Physiopathology, e.g. in cardiac ischemia.
American Journal of Physiology-Endocrinology and Metabolism, 1990
The presence of different types [long lasting (L) and transient (T)] of active voltage-operated C... more The presence of different types [long lasting (L) and transient (T)] of active voltage-operated Ca2+ channels in islet cells was investigated by comparing the effects of Cd2+, Ni2+, and 1,4-dihydropyridines on 45Ca uptake, 45Ca efflux, and insulin release in intact rat pancreatic islets. In several other excitable cells the L-channel has been shown to be modulated by 1,4-dihydropyridines and Cd2+, whereas the T-channel was reported to be sensitive to Ni2+. Nifedipine and Cd2+ inhibited whereas BAY K 8644 enhanced the glucose (11.1, 22.2 mM)-stimulated short-term 45Ca uptake, 45Ca efflux, and insulin release. In contrast, the stimulatory effects of glucose (11.1, 22.2 mM) on 45Ca uptake, 45Ca efflux, and insulin release were unaffected by Ni2+. These findings confirm that glucose provokes Ca2+ entry mainly by activating voltage-sensitive Ca2+ channels of the L-type and suggest that the B-cell plasma membrane is not equipped with active T-type Ca2+ channels.
The Journal of pharmacology and experimental therapeutics, 1989
The present study aimed at comparing the effects of pinacidil, a putative K+ channel opener, and ... more The present study aimed at comparing the effects of pinacidil, a putative K+ channel opener, and diazoxide on ionic and secretory events in rat pancreatic islets. Pinacidil and diazoxide provoked a dose-dependent increase in 86Rb outflow from pancreatic islets perifused in the presence of glucose. Both drugs inhibited the glucose- and tolbutamide-induced increase in 45Ca outflow and insulin release whereas failing to affect the ionic and secretory responses to K+ depolarization. Pinacidil and diazoxide, in contrast to quinine, failed to affect 86Rb outflow from pancreatic islets stimulated by the Ca++-ionophore A23187. Pinacidil as well as diazoxide abolished the glucose-induced increase in [Ca++]i but did not modify the rise in [Ca++]i provoked by KCl. Lastly, both drugs were shown to stimulate an ouabain-resistant modality of 86Rb inflow into the islet cells. The close similarities between the ionic and secretory events mediated by pinacidil and diazoxide suggest that pinacidil co...
The Journal of pharmacology and experimental therapeutics, 1991
Minoxidil sulfate is an antihypertensive agent belonging to the new class of vasodilators, the &q... more Minoxidil sulfate is an antihypertensive agent belonging to the new class of vasodilators, the "K+ channel openers." The present study was undertaken to characterize the effects of minoxidil sulfate on ionic and secretory events in rat pancreatic islets. The drug unexpectedly provoked a concentration-dependent decrease in 86Rb outflow. This inhibitory effect was reduced in a concentration-dependent manner by glucose and tolbutamide. Minoxidil sulfate did not affect 45Ca outflow from islets perfused in the presence of extracellular Ca++ and absence or presence of glucose. However, in islets exposed to a medium deprived of extracellular Ca++, the drug provoked a rise in 45Ca outflow. Whether in the absence or presence of extracellular Ca++, minoxidil sulfate increased the cytosolic free Ca++ concentration of islet cells. Lastly, minoxidil sulfate increased the release of insulin from glucose-stimulated pancreatic islets. These results suggest that minoxidil sulfate reduces t...
Recent in vivo and in vitro experiments suggested that the smooth muscle relaxation mediated by d... more Recent in vivo and in vitro experiments suggested that the smooth muscle relaxation mediated by diverse pharmacologic agents resulted from K + channel opening. Pinacidil, cromakalim, nicorandil, RP 49356, minoxidil sulfate and diazoxide belong to this new group of smooth muscle relaxants : the "K + channel openers". Because modifications in the K + permeability are known to represent a critical event in the insulin-releasing process, numerous studies have been performed in order to examine the putative effects of K + channel openers on B-cell function. The aim of the present review is to summarize these experimental data which are sometimes divergent. Under physiological conditions, the maintenance of homeostatic blood glucose concentrations is mainly dependent on an appropriate secretion of insulin from the pancreatic B-cell. The primary physiological stimulant and metabolic substrate of the B-cell is the molecule of glucose. Today, it is generally believed that the metabolism of the nutrient in the pancreatic B-cell leads to an extensive remodeling of ionic fluxes across the plasma membrane (1). Radioisotopic and electrophysiological experiments revealed that a rise in the extracellular glucose concentration initially provokes a decrease in membrane permeability to K + (2,3). This reduction in B-cell membrane K + permeability appears to reflect the closure of ATP-sensitive K + channels resulting from the increase in the ATP/ADP ratio mediated by glucose metabolism (4). Notably, the activity of the ATP-regulated K + channels equipping the B-cell plasma membrane is also reduced by hypoglycemic sulfonylureas (4-6). Because the resting potential of the pancreatic B-cell is mainly determined by a high permeability to K + ions, the decrease in K + channels activity leads to membrane depolarization.
Potassium channels, which are regulated by changes in intracellular levels of adenosine triphosph... more Potassium channels, which are regulated by changes in intracellular levels of adenosine triphosphate (ATPsensitive K+ channels or KAW channels), have been identified in cardiac cells,l pancreatic B-cells,2 skeletal muscle: smooth muscle> central neurons: and adenohypophysis cells.e It has been suggested that the so-called potassium channel openers (PCO's), a new class of compounds that specifically enhance K+ channel permeability of cell membranes, may open the KAW channel in a number of tissue^.^-^^ However, the unique implication of this channel in the mode of action of PCOs still remains
The nitric oxide (NO) d onor SIN-1 (3.morpholinosydnonimine) induced a concentrationdependent inh... more The nitric oxide (NO) d onor SIN-1 (3.morpholinosydnonimine) induced a concentrationdependent inhibition of the secretory response to glucose. The negative insulinotropic action of SIN-1 was attenuated by the hypoglycemic sulfonylurea gl~benclam~de. Moreover, the NO donor enhanced 86Rb outflow from perfused islets and reduced the glucose-induced increase in 45Ca outflow. The present data provide further evidence that NO donors impair the secretory response Ko glucose, at least in part, by activating the ATPsensitive K' channels.
The possible participation of enzymatic methylation reactions in the process of insulin release w... more The possible participation of enzymatic methylation reactions in the process of insulin release was investigated in rat pancreatic islets. The combination of 3-deazaadenosine and DL-homocysteine impaired the incorporation of 3H-methyl from L-[methyl-3H]methionine into endogenous islet proteins and phospholipids, but failed to affect turnover in the phosphatidylinositol cycle. The inhibitors of methylation decreased insulin release evoked by D-glucose or the combinations of D-glucose and gliclazide, L-leucine and L-glutamine, or Ba2+ and theophylline. The inhibitors of methylation did not impair either the oxidation of D-glucose or affect its capacity to decrease K+ conductance, stimulate Ca2+ inflow and provoke 45Ca accumulation in pancreatic islets. It is proposed that, in the process of insulin secretion, a methyl acceptor protein and/or phospholipid play(s) a limited modulatory role in the coupling of cytosolic Ca2+ accumulation to exocytosis.
The Journal of pharmacology and experimental therapeutics, 1996
The present study was undertaken to characterize the effects of BPDZ 62, an original pyridothiadi... more The present study was undertaken to characterize the effects of BPDZ 62, an original pyridothiadiazine derivative structurally related to both diazoxide and pinacidil, on ionic and secretory events in the rat pancreatic islet cells. BPDZ 62 increased the rate of 86Rb outflow from islets perfused in the presence or absence of extracellular glucose. These effects persisted in the absence of extracellular Ca++ but were abolished by glibenclamide. Such data support the view that BPDZ 2 activates ATP-sensitive K+ (K(ATP)) channels. This proposal was substantiated by the finding that the drug enhanced the flow of current through K(ATP) channels in excised inside-out membrane patches. BPDZ 62 markedly decreased 45Ca uptake, 45Ca outflow and insulin output from islets incubated in the presence of 16.7 mM glucose. By contrast, the drug did not affect the increase in 45Ca outflow and 45Ca uptake mediated by K+ depolarization. In single B cells, BPDZ 62 inhibited the glucose but not the KCl-in...
The diagnostic value of the dexamethasone suppression test (DST) in "endogenous&quot... more The diagnostic value of the dexamethasone suppression test (DST) in "endogenous" depression was evaluated in 209 psychiatric inpatients. A high incidence of abnormal DST results was observed in "endogenous" depressives (52%), schizo-affective (69%) and borderline patients (38%). However, 25% of the patients with other psychiatric disease also failed to suppress on the DST. Diagnostic criteria, previous history of alcoholism, psychiatric drug treatment, age and sex did not significantly affect DST performance. The present data do not indicate that the DST represents a highly specific marker of "endogenous" depression.
Abstract Glucose and other nutrients which stimulate insulin release increase the rate of H+ gene... more Abstract Glucose and other nutrients which stimulate insulin release increase the rate of H+ generation and inhibit Na+Ca2+ counter-transport in the pancreatic B-cell. It is proposed that the latter phenomena are linked together by interference with an ionophoretic system. Indeed, in an artificial model, it is possible to mimick the process of Ca2+ countertransport and its inhibition in response to intracellular acidosis, by using native ionophores extracted from isolated pancreatic islets.
The metabolism of -L-glucose pentaacetate and its interference with the catabolism of L-[U-14 C]g... more The metabolism of -L-glucose pentaacetate and its interference with the catabolism of L-[U-14 C]glutamine, [U-14 C]palmitate, D-[U-14 C]glucose, and D-[5-3 H]glucose were examined in rat pancreatic islets. Likewise, attention was paid to the effects of this ester on the ...
Advances in Experimental Medicine and Biology, 1979
In the stimulus-secretion coupling for insulin release, a remodelling of ionic fluxes in the panc... more In the stimulus-secretion coupling for insulin release, a remodelling of ionic fluxes in the pancreatic B-cell may represent the essential link between the site of identification of secretagogues and the site of release of secretory granules (1). This paper reviews the participation of several cations (K+, Na+, H+, Mg2+, Ba2+, and Ca2+) in the process of insulin release and in delineating the influence of insulinotropic agents, especially glucose, upon the handling of such cations.
1. 3-Phenylpyruvate caused a dose-related stimulation of insulin release from rat pancreatic isle... more 1. 3-Phenylpyruvate caused a dose-related stimulation of insulin release from rat pancreatic islets deprived of exogenous nutrient or incubated in the presence of 5.6 or 8.3 mM-D-glucose. 2. 3-Phenylpyruvate inhibited insulin release evoked by high concentrations of D-glucose (16.7 or 27.8 mM) or 4-methyl-2-oxopentanoate (10.0 mM). This inhibitory effect appeared to be attributable to impairment of 2-oxo-acid transport into the mitochondria, with resulting inhibition of D-glucose, pyruvate or 4-methyl-2-oxopentanoate oxidation. 3. 3-Phenylpyruvate failed to affect the oxidation of, and secretory response to, L-leucine, and did not augment insulin release evoked by a non-metabolized analogue of the latter amino acid. 4. L-Glutamine augmented 3-phenylpyruvate-induced insulin release. The release of insulin evoked by the combination of 3-phenylpyruvate and L-glutamine represented a sustained phenomenon, abolished in the absence of extracellular Ca2+ or the presence of menadione and pot...
Na+/Ca2+ exchange in the B cell was recently characterized by measuring intracellular-Na(+)-depen... more Na+/Ca2+ exchange in the B cell was recently characterized by measuring intracellular-Na(+)-dependent 45Ca2+ uptake in isolated rat pancreatic islet cells. The aim of the present study was to investigate the regulation of this process. Extracellular pH (pHo) and intracellular pH (pHi) markedly affected Na+/Ca2+ exchange. A fall of 0.04 unit in pHi decreased the exchange by 45%, whereas a rise of 0.13 unit increased the uptake by 70%. Mitochondrial poisons (oligomycin, antimycin A and 2,4-dinitrophenol) inhibited reverse Na+/Ca2+ exchange by about 25-50%. The exchanger displayed a low Q10 (temperature coefficient), indicating that it is only indirectly dependent on metabolic energy. The phorbol ester phorbol 12-myristate 13-acetate did not affect Na+/Ca2+ exchange. Likewise, lowering the extracellular K+ concentration did not inhibit 45Ca2+ uptake. In conclusion, the pHi and the metabolic state of the cell may represent important modulatory signals by which insulin secretagogues such...
Oral glucose tolerance tests were performed on 218 individuals, representative of 1000 employees ... more Oral glucose tolerance tests were performed on 218 individuals, representative of 1000 employees of a pharmaceutical firm who cooperated in a diabetes detection drive. Blood was obtained fasting and at half hourly intervals following 50 g liquid glucose. ...
The mechanisms by which glucose provokes the intracellular accumulation of calcium in the B-cell ... more The mechanisms by which glucose provokes the intracellular accumulation of calcium in the B-cell were investigated by monitoring the efflux of 45Ca from preloaded and perifused rat pancreatic islets. Glucose provoked an initial fall followed by a secondary rise in 45Ca efflux. These two movements are sustained and reversible. They display distinct sensitivities towards glucose but both movements depend on the integrity of glucose metabolism in the islets. The secondary rise in 45Ca efflux reflects the rate of calcium influx through voltage-sensitive calcium channels and corresponds to a process of calcium-calcium exchange. Glucose gates the calcium channels by increasing the endogenous generation of reduced pyridine nucleotides. The absence of extracellular sodium reduced the efflux of 45Ca and the inhibitory effect of glucose on calcium outflow. This suggests the existence in the islets of a process of sodium-calcium countertransport responsible for calcium extrusion from the B-cel...
Bulletin et mémoires de l'Académie royale de médecine de Belgique, 1996
Na/Ca exchange is an important regulatory mechanism of the cytosolic free Ca2+ concentration in m... more Na/Ca exchange is an important regulatory mechanism of the cytosolic free Ca2+ concentration in most cells. This transporter, localized at the level of the plasma membrane, represents with the plasma membrane Ca2+ ATPase, one of the two systems allowing active Ca2+ extrusion from the cells. Renewed interest for this system comes from recent advances in the molecular biology of the exchanger and the identification of the major role played by the exchanger in Ca2+ extrusion from cardiac cells. These recent progresses may allow a better understanding of the role played by Na/Ca in Physiology and in Physiopathology, e.g. in cardiac ischemia.
American Journal of Physiology-Endocrinology and Metabolism, 1990
The presence of different types [long lasting (L) and transient (T)] of active voltage-operated C... more The presence of different types [long lasting (L) and transient (T)] of active voltage-operated Ca2+ channels in islet cells was investigated by comparing the effects of Cd2+, Ni2+, and 1,4-dihydropyridines on 45Ca uptake, 45Ca efflux, and insulin release in intact rat pancreatic islets. In several other excitable cells the L-channel has been shown to be modulated by 1,4-dihydropyridines and Cd2+, whereas the T-channel was reported to be sensitive to Ni2+. Nifedipine and Cd2+ inhibited whereas BAY K 8644 enhanced the glucose (11.1, 22.2 mM)-stimulated short-term 45Ca uptake, 45Ca efflux, and insulin release. In contrast, the stimulatory effects of glucose (11.1, 22.2 mM) on 45Ca uptake, 45Ca efflux, and insulin release were unaffected by Ni2+. These findings confirm that glucose provokes Ca2+ entry mainly by activating voltage-sensitive Ca2+ channels of the L-type and suggest that the B-cell plasma membrane is not equipped with active T-type Ca2+ channels.
The Journal of pharmacology and experimental therapeutics, 1989
The present study aimed at comparing the effects of pinacidil, a putative K+ channel opener, and ... more The present study aimed at comparing the effects of pinacidil, a putative K+ channel opener, and diazoxide on ionic and secretory events in rat pancreatic islets. Pinacidil and diazoxide provoked a dose-dependent increase in 86Rb outflow from pancreatic islets perifused in the presence of glucose. Both drugs inhibited the glucose- and tolbutamide-induced increase in 45Ca outflow and insulin release whereas failing to affect the ionic and secretory responses to K+ depolarization. Pinacidil and diazoxide, in contrast to quinine, failed to affect 86Rb outflow from pancreatic islets stimulated by the Ca++-ionophore A23187. Pinacidil as well as diazoxide abolished the glucose-induced increase in [Ca++]i but did not modify the rise in [Ca++]i provoked by KCl. Lastly, both drugs were shown to stimulate an ouabain-resistant modality of 86Rb inflow into the islet cells. The close similarities between the ionic and secretory events mediated by pinacidil and diazoxide suggest that pinacidil co...
The Journal of pharmacology and experimental therapeutics, 1991
Minoxidil sulfate is an antihypertensive agent belonging to the new class of vasodilators, the &q... more Minoxidil sulfate is an antihypertensive agent belonging to the new class of vasodilators, the "K+ channel openers." The present study was undertaken to characterize the effects of minoxidil sulfate on ionic and secretory events in rat pancreatic islets. The drug unexpectedly provoked a concentration-dependent decrease in 86Rb outflow. This inhibitory effect was reduced in a concentration-dependent manner by glucose and tolbutamide. Minoxidil sulfate did not affect 45Ca outflow from islets perfused in the presence of extracellular Ca++ and absence or presence of glucose. However, in islets exposed to a medium deprived of extracellular Ca++, the drug provoked a rise in 45Ca outflow. Whether in the absence or presence of extracellular Ca++, minoxidil sulfate increased the cytosolic free Ca++ concentration of islet cells. Lastly, minoxidil sulfate increased the release of insulin from glucose-stimulated pancreatic islets. These results suggest that minoxidil sulfate reduces t...
Recent in vivo and in vitro experiments suggested that the smooth muscle relaxation mediated by d... more Recent in vivo and in vitro experiments suggested that the smooth muscle relaxation mediated by diverse pharmacologic agents resulted from K + channel opening. Pinacidil, cromakalim, nicorandil, RP 49356, minoxidil sulfate and diazoxide belong to this new group of smooth muscle relaxants : the "K + channel openers". Because modifications in the K + permeability are known to represent a critical event in the insulin-releasing process, numerous studies have been performed in order to examine the putative effects of K + channel openers on B-cell function. The aim of the present review is to summarize these experimental data which are sometimes divergent. Under physiological conditions, the maintenance of homeostatic blood glucose concentrations is mainly dependent on an appropriate secretion of insulin from the pancreatic B-cell. The primary physiological stimulant and metabolic substrate of the B-cell is the molecule of glucose. Today, it is generally believed that the metabolism of the nutrient in the pancreatic B-cell leads to an extensive remodeling of ionic fluxes across the plasma membrane (1). Radioisotopic and electrophysiological experiments revealed that a rise in the extracellular glucose concentration initially provokes a decrease in membrane permeability to K + (2,3). This reduction in B-cell membrane K + permeability appears to reflect the closure of ATP-sensitive K + channels resulting from the increase in the ATP/ADP ratio mediated by glucose metabolism (4). Notably, the activity of the ATP-regulated K + channels equipping the B-cell plasma membrane is also reduced by hypoglycemic sulfonylureas (4-6). Because the resting potential of the pancreatic B-cell is mainly determined by a high permeability to K + ions, the decrease in K + channels activity leads to membrane depolarization.
Potassium channels, which are regulated by changes in intracellular levels of adenosine triphosph... more Potassium channels, which are regulated by changes in intracellular levels of adenosine triphosphate (ATPsensitive K+ channels or KAW channels), have been identified in cardiac cells,l pancreatic B-cells,2 skeletal muscle: smooth muscle> central neurons: and adenohypophysis cells.e It has been suggested that the so-called potassium channel openers (PCO's), a new class of compounds that specifically enhance K+ channel permeability of cell membranes, may open the KAW channel in a number of tissue^.^-^^ However, the unique implication of this channel in the mode of action of PCOs still remains
The nitric oxide (NO) d onor SIN-1 (3.morpholinosydnonimine) induced a concentrationdependent inh... more The nitric oxide (NO) d onor SIN-1 (3.morpholinosydnonimine) induced a concentrationdependent inhibition of the secretory response to glucose. The negative insulinotropic action of SIN-1 was attenuated by the hypoglycemic sulfonylurea gl~benclam~de. Moreover, the NO donor enhanced 86Rb outflow from perfused islets and reduced the glucose-induced increase in 45Ca outflow. The present data provide further evidence that NO donors impair the secretory response Ko glucose, at least in part, by activating the ATPsensitive K' channels.
The possible participation of enzymatic methylation reactions in the process of insulin release w... more The possible participation of enzymatic methylation reactions in the process of insulin release was investigated in rat pancreatic islets. The combination of 3-deazaadenosine and DL-homocysteine impaired the incorporation of 3H-methyl from L-[methyl-3H]methionine into endogenous islet proteins and phospholipids, but failed to affect turnover in the phosphatidylinositol cycle. The inhibitors of methylation decreased insulin release evoked by D-glucose or the combinations of D-glucose and gliclazide, L-leucine and L-glutamine, or Ba2+ and theophylline. The inhibitors of methylation did not impair either the oxidation of D-glucose or affect its capacity to decrease K+ conductance, stimulate Ca2+ inflow and provoke 45Ca accumulation in pancreatic islets. It is proposed that, in the process of insulin secretion, a methyl acceptor protein and/or phospholipid play(s) a limited modulatory role in the coupling of cytosolic Ca2+ accumulation to exocytosis.
The Journal of pharmacology and experimental therapeutics, 1996
The present study was undertaken to characterize the effects of BPDZ 62, an original pyridothiadi... more The present study was undertaken to characterize the effects of BPDZ 62, an original pyridothiadiazine derivative structurally related to both diazoxide and pinacidil, on ionic and secretory events in the rat pancreatic islet cells. BPDZ 62 increased the rate of 86Rb outflow from islets perfused in the presence or absence of extracellular glucose. These effects persisted in the absence of extracellular Ca++ but were abolished by glibenclamide. Such data support the view that BPDZ 2 activates ATP-sensitive K+ (K(ATP)) channels. This proposal was substantiated by the finding that the drug enhanced the flow of current through K(ATP) channels in excised inside-out membrane patches. BPDZ 62 markedly decreased 45Ca uptake, 45Ca outflow and insulin output from islets incubated in the presence of 16.7 mM glucose. By contrast, the drug did not affect the increase in 45Ca outflow and 45Ca uptake mediated by K+ depolarization. In single B cells, BPDZ 62 inhibited the glucose but not the KCl-in...
The diagnostic value of the dexamethasone suppression test (DST) in "endogenous&quot... more The diagnostic value of the dexamethasone suppression test (DST) in "endogenous" depression was evaluated in 209 psychiatric inpatients. A high incidence of abnormal DST results was observed in "endogenous" depressives (52%), schizo-affective (69%) and borderline patients (38%). However, 25% of the patients with other psychiatric disease also failed to suppress on the DST. Diagnostic criteria, previous history of alcoholism, psychiatric drug treatment, age and sex did not significantly affect DST performance. The present data do not indicate that the DST represents a highly specific marker of "endogenous" depression.
Abstract Glucose and other nutrients which stimulate insulin release increase the rate of H+ gene... more Abstract Glucose and other nutrients which stimulate insulin release increase the rate of H+ generation and inhibit Na+Ca2+ counter-transport in the pancreatic B-cell. It is proposed that the latter phenomena are linked together by interference with an ionophoretic system. Indeed, in an artificial model, it is possible to mimick the process of Ca2+ countertransport and its inhibition in response to intracellular acidosis, by using native ionophores extracted from isolated pancreatic islets.
The metabolism of -L-glucose pentaacetate and its interference with the catabolism of L-[U-14 C]g... more The metabolism of -L-glucose pentaacetate and its interference with the catabolism of L-[U-14 C]glutamine, [U-14 C]palmitate, D-[U-14 C]glucose, and D-[5-3 H]glucose were examined in rat pancreatic islets. Likewise, attention was paid to the effects of this ester on the ...
Advances in Experimental Medicine and Biology, 1979
In the stimulus-secretion coupling for insulin release, a remodelling of ionic fluxes in the panc... more In the stimulus-secretion coupling for insulin release, a remodelling of ionic fluxes in the pancreatic B-cell may represent the essential link between the site of identification of secretagogues and the site of release of secretory granules (1). This paper reviews the participation of several cations (K+, Na+, H+, Mg2+, Ba2+, and Ca2+) in the process of insulin release and in delineating the influence of insulinotropic agents, especially glucose, upon the handling of such cations.
1. 3-Phenylpyruvate caused a dose-related stimulation of insulin release from rat pancreatic isle... more 1. 3-Phenylpyruvate caused a dose-related stimulation of insulin release from rat pancreatic islets deprived of exogenous nutrient or incubated in the presence of 5.6 or 8.3 mM-D-glucose. 2. 3-Phenylpyruvate inhibited insulin release evoked by high concentrations of D-glucose (16.7 or 27.8 mM) or 4-methyl-2-oxopentanoate (10.0 mM). This inhibitory effect appeared to be attributable to impairment of 2-oxo-acid transport into the mitochondria, with resulting inhibition of D-glucose, pyruvate or 4-methyl-2-oxopentanoate oxidation. 3. 3-Phenylpyruvate failed to affect the oxidation of, and secretory response to, L-leucine, and did not augment insulin release evoked by a non-metabolized analogue of the latter amino acid. 4. L-Glutamine augmented 3-phenylpyruvate-induced insulin release. The release of insulin evoked by the combination of 3-phenylpyruvate and L-glutamine represented a sustained phenomenon, abolished in the absence of extracellular Ca2+ or the presence of menadione and pot...
Na+/Ca2+ exchange in the B cell was recently characterized by measuring intracellular-Na(+)-depen... more Na+/Ca2+ exchange in the B cell was recently characterized by measuring intracellular-Na(+)-dependent 45Ca2+ uptake in isolated rat pancreatic islet cells. The aim of the present study was to investigate the regulation of this process. Extracellular pH (pHo) and intracellular pH (pHi) markedly affected Na+/Ca2+ exchange. A fall of 0.04 unit in pHi decreased the exchange by 45%, whereas a rise of 0.13 unit increased the uptake by 70%. Mitochondrial poisons (oligomycin, antimycin A and 2,4-dinitrophenol) inhibited reverse Na+/Ca2+ exchange by about 25-50%. The exchanger displayed a low Q10 (temperature coefficient), indicating that it is only indirectly dependent on metabolic energy. The phorbol ester phorbol 12-myristate 13-acetate did not affect Na+/Ca2+ exchange. Likewise, lowering the extracellular K+ concentration did not inhibit 45Ca2+ uptake. In conclusion, the pHi and the metabolic state of the cell may represent important modulatory signals by which insulin secretagogues such...
Oral glucose tolerance tests were performed on 218 individuals, representative of 1000 employees ... more Oral glucose tolerance tests were performed on 218 individuals, representative of 1000 employees of a pharmaceutical firm who cooperated in a diabetes detection drive. Blood was obtained fasting and at half hourly intervals following 50 g liquid glucose. ...
The mechanisms by which glucose provokes the intracellular accumulation of calcium in the B-cell ... more The mechanisms by which glucose provokes the intracellular accumulation of calcium in the B-cell were investigated by monitoring the efflux of 45Ca from preloaded and perifused rat pancreatic islets. Glucose provoked an initial fall followed by a secondary rise in 45Ca efflux. These two movements are sustained and reversible. They display distinct sensitivities towards glucose but both movements depend on the integrity of glucose metabolism in the islets. The secondary rise in 45Ca efflux reflects the rate of calcium influx through voltage-sensitive calcium channels and corresponds to a process of calcium-calcium exchange. Glucose gates the calcium channels by increasing the endogenous generation of reduced pyridine nucleotides. The absence of extracellular sodium reduced the efflux of 45Ca and the inhibitory effect of glucose on calcium outflow. This suggests the existence in the islets of a process of sodium-calcium countertransport responsible for calcium extrusion from the B-cel...
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