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Biomedical subjects

A Sener

Publications and source records attributed to A Sener.

At least 307 records · Page 17Linked to original sources
PubMed1981

The stimulus-secretion coupling of amino acid-induced insulin release. Metabolic interaction of L-glutamine and 2-ketoisocaproate in pancreatic islets.

1. The metabolic situation found in pancreatic islets exposed to both L-glutamine and 2-ketoisocaproate was investigated in order to assess its relevance to the synergistic effects of these nutrients upon insulin release. 2. In islet homogenates, serveral 2-keto acids could be used as partners for the transamination of L-glutamate to 2-ketoglutarate. The rate of transamination did not correlate positively with the capacity of each 2-keto acid to stimulate insulin release in the presence of L-glutamine. 3. L-Glutamine enhanced the production of L-leucine from 2-ketoisocaproate and inhibited the conversion of the 2-keto acid to acetoacetate and CO2. L-Glutamine also inhibited the oxidation of pyruvate. 4. In the presence of 2-ketoisocaproate, the rate of generation of 2-ketoglutarate from exogenous L-glutamine was increased, but the oxidative deamination of glutamate was suppressed. 5. L-Valine antagonized the effect of 2-ketoisocaproate to augment 14CO2 output from islets prelabelled with L-[U-14C]glutamine. 6. L-Glutamine did not increase the islet content of reduced pyridine nucleotides beyond the high level reached in the sole presence of 2-ketoisocaproate. 7. If allowance was made for the influence of exogenous nutrients upon the oxidation of endogenous nutrients, the insulin output evoked by L-glutamine and/or 2-keto acids tightly depended on the increment in oxidation rate attributable to these nutrients. 8. The metabolic and secretory responses to L-glutamine and 2-ketoisocaproate were best explained by a stimulation of transamination reactions between 2-ketoisocaproate and glutamate derived from exogenous glutamine.

Animals↗
PubMed1981

Ionic mechanism of diphenylhydantoin action on glucose-induced insulin release.

Diphenylhydantoin inhibits glucose-stimulated insulin release. The mode of action of diphenylhydantoin was investigated by characterizing its effect on 86Rb and 45Ca fluxes in isolated pancreatic islets. The inhibition of glucose-stimulated insulin release by diphenylhydantoin was apparently not attributable to activation of a Na+ + K+ATPase as diphenylhydantoin failed to affect 86Rb net uptake, at least in glucose-stimulated islets. Diphenylhydantoin decreased 45Ca net uptake by the islets, an effect possibly due to inhibition of Ca2+ entry into the islet cells. Diphenylhydantoin indeed markedly inhibited the glucose-induced increase in 45Ca outflow and decreased the process of 40Ca-45 exchange evoked by a rise in extracellular Ca2+ concentration. Diphenylhydantoin failed to affect the inhibitory action of glucose upon 45Ca outflow whether in the presence or absence of extracellular Ca2+, and did not impair the antimycin A-induced release of 45Ca from intracellular organelles. These findings suggest that the inhibitory effect of diphenylhydantoin upon glucose-stimulated insulin release is attributable mainly to a blockade of Ca2+ inflow into the beta-cell.

Animals↗
PubMed1981

Regulation of calcium fluxes in rat pancreatic islets. Quinine mimics the dual effect of glucose on calcium movements.

The effects of quinine and 9-aminoacridine, two blockers of potassium conductance in islet cells, on 45Ca efflux and insulin release from perifused islets were investigated in order to elucidate the mechanisms by which glucose initially reduces 45Ca efflux and later stimulates calcium inflow in islet cells. In the absence of glucose, 100 microM quinine stimulated 45Ca net uptake, 45Ca outflow rate and insulin release. Quinine also dramatically enhanced the cationic and the secretory response to intermediate concentrations of glucose, but had little effect on 45Ca net uptake, 45Ca fractional outflow rate and insulin release at a high glucose concentration (16.7 mM). The ability of quinine to stimulate 45Ca efflux depended on the presence of extracellular calcium, suggesting that it reflects a stimulation of calcium entry in the islet cells. In the absence of extracellular calcium, quinine provoked a sustained decrease in 45Ca efflux. Such an inhibitory effect was not additive to that of glucose, and was reduced at low extracellular Na+ concentration. At a low concentration (5 microM), quinine, although reducing 86Rb efflux from the islets to the same extent as a non-insulinotropic glucose concentration (4.4 mM), failed to inhibit 45Ca efflux. In the presence of extracellular calcium, 9-aminoacridine produced an important but transient increase in 45Ca outflow rate and insulin release from islets perifused in the absence of glucose. In the absence of extracellular calcium, 9-aminoacridine, however, failed to reduced 45Ca efflux from perifused islets. It is concluded that quinine, by reducing K+ conductance, reproduces the effect of glucose to activate voltage-sensitive calcium channels and to stimulate the entry of calcium into the B-cell. However, the glucose-induced inhibition of calcium outflow rate, which may also participate in the intracellular accumulation of calcium, does not appear to be mediated by changes in K+ conductance.

Aminacrine↗
PubMed1981

The stimulus-secretion coupling of amino acid-induced insulin release. Biosynthetic and secretory responses of rat pancreatic islet to L-leucine and L-glutamine.

L-glutamine dramatically augments insulin release evoked by L-leucine. The dynamics, specificity and environmental modifications of the insulin secretory response to the combination of L-glutamine and L-leucine were investigated. L-glutamine alone failed to stimulate proinsulin biosynthesis or insulin release in rat pancreatic islets, but augmented synthesis and secretion evoked by L-leucine. In relation to the secretory response, L-glutamine could be replaced by L-asparagine but not L-glutamate; L-leucine could be replaced by L-norvaline or L-isoleucine but not by L-valine, L-norleucine, glycine, L-serine, L-lysine, L-phenylalanine or L-arginine. The secretory response to L-leucine was rapid and biphasic whereas the enhancing action of L-glutamine upon insulin release was progressive. The release of insulin evoked by the combination of L-leucine and L-glutamine was inhibited by antimycin A, menadione, ammonium ions, verapamil, adrenaline, and by the absence of extracellular Ca2+. It was increased at high carbon dioxide tension, and by glucose, theophylline and cytochalasin B. It is concluded that the enhancing action of L-glutamine upon insulin release evoked by certain amino acids represents a phenomenon dependent on the integrity of oxidative metabolism and involving essentially the same sequence of metabolic, ionic and motile events as that characterizing the process of glucose-induced insulin release.

Animals↗
PubMed1981

The stimulus-secretion coupling of amino acid-induced insulin release. IV. Ionic response to L-Leucine and L-Glutamine.

L-Glutamine enhances insulin release evoked by L-leucine in isolated rat pancreatic islets. The enhancing action of L-glutamine, which is a rapid but steadily increasing and not rapidly reversible phenomenon is not attributable to any major change in either K+ or Ca2+ outflow from the islet cells. It coincides with an apparent increase in Ca2+ inflow rate and, hence, with Ca accumulation in the islets. The initial ionic response to L-leucine is not qualitatively altered by the presence of L-glutamine. In their combined capacity to stimulate 45Ca net uptake in the islets, L-glutamine can be replaced by L-asparagine but not by L-glutamate, whereas L-leucine can be replaced by L-norvaline or L-isoleucine, but not by L-valine, glycine or L-lysine. Such a specificity is identical to that characterizing the effect of these various amino acids upon insulin release. It is postulated that the release of insulin evoked by the combination of L-leucine and L-glutamine involves essentially the same remodelling of ionic fluxes as that evoked by other nutrient secretagogues with, however, an unusual time course for the functional response to L-glutamine.

Amino Acids↗
PubMed1981

Insulin release: reconciliation of the receptor and metabolic hypotheses. Nutrient receptors in islet cells.

Nutrients which stimulate insulin secretion are currently thought to initiate the series of cellular events eventually leading to insulin release either by interacting with a stereospecific receptor system (the regulatory site hypothesis) or by acting as a fuel (the substrate site hypothesis) in the pancreatic B-cell. The latter hypothesis is supported by a number of observations indicating that the capacity of nutrients to stimulate insulin release is indeed highly dependent on their capacity to increase catabolic fluxes in isolated pancreatic islets. However, these observations do not rule out the existence of nutrient receptors in islet cells. For instance, a nonmetabolized analog of L-leucine stimulates insulin release by causing allosteric activation of glutamate dehydrogenase, which should be considered, therefore, as a receptor for certain amino acids. Likewise, the increase in glycolytic flux, which is associated with the process of glucose-stimulated insulin release, is attributable not solely to a mass action phenomenon but also to the activation of phosphofructokinase by fructose 2.6-bisphosphate. The biosynthesis of this activator may involve a glucose receptor system. The fact that certain nutrient secretagogues (e.g. D-glucose and L-leucine) act in the B-cell both as substrates and enzyme activators permits reconciliation of the substrate site and regulatory site hypotheses for insulin release.

Allosteric Regulation↗
PubMed1981

Sorbitol content of plasma and erythrocytes during induced short-term hyperglycemia.

Plasma glucose concentration was increased from a mean basal value of 3.3 +/- 0.1 to 13.3 +/- 1.5 mmol/L by the intravenous administration of glucose for 60 minutes to four healthy volunteers. The sorbitol content of erythrocytes was increased during the period of hyperglycemia from a mean basal value of 65 +/- 9 to 106 -/+ 6 mumol/L. The plasma sorbitol concentration remained constant at 12 +/- 1 mumol/L. This dissociated response indicates that the plasma concentration of sorbitol is not significantly affected by a short-term hyperglycemia sufficient to cause intracellular sorbitol accumulation.

Adult↗
PubMed1981

Stimulus-secretion coupling of glucose-induced insulin release. Timing of early metabolic, ionic, and secretory events.

The timing of the early metabolic, ionic, and secretory responses to glucose in rat pancreatic islets was monitored by measuring, at 12 sec intervals, the concentrations of glucose, lactic, and pyruvic acids, 32P, 86Rb, 45ca, and insulin in the effluent of perifused prelabeled islets. The increase in glucose concentration from zero to 16.7 mM was complete within 133 sec. The output of organic acids increased after 24 sec of exposure to glucose and, in the case of lactic acid, fell slightly after the initial elevation. The phosphate flush was initiated only after 96 sec of exposure to glucose, whereas the decreases in 86Rb and 45Ca outflow were both detectable within 72 sec of stimulation. The secondary rise in 45Ca efflux was first seen after 157 sec of stimulation and its time course was not vastly different from that of insulin release. These data indicate that, in the secretory sequence, metabolic changes precede both the remodelling of ionic fluxes and the stimulation of insulin release. The results are compatible with the view that the secondary rise in 45Ca outflow is attributable, in part at least, to the glucose-induced decrease in K conductance (but not to the increase in phosphate outflow), with resulting membrane depolarization and gating of voltage-dependent Ca channels.

Animals↗
PubMed1981

Stimulation of pancreatic islet metabolism and insulin release by a nonmetabolizable amino acid.

The leucine analog beta-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) activates glutamate dehydrogenase [L-glutamate:NAD+ oxidoreductase (deaminating), EC 1.4.1.2] in pancreatic islet homogenates. In intact islets, BCH increased the islet content or output of NH4+, 2-ketoglutarate, malate, pyruvate, and alanine. BCH caused a dose-related increase in 14CO2 output from islets prelabeled with L-[U-14C]glutamine. BCH increased the islet content of ATP and stimulated both 45Ca net uptake and insulin release. The capacity of seven distinct amino acids to activate glutamate dehydrogenase tightly correlated with their ability to augment 14CO2 output from islets prelabeled with [U-14C]-glutamine and to stimulate insulin release in the presence of L-glutamine. The activation of glutamate dehydrogenase by BCH may thus account for the insulin-releasing capacity of the leucine analog.

Adenine Nucleotides↗
PubMed1981

Influence of carbohydrate intake soon plasma sorbitol concentration in normal subjects.

Nine healthy volunteers received either a normal diet or an isocaloric diet of which the carbohydrate content was reduced to 5% of the total caloric intake. Within 2 days of administration of the carbohydrate-poor diet, the concentration of sorbitol in plasma was decreased by 1.6 +/- 0.2 microM below the initial value (4.1 +/- 0.4 microM). When the subjects were returned to the normal diet, a reascension in plasma sorbitol concentration ws observed within 1 or 2 days. It is proposed tht, in normal subjects, the sorbitol concentration in plasma depends on and can be used as an indication of the carbohydrate intake.

Adult↗
PubMed1981

The stimulus-secretion coupling of amino acid-induced insulin release: insulinotropic action of branched-chain amino acids at physiological concentrations of glucose and glutamine.

The stimulant action of branched-chain amino acids upon insulin release was examined in rat pancreatic islets incubated at physiological concentrations of D-glucose and L-glutamine. In the presence of the latter nutrients, L-leucine and L-isoleucine used together at a physiological concentration (0.25 mmol/l each) doubled insulin secretion rate. The effect of L-leucine upon insulin release was dose-related without any indication of of a threshold phenomenon. The insulinotropic action of L-leucine was mimicked, to a limited extent, by its nonmetabolized analogue, 2-aminobicyclo[2,2,1] heptane-2-carboxylic acid. L-Glutamine slightly inhibited glucose-stimulated insulin release. It is concluded that, under close-to-physiological conditions, L-leucine stimulates insulin release by acting in the islet cells both as a fuel and as an allosteric activator of glutamate dehydrogenase.

Amino Acids↗
PubMed1981

The stimulus-secretion coupling of glucose-induced insulin release. XLVII. The possible role of calmodulin.

Pancreatic islets contain calmodulin. This protein activates adenylate cyclase in a subcellular fraction of rat islets in a calcium-dependent fashion. The Km for calmodulin was close to 0.1 microM, well below the concentration of endogenous calmodulin. Trifluoperazine and the trifluoromethylphenothiazine derivative of domperidone inhibited glucose-stimulated insulin release without affecting glucose oxidation by the islets. When insulin release was inhibited by 30% or more, this inhibition coincided with a reduction in the 45Ca net uptake by the islets. Both drugs suppressed the increment in adenylate cyclase activity evoked by calmodulin in a particulate fraction derived from the islets. However, the drugs also decreased basal and NaF-stimulated adenylate cyclase activities. Within limits, these data are compatible with the participation of endogenous calmodulin in the normal process of insulin release.

Adenylyl Cyclases↗