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Biomedical subjects

A Sener

Publications and source records attributed to A Sener.

At least 289 records · Page 16Linked to original sources
PubMed1983

Stimulus-secretion coupling of glucose-induced insulin release. LI. Divalent cations and ATPase activity in pancreatic islets.

Pancreatic islets can be viewed as a fuel-sensor organ. The amount of ATP used by the islet cells for the maintenance of adequate Ca2+ gradients across membranes is not known. An indirect approach to this issue consists in the measurement of Ca-ATPase activity. The kinetics of Ca-ATPase in islet homogenates yielded a Km for ATP close to 0.1 mM and two Km values for Ca2+ close to 0.13 and 4-6 microM, respectively. Within limits, the Ca-ATPase appeared as a distinct entity from Mg-ATPase. Several divalent cations, including Mg2+, inhibited the Ca-ATPase activity. Calmodulin also inhibited, significantly albeit modestly Ca-ATPase. The activity of the enzyme was increased at high pH or in the presence of bicarbonate. The reaction velocity at close-to-physiological concentrations of ATP, Ca2+ and H+ suggests that the consumption of ATP by the Ca-ATPase may account for a major fraction of the overall rate of ATP breakdown in intact islets.

Adenosine Triphosphatases↗
PubMed1983

Synergistic effect of a tumor-promoting phorbol ester and a hypoglycemic sulfonylurea upon insulin release.

The tumor-promoting phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and the hypoglycemic sulfonylurea gliclazide both stimulate insulin release from rat pancreatic islets incubated at a low concentration of glucose (2.8 mM). The increment in secretion rate evoked by the combination of these two secretagogues was at least 7 times higher than the sum of increments evoked by each agent alone. TPA augmented insulin release evoked by gliclazide more efficiently than that induced by glucose. The enhancing action of TPA could not be attributed solely to changes in the capacity of gliclazide to inhibit 86Rb outflow, to provoke an exchange between influent 40Ca and effluent 45Ca, or to stimulate the net uptake of 45Ca by the islets. Nevertheless, the facilitation by TPA of gliclazide-induced insulin release suggests that a biophysical interference with the handling of cations at the plasma membrane level represents the primary site of action of hypoglycemic sulfonylureas in the pancreatic B cell.

Animals↗
PubMed1982

The stimulus-secretion coupling of amino acid-induced insulin release. Metabolic response of pancreatic islets of L-glutamine and L-leucine.

L-Glutamine markedly enhances insulin release evoked by L-leucine in rat pancreatic islets. The metabolic situation found in the islets exposed to both L-glutamine and L-leucine was investigated. L-Leucine slightly decreased the rate of L-glutamine deamidation, inhibited the conversion of glutamate to 2-ketoglutarate by transamination, increased the oxidative deamination of L-glutamate, stimulated the recirculation of 2-ketoglutarate to glutamate and inhibited the further oxidative metabolism of 2-ketoglutarate. L-Glutamine slightly decreased the rate of L-leucine conversion to 2-ketoisocaproate, but inhibited more severely the conversion of 2-ketoisocaproate to acetoacetate and CO2. Several of these findings appeared attributable to activation of glutamate dehydrogenase by L-leucine. When allowance was made for the influence of exogenous amino acids on the oxidation of endogenous fatty acids, a close parallelism was found between the rate of generation of reducing equivalents or O2 uptake and the insulin secretory response to L-leucine and/or L-glutamine. These findings reinforce the view that the process of nutrient-stimulated insulin release coincides with and may be attributable to an increase in catabolic fluxes in the islet cells.

Animals↗
PubMed1982

The stimulus-secretion coupling of amino acid-induced insulin release. Influence of a nonmetabolized analog of leucine on the metabolism of glutamine in pancreatic islets.

L-Glutamine causes a dose-related enhancement of insulin release evoked, in rat pancreatic islets, by the nonmetabolized analog of leucine, 2-aminobicyclo-[2,2,1]heptane-2-carboxylic acid (BCH). The influence of BCH upon the metabolism of L-glutamine was investigated. In the islets exposed to L-glutamine, BCH decreased the deamidation of glutamine, but stimulated the oxidative deamination of glutamate, increased the rate of generation and islet content of 2-ketoglutarate, and augmented the oxidation of L-[U-14C]glutamine. BCH antagonized the sparing action of L-glutamine upon the oxidation of endogenous fatty acids. The stimulation of insulin release by the association of L-glutamine and BCH was commensurate with the estimated increase in O2 consumption and coincided with an increase in the islet NADPH/NADP+ ratio, net uptake of 45Ca, and cyclic AMP concentration. It is concluded that insulin release evoked by these amino acids is causally linked to an increase in catabolic fluxes, the secretagogues acting in the islet cells as a fuel (glutamine) or enzyme activator (BCH).

Adenine Nucleotides↗
PubMed1982

The stimulus-secretion coupling of glucose-induced insulin release. Environmental influences on L-glutamine oxidation in pancreatic islets.

L-Glutamine at a near-physiological concentration (1.0mM) was rapidly taken up and metabolized in rat pancreatic islets. The rate of glutamine deamidation much exceeded that of glutamate conversion into 2-oxoglutarate, the latter conversion being mediated mainly by transamination reactions. The production of 14CO2 from L-[U-14C]glutamine, which reflected the generation of ATP through the metabolism of exogenous glutamine, appeared to be regulated by the redox state of nicotinamide nucleotides and the ATP content of the islet cells. The influence of environmental factors on glutamine oxidation was examined in order to identify ATP-requiring processes. Glutamine oxidation was decreased in the absence of extracellular Ca2+, under conditions aiming at inhibition of the (Na+ + NA+)-dependent ATPase and, provided that glucose was present in the incubation medium, by cycloheximide. These findings were interpreted to suggest that the handling of Ca2+ by the islet cells, the active transport of univalent cations and the biosynthesis of proinsulin represent three major ATP-consuming processes in this fuel-sensor organ.

Adenosine Triphosphate↗
PubMed1982

Stimulus-secretion coupling of amino acid-induced insulin release VII. The B-cell memory for L-glutamine.

In the absence of another exogenous nutrient, L-glutamine does not stimulate insulin release from rat pancreatic islets or isolated perfused pancreases. L-glutamine, however, augments insulin release evoked by L-leucine. These two amino acids could interact by providing both the substrate (L-glutamate) and an activator (L-leucine) for the reaction catalyzed by glutamate dehydrogenase. Under suitable experimental conditions, as little as 0.5 mM L-glutamine is sufficient to enhance leucine-stimulated insulin release. When the pancreases or islets are first exposed to L-glutamine and then stimulated with L-leucine, the rate of secretion is much higher than that evoked by L-leucine in tissue not first exposed to L-glutamine. The memory of a prior exposure to L-glutamine persists for at least 25 min after removal of the latter amino acid from the extracellular fluid. This memory phenomenon is not dependent on the presence of Ca2+ in the extracellular fluid during the first exposure to L-glutamine, but is suppressed when such a prior exposure is performed in the absence of extracellular K+. The memory phenomenon could be due, in part at least, to inhibition by L-glutamine of K+ conductance in the B-cell plasma membrane. Moreover, the amount of L-glutamate which accumulates in islets exposed to L-glutamine is sufficient to maintain, for a much longer period than with other nutrient secretagogues, a sustained increase in catabolic fluxes after removal of the amino acid from the extracellular fluid.

Animals↗
PubMed1982

The stimulus-secretion coupling of glucose-induced insulin release. Thiol: disulfide balance in pancreatic islets.

An increase in the production rate of reduced pyridine nucleotides is currently considered as a coupling factor between metabolic and distal events in the process of glucose-stimulated insulin release. The possible participation in such a coupling of thiol: disulfide interchanges was investigated in rat pancreatic islets. NADPH-dependent glutathione reductase and glutathione-cystine transhydrogenase activities were present in islet homogenates, whereas no glutathione peroxidase activity could be detected. In intact islets, glucose (16.7 mM) augmented both the GSH/GSSG ratio (from a basal value of 6.7 +/- 0.6 to 8.4 +/- 0.4) and the tissue content of sulphydryl groups (from a basal value of 119 +/- 7 to 170 +/- 9 pmol/microgram protein). The latter effect was mimicked by D-glyceraldehyde, 2-ketoisocaproate, anoxia and KCN; it failed to be reproduced by L-glucose or D-fructose, was unaffected by theophylline, and was inhibited by D-mannoheptulose, iodoacetate, menadione, cytochalasin B and the absence of extracellular Ca2+. These findings support the view that a glucose-induced reduction of disulphide bridges to sulphydryl groups participates in the stimulus-secretion coupling of nutrient-induced insulin release.

Animals↗
PubMed1982

The stimulus-secretion coupling of amino acid-induced insulin release. XI. Kinetics of deamination and transamination reactions.

L-Leucine and its nonmetabolized analogue, 2-aminobicyclo-[2,2,1]heptane-2-carboxylic acid (BCH) activate glutamate dehydrogenase in pancreatic islets, whether the reaction velocity is measured in the direction of glutamate synthesis or glutamate deamination. The rate of glutamate oxidative deamination is increased by ADP and inhibited by 2-ketoglutarate, NH4+ and GTP. The islet homogenate catalyzes the transamination between L-glutamate and either 2-ketoisocaproate or pyruvate, and between 2-ketoglutarate and L-leucine, L-aspartate, L-alanine, L-isoleucine, L-valine, L-norvaline or L-norleucine, but not b (+/-) BCH. The glutamate-aspartate transaminase is preferentially located in mitochondria relative to other transaminases. The parallel effects of L-leucine and BCH on glutamate dehydrogenase and their vastly different abilities to act as transamination partners may account for both analogies and discrepancies in the metabolic and functional responses of the islets to these two branched-chain amino acids.

Adenosine Diphosphate↗
PubMed1982

The stimulus-secretion coupling of amino acid-induced insulin release. XII. Contrasting effects of L-leucine and a nonmetabolized analog upon islet metabolism and insulin secretion.

L-Leucine and its nonmetabolized analog, 2-aminobicyclo-[2,2,1]heptane-2-carboxylic acid (BCH), do not act identically in pancreatic islets. For instance, BCH stimulates more markedly than leucine the output of 14 CO2 from islets prelabelled with L-[U-14C] glutamine. Although leucine and BCH stimulate insulin release to the same extent in the presence of glutamine, the rate of secretion is higher in leucine-stimulated than in BCH-stimulated islets when 2-ketoisocaproate is present in the incubation medium alone or together with glutamine. Such a difference in secretory rate coincides with contrasting effects of leucine and BCH, respectively, on both NH4+ production and glutamine oxidation by the islets exposed to 2-keto-isocaproate. These differences are best explained by the inability of BCH, as distinct from leucine, to act as a transamination partner of 2-ketoglutarate, and emphasize the view that the secretory response to nutrients tightly depends on the regulation of catabolic events in the islet cells.

Amino Acids↗
PubMed1982

Determinants of the selective toxicity of alloxan to the pancreatic B cell.

The diabetogenic agent alloxan exerts a preferential cytotoxic effect on the pancreatic B cell. The determinants of such a tissue specificity were investigated. Alloxan accumulated rapidly in liver and pancreatic islets but much more slowly in muscle. The activity of glutathione peroxidase and the resistance to exogenous peroxide were approximately 20 times higher in liver and kidney than in islets, intermediate values being found in exocrine pancreas and muscle. These findings suggest that the selective cytotoxicity of alloxan to the pancreatic B cell is attributable to the conjunction of two features: a rapid cellular uptake of the drug and an exquisite sensitivity of the B cell to peroxide.

Alloxan↗
PubMed1982

Noncarbohydrate nutrients protect against alloxan-induced inhibition of insulin release.

Noncarbohydrate nutrients such as 2-ketoisocaproate, L-glutamine, L-leucine and its nonmetabolized analog, beta-2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) were able to mimic, to a limited extent, the protective action of D-glucose against the inhibitory effect of alloxan on glucose-stimulated insulin release. L-glutamine potentiated the protective action of BCH but not that of 2-ketoisocaproate or L-leucine. These data lend support to the view that the cytotoxic effect of alloxan is linked to the generation of peroxide. Agents which stimulate islet metabolism may protect against such a cytotoxic effect by increasing the production rate of reducing equivalents in the islet cells.

Alloxan↗
PubMed1982

The stimulus-secretion coupling of glucose-induced insulin release: effect of aminooxyacetate upon nutrient-stimulated insulin secretion.

A possible role for the transfer of reducing equivalents between mitochondrial and cytoplasmic pools in the process of nutrient-stimulated insulin secretion was investigated by exposing rat pancreatic islets to aminooxyacetate, which inhibits transamination reactions and, hence, could impair the operation of the malate-aspartate shuttle. Aminooxyacetate (5.0 mM) decreased by 72-79% the transamination of exogenous pyruvate, L-leucine, or 2-ketoisocaproate but failed to affect the oxidation of glucose, L-leucine, or 2-ketoisocaproate and reduced by no more than 28-31% the oxidation of L-glutamine. In the 0.5-5.0 mM range, aminooxyacetate caused a dose-related inhibition of nutrient-stimulated insulin release, and lowered the cellular malate to pyruvate ratio. In the absence of both extracellular Ca2+ and exogenous nutrient, aminooxyacetate also inhibited the insulin release evoked by the combination of Ba2+ and theophylline. These findings suggest that a transfer of reducing equivalents to extramitochondrial sites participates in the process of insulin release, whether the latter involves the oxidation of exogenous or endogenous nutrients.

Acetates↗
PubMed1982

Glucose-induced accumulation of fructose-2,6-bisphosphate in pancreatic islets.

Rat islets contain the acid-labile activator of phosphofructokinase, fructose-2,6-bisphosphate. The islet content in activator is higher in islets exposed to glucose (16.7 mM) than in islets deprived of glucose. The islets display fructose-6-phosphate, 2-kinase activity with a Km for fructose-6-phosphate close to 0.08 mM. Glucose fails to affect the activity of this enzyme. It is proposed that the effect of glucose to increase the islet content of fructose-2,6-bisphosphate is attributable, in part at least, to the glucose-induced increase in the concentration of fructose-6-phosphate in the islet cells.

Animals↗