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Biomedical subjects

A Sener

Publications and source records attributed to A Sener.

At least 271 records · Page 15Linked to original sources
PubMed1984

Inhibitory effect of clonidine upon adenylate cyclase activity, cyclic AMP production, and insulin release in rat pancreatic islets.

Conflicting opinions were recently expressed concerning the possible effect of alpha 2-adrenergic agonists upon cyclic AMP production in pancreatic islets. In the present study, clonidine inhibited glucose-induced insulin release from rat pancreatic islets, this inhibitory effect being abolished by idazoxan. Clonidine did not suppress the capacity of forskolin to augment glucose-induced insulin release. In a particulate subcellular fraction derived from the islets, adenylate cyclase was activated by calmodulin (in the presence of Ca2+), NaF, GTP, L-arginine, and forskolin, and slightly inhibited by clonidine. The inhibitory action of clonidine upon basal adenylate cyclase activity was more pronounced in islet crude homogenates. The inhibitory effect of clonidine was antagonized by forskolin whether in the particulate fraction or crude homogenate. At variance with the modest effects of glucagon, D-glucose, L-arginine, or a tumor-promoting phorbol ester upon cyclic AMP production by intact islets, forskolin caused a six-fold increase in cyclic AMP production. Clonidine inhibited cyclic AMP production by intact islets, whether in the absence or presence of forskolin. It is proposed that the inhibitory action of clonidine upon insulin release is attributable, in part at least, to inhibition of adenylate cyclase.

Adenylyl Cyclases↗
PubMed1984

Methylamines and islet function: cationic aspects.

Methylamine (2 to 10 mM) caused a dose-related inhibition of insulin release evoked in rat pancreatic islets by nutrient or non nutrient secretagogues. Trimethylamine exerted comparable effects upon insulin release. Methylamine (2 mM) inhibited insulin secretion but failed to affect 45Ca uptake and efflux in response to a rise in extracellular K+ concentration, suggesting that methylamine acts, to a certain extent at least, at a distal site in the secretory sequence. Methylamine, however, also exerted untoward ionic effects. First, methylamine (2 to 10 mM) apparently caused a dose-related increase in cellular pH. Second, methylamine (2mM) augmented 86Rb outflow from islets perifused either in the absence or presence of glucose or gliclazide, and inhibited Ca2+ inflow (as judged from the net uptake or efflux of 45Ca) in islets stimulated by D-glucose, L-leucine or 2-ketoisocaproate. This multiplicity of ionic and other effects may account for the fact that, in the presence of distinct secretagogues, the secretory process appeared more or less sensitive towards methylamine, depending on the relative importance of changes in cellular pH, K+ permeability and intracellular Ca2+ distribution as determinants of the secretory response.

Acyltransferases↗
PubMed1984

A micromethod for the assay of aldose reductase, its application to pancreatic islets.

A micromethod for the assay of aldose reductase is described. The method, which is based on the fluorometric measurement of the NADP+ formed when an aldose is converted to its corresponding polyol, was applied to lens and pancreatic islet crude homogenates, as well as semipurified lens aldose reductase. The fluorometric method has proved to be reproducible, more rapid, and more sensitive than the classical spectrophotometric procedure, and should find ready application in the screening of potential aldose reductase inhibitors.

Aldehyde Reductase↗
PubMed1984

Inhibition by L-valine and L-norleucine of 3-phenylpyruvate-induced insulin release.

Insulin release induced by 3-phenylpyruvate in isolated rat pancreatic islets was inhibited by L-valine, L-norleucine or aminooxyacetate. The inhibitory effect of these three agents coincided with a lesser stimulation by 3-phenylpyruvate of 14CO2 output from islets prelabelled with L-[U-14C] glutamine. Conversely, 3-phenylpyruvate augmented the rate of conversion of L-valine to 2-ketoisovalerate and that of L-norleucine to 2-ketocaproate. However, 3-phenylpyruvate, which increased 2-ketoisovalerate oxidative decarboxylation, inhibited 14CO2 production by islets exposed to D, L-[1-14C] norleucine. These findings reveal that distinct nutrient secretagogues (e.g. 3-phenylpyruvate and L-norleucine), which are each able to stimulate insulin release, may act antagonistically upon the secretory process when used in combination. The present results also emphasize the relevance of both mitochondrial oxidation and intracellular transfer of reducing equivalents as determinants of the secretory response to such nutrients as 3-phenylpyruvate and norleucine.

Aminocaproates↗
PubMed1984

Methylamine and islet function: possible relationship to Ca2+-sensitive transglutaminase.

Pancreatic islet homogenates display Ca2+-dependent transglutaminase activity. Methylamine inhibits the enzyme activity, accumulates in intact islet cells, is incorporated in endogenous islet proteins, and inhibits glucose-stimulated insulin release. The inhibition by methylamine of both enzyme activity and insulin release is inversely related to the ambient Ca2+ concentration. Dimethylamine also inhibits transglutaminase activity and glucose-stimulated insulin release. However, trimethylamine, which does not affect transglutaminase activity, again inhibits glucose-stimulated insulin release, the latter inhibition being also inversely related to the Ca2+ concentration. It is concluded that the impairment of insulin release by methylamines is not necessarily linked to inhibition of transglutaminase activity.

Acyltransferases↗
PubMed1984

Forskolin-induced activation of adenylate cyclase, cyclic adenosine monophosphate production and insulin release in rat pancreatic islets.

Forskolin activated adenylate cyclase in rat islet homogenates and stimulated cAMP production in intact islets incubated in the absence or presence of either D-glucose or Ca2+. Forskolin failed to affect D-[U-14C]glucose oxidation, glucose-stimulated net 45Ca uptake, or basal insulin release, but enhanced insulin secretion evoked by either nutrients (D-glucose, 2-ketoisocaproate, L-leucine alone or in combination with L-glutamine), or nonnutrient secretagogues (12-O-tetradecanoylphorbol-13-acetate, Ba2+ alone or in combination with theophylline). Forskolin stimulated insulin release from islets incubated in the presence of glucose but in the absence of Ca2+. These findings confirm that a marked increase in cAMP production is not sufficient to cause sustained insulin release. They also suggest that the enhancing action of endogenous cAMP upon insulin release does not depend on a facilitation of Ca2+ influx into islet cells.

1-Methyl-3-isobutylxanthine↗
PubMed1984

The stimulus-secretion coupling of amino acid-induced insulin release. Secretory and oxidative response of pancreatic islets to L-asparagine.

L-Asparagine (2-10 mM) failed to affect insulin secretion from rat pancreatic islets incubated in the absence of exogenous nutrient or presence of D-glucose, but caused a dose-related and progressive enhancement of insulin release evoked by L-leucine, 2-aminobicyclo[2,2,1]heptane-2-carboxylate, or 2-ketoisocaproate. The secretory response to the combination of L-asparagine and L-leucine was augmented by theophylline and inhibited in the absence of extracellular Ca2+ or presence of either menadione or methylamine. L-Asparagine augmented leucine-stimulated 45Ca net uptake. The ATP content, rate of O2 uptake, and malate/pyruvate ratio were not significantly different in islets exposed to L-leucine alone or to both L-asparagine and L-leucine, respectively. In the sole presence of L-asparagine, however, the malate/oxalacetate ratio was decreased and the malate/pyruvate ratio increased, relative to basal values. It is proposed that the enhancing action of L-asparagine upon insulin release evoked by L-leucine might be due to an accelerated generation rate of cytosolic NADPH, rather than to any sizable increase in either islet respiration or steady-state cytosolic NADPH/NADP+ ratio.

Amino Acids↗
PubMed1984

Inhibition of transglutaminase by hypoglycaemic sulphonylureas in pancreatic islets and its possible relevance to insulin release.

Pancreatic islet homogenates display calcium-sensitive transglutaminase activity, but the role of this enzyme in the process of insulin release remains to be elucidated. Tolbutamide, gliclazide, glisoxepide, glipizide and glibenclamide inhibited transglutaminase activity in islet homogenates. When the cationic response of islet cells to hypoglycaemic sulphonylureas was suppressed by exposing intact islets to quinine, tolbutamide, gliclazide and glibenclamide caused a rapid, sustained, reversible and dose-related inhibition of insulin release. The relative efficiency of distinct hypoglycaemic sulphonylureas as inhibitor of transglutaminase activity was in mirror image of their relative potency as insulin secretagogue. However, the dose-action relationship for the inhibitory action of these agents upon insulin release from quinine-treated islets was similar in response to either tolbutamide, gliclazide or glibenclamide. These results indicate that hypoglycaemic sulphonylureas may exert an inhibitory action upon insulin release, but suggest that such an effect is not tightly related to inhibition of transglutaminase.

Acyltransferases↗
PubMed1984

Does glucose affect phospholipase A2 activity in pancreatic islets?

Rat pancreatic islet homogenates catalyzed the production of labelled oleate and lysophosphatidylcholine from 1-palmitoyl-2-[1-14C] oleoylphosphatidylcholine and di[1-14C] stearoylphosphatidylcholine, respectively. The phospholipase A2 was activated by Ca2+ (Ka approximately 0.5 mM) and inhibited by mepacrine. No difference in enzymic activity was found in glucose-deprived and glucose-stimulated islets, respectively.

Animals↗
PubMed1983

Transglutaminase activity in pancreatic islets.

1. Pancreatic islet homogenates catalyze, in a Ca2+-dependent fashion, the incorporation of [2,5-3H]histamine, [1,4-14C]putrescine, [1,2-3H]agmatine, [14C]methylamine and L-[U-14C]lysine in N,N-dimethylcasein. 2. Using [2,5-3H]histamine as the amine donor, the Km for Ca2+ and histamine amounts to 90 microM and 0.7 mM, respectively. 3. The incorporation of [2,5-3H]histamine into N,N-dimethylcasein is inhibited by monodansylcadaverine, N-p-tosyl glycine, bacitracin and methylamine, the relative extent of inhibition depending on the respective concentrations of Ca2+, inhibitor and amine donor. 4. Bacitracin and methylamine, but not N-p-tosyl glycine, cause a dose-related inhibition of glucose-stimulated insulin release. 5. It is concluded that, in pancreatic islets, the Ca2+-responsive transglutaminase activity plays a critical role in the process of glucose-induced insulin release.

Acyltransferases↗
PubMed1983

The stimulus-secretion coupling of glucose-induced insulin release: fuel metabolism in islets deprived of exogenous nutrient.

The fuel hypothesis for insulin release postulates that the secretory response to nutrient secretagogues reflects their capacity to augment catabolic fluxes in pancreatic islet cells. Hence, both the oxidation of exogenous nutrients and their effect upon the metabolism of endogenous nutrients should be taken into consideration to account for the stimulation of insulin release. In the present work, an attempt was made to quantify the respective contribution of carbohydrates, fatty acids, and amino acids in the respiration of islets deprived of exogenous nutrient. The metabolism of glycerol, fatty acids, and amino acids was found to account for the major part of the basal respiratory rate. Glucose modestly decreased the oxidation of endogenous fatty acids, lowered the production of NH4+, but did not impair the oxidative catabolism of 2-keto acids derived from endogenous amino acids. These findings suggest that the catabolism of noncarbohydrate nutrients largely contributes to the respiration of the islets, even when the latter are exposed to circulating glucose in its physiological concentration.

Amino Acids↗
PubMed1983

Does leucine- and norleucine-induced insulin release depend on amino acid aminotransferase activity?

In the absence of another exogenous nutrient, L-leucine but not L-norleucine stimulates insulin release from rat pancreatic islets, although the corresponding keto acids, 2-ketoisocaproate and 2-ketocaproate, are equally potent secretagogues. Such a situation cannot be ascribed to the preferential transamination of L-leucine as compared to L-norleucine in islet homogenates. Indeed, in the presence of a suitable activator of glutamate dehydrogenase, L-leucine and L-norleucine stimulate secretion to the same extent. It is concluded that the rate of transamination of these amino acids in intact islet cells depends on the availability of a 2-keto acid partner rather than on the assayed amino acid aminotransferase activity.

Amino Acids↗
PubMed1983

Mechanism of 3-phenylpyruvate-induced insulin release. Secretory, ionic and oxidative aspects.

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 potentiated by theophylline. 5. Whether in the presence or in the absence of L-glutamine, the secretory response to 3-phenylpyruvate coincided with an increase in O2 uptake, a decrease in K+ conductance, a stimulation of both Ca2+ inflow and 45Ca2+ net uptake and an increase in cyclic AMP content. 6. It is concluded that the release of insulin induced by 3-phenylpyruvate displays features classically encountered when the B-cell is stimulated by nutrient secretagogues, and is indeed attributable to an increase in nutrient catabolism.

Animals↗
PubMed1983

Mechanism of 3-phenylpyruvate-induced insulin release. Metabolic aspects.

1. The metabolism and metabolic effects of 3-phenylpyruvate were examined in rat pancreatic islets. 2. Islet homogenates catalysed transamination reactions between 3-phenylpyruvate and L-glutamate, L-leucine, L-norleucine or L-valine. 3-Phenylpyruvate failed to activate glutamate dehydrogenase. 3. 3-Phenylpyruvate rapidly entered into islet cells, was extensively converted into phenylalanine but slowly oxidized. 4. The conversion of phenylpyruvate into phenylalanine coincided with a fall in the content of several amino acids (especially glutamate and aspartate) in the islets and incubation medium, the accumulation of 2-oxoglutarate and a modest fall in the NH4+ production rate. 5. 3-Phenylpyruvate failed to affect 14CO2 output from islets prelabelled with [U-14C]palmitate, but augmented 14CO2 output from islets prelabelled or incubated with L-[U-14C]glutamine. 6. In the presence of L-glutamine, 3-phenylpyruvate augmented the ATP/ADP ratio and NAD(P)H islet content, and caused a rapid and sustained decrease in the outflow of radioactivity from islets prelabelled with [2-3H]adenosine. 7. These data support the view that the insulin-releasing capacity of 3-phenylpyruvate coincides with an increase in the catabolism of endogenous amino acids acting as 'partners' in transamination reactions leading to the conversion of 3-phenylpyruvate into phenylalanine.

Adenine Nucleotides↗
PubMed1983

Contrasting modes of action of D-glucose and 3-O-methyl-D-glucose as protectors of the rat pancreatic B-cell against alloxan.

Both D-glucose and its nonmetabolized analog 3-O-methyl-D-glucose are known to protect the pancreatic B-cell against the toxic action of alloxan, as if the protective action of hexoses were to involve a membrane-associated glucoreceptor site. In the present study, the protective actions of the two hexoses were found to differ from one another in several respects. Using the process of glucose-stimulated insulin release by rat pancreatic islets as an index of alloxan cytotoxicity, we observed that the protective action of D-glucose was suppressed by D-mannoheptulose and menadione, impaired by NH4Cl, and little affected by aminooxyacetate. These findings and the fact that D-glucose failed to decrease [2-14C]alloxan uptake by the islets suggest that the protective action of D-glucose depends on an increase in the generation rate of reducing equivalents (NADH and NADPH). The latter view is supported by the observation that the protective action of a noncarbohydrate nutrient, 2-ketoisocaproate, was also abolished by menadione. Incidentally, the protective action of 2-ketoisocaproate was apparently a mitochondrial phenomenon, it not being suppressed by aminooxyacetate. In contrast to that of glucose, the protective action of 3-O-methyl-D-glucose was unaffected by D-mannoheptulose, failed to be totally suppressed by menadione, and coincided with a decreased uptake of [2-14C]-alloxan by the islets. It is concluded that the protective action of D-glucose in linked to the metabolism of the sugar in islet cells, whereas that of 3-O-methyl-D-glucose results from inhibition of alloxan uptake. This conclusion reinforces our opinion that the presence in the B-cell of an alleged stereospecific membrane glucoreceptor represents a mythical concept.

3-O-Methylglucose↗
PubMed1983

Metabolism of glucose and mannose anomers in pancreatic islets.

The alpha-anomers of D-glucose and D-mannose stimulate insulin release more efficiently than the corresponding beta-anomers. This coincides with higher glycolytic and oxidative fluxes in pancreatic islets exposed to alpha- than to beta-anomers. This situation may be attributable, in the case of alpha-D-glucose, not solely to the alpha-stereospecificity of phosphoglucose isomerase but also to that of phosphoglucomutase resulting in a higher islet content of glucose-1,6-bisphosphate, an activator of phosphofructokinase. Likewise, more aldohexose-bisphosphate accumulates in the islets exposed to alpha-D-mannose than in those incubated with beta-D-mannose. The anomeric specificity of hexose metabolism in pancreatic islets supports the fuel hypothesis for insulin release.

Animals↗