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Biomedical subjects

A Sener

Publications and source records attributed to A Sener.

At least 325 records · Page 18Linked to original sources
PubMed1981

Islet metabolism: recent acquisitions.

Isolated pancreatic rat islets deprived of exogenous nutrients maintain a sustained rate of O2 consumption. Glucose exerts little effect upon the utilization of endogenous nutrients. It is proposed that, under physiological conditions circulating L-glutamine represents a major fuel to cover the basal energy expenditure of the islets. Exogenous L-glutamine, which is actively metabolized in the islets, also provides an adequate substrate for the reaction catalyzed by glutamate dehydrogenase. L-glutamine dramatically enhances insulin release evoked by those amino acids which cause allosteric activation of the latter enzyme, e.g. L-leucine or b(-)BCH.

Amino Acids↗
PubMed1980

Stimulation of insulin release by L-glutamine.

Under normal environmental conditions, L-glutamine is well oxidized but fails to stimulate insulin release in rat pancreatic islets. However, a marked stimulation of insulin release by L-glutamine, without alteration in its oxidation rate occurs when the intracellular pH of the islet cells is decreased and/or when theophylline is added to the incubation medium.

Animals↗
PubMed1980

Regulation of calcium fluxes in rat pancreatic islets: calcium extrusion by sodium-calcium countertransport.

The mechanisms by which glucose regulates calcium fluxes in pancreatic endocrine cells were investigated by monitoring the efflux of 45Ca from prelabeled and perifused rat pancreatic islets. In the absence of both extracellular calcium and glucose, partial or total removal of extracellular sodium decreases the efflux of 45Ca from prelabeled islets. Glucose also reduces the efflux of 45Ca from islets perifused in the absence of extracellular calcium. This inhibitory effect of glucose on 45Ca efflux is decreased by half when the extracellular concentration of sodium is lowered to 24 mM. In the absence of extracellular calcium but presence of glucose, partial or even total removal of extracellular sodium fails to decrease the efflux of 45Ca. At normal extracellular calcium concentration (1 mM) partial removal of extracellular sodium dramatically increases 45Ca efflux from pancreatic islets. This increase in 45Ca efflux is partially but not totally suppressed by either 16.7 mM glucose or cobalt. It is totally suppressed by 4.4 mM glucose or by the combination of 16.7 mM glucose and cobalt. At normal extracellular calcium concentration, glucose initially reduces and subsequently increases 45Ca efflux. The initial fall is unaffected by tetrodotoxin but decreased by 50% at low extracellular sodium concentration (24 mM). The present results suggest the existence in pancreatic endocrine cells of a glucose-sensitive process of sodium-calcium counter-transport. By inhibiting such a process, glucose may decrease the efflux of calcium from islet cells. The effect of glucose is not mediated by an increase in intracellular sodium concentration. It could contribute to the intracellular accumulation of calcium which is thought to trigger insulin release.

Animals↗
PubMed1980

L-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase.

The release of insulin evoked by nutrients in the pancreatic beta-cell is attributed to either the activation of a stereospecific receptor by the nutrient molecule itself or the generation of one or more signal(s) through the intracellular metabolism of the nutrient secretagogue. The first of these hypotheses is apparently supported by the fact the nonmetabolized amino acids, especially the L-leucine analogue b(-)2-amino-bicyclo[2,2,1]heptane-2-carbocyclic acid (BCH), stimulate insulin release. However, we now report evidence in support of the second hypothesis. We present data consistent with the idea that BCH induces insulin release through the allosteric activation of glutamate dehydrogenase. This is compatible with the fuel hypothesis, which states that the secretory response to nutrient secretagogues depends always on an increase of catabolic fluxes in the islet cells.

Animals↗
PubMed1980

Interaction of branched chain amino acids and keto acids upon pancreatic islet metabolism and insulin secretion.

Insulin release evoked by 2-ketoisocaproate from isolated rat pancreatic islets was inhibited by L-valine, L-isoleucine, L-norvaline, and L-norleucine. The stereo-specificity of the inhibition and the finding that the decrease in secretory rate was correlated to the capacity of these amino acids to undergo transamination with the keto acid secretagogue suggested that a branched chain amino acid aminotransferase enzyme was the site of interaction of these substrates. The stimulation of transamination by these amino acids was accompanied by a decrease in the primary decarboxylation and oxidation of 2-ketoisocaproate in the tissue and a reduction in islet acetoacetate production. The oxidation of the amino acid substrate was slightly increased in the presence of 2-ketoisocaproate. Nevertheless, the oxidation rate of exogenous substrates and respiration were higher in the presence of 2-ketoisocaproate than when this substrate was combined with an amino acid. The action of 2-ketoisocaproate to increase the ratios of NADH/NAD+ and NADPH/NADP+, to enhance the uptake of 45Ca by islet tissue, and to promote proinsulin biosynthesis was also suppressed by the addition of branched chain amino acids to the incubation media. Radioisotopic uptake measurements suggested that many of these observations could be related to changes in the intracellular concentration of 2-ketoisocaproate in islet tissue.

Amino Acids, Branched-Chain↗
PubMed1980

The stimulus-secretion coupling of glucose-induced insulin release. Metabolism of glucose in K+-deprived islets.

1. When pancreatic islets were exposed to a K(+)-free medium, the intracellular concentration of K(+) was decreased and that of Na(+) increased. 2. In the K(+)-deprived islets, the utilization of [5-(3)H]glucose, output of lactic acid and oxidation of [U-(14)C]-glucose were decreased by about 30-40% below the control values found at normal extracellular K(+) concentration (5.0mm). However, the oxidation of [U-(14)C]pyruvate was unaffected. 3. The omission of extracellular K(+) little affected the production of (14)CO(2) from islets prelabelled with [U-(14)C]palmitate and incubated in the absence of glucose, despite the fact that K(+) deprivation significantly increased the ATP concentration and ATP/ADP concentration ratio in the glucose-deprived islets. 4. At normal K(+) concentration, glucose increased the concentrations of phosphoenolpyruvate, NAD(P)H and ATP in the islets. In the glucose-stimulated islets, the concentration of phosphoenolpyruvate, but not that of either NAD(P)H or ATP, was higher in the absence than in the presence of extracellular K(+). In islet homogenates, the activity of pyruvate kinase (EC 2.7.1.40) was stimulated by K(+) (optimal activity at 100-150mm-K(+)) and inhibited by Na(+) (except at very low K(+) concentrations). 5. K(+) could be replaced by NH(4) (+), Rb(+), Cs(+) or Na(+) to maintain, at least to some extent, pyruvate kinase activity in islet homogenates. Addition of Rb(+) or Cs(+), but not NH(4) (+), to K(+)-deprived media also increased [U-(14)C]glucose oxidation by intact islets. 6. The omission of K(+) did not cause any obvious anomaly in the apparent dependency of (45)Ca(2+) net uptake on NAD(P)H concentration in the islets. 7. These data suggest that the coupling between metabolic and ionic events in the islet cells involves feedback mechanisms through which glucose oxidation may be modulated by cationic factors.

Adenine Nucleotides↗
PubMed1980

Metabolic, cationic and secretory effects of hypoglycemic sulfonylureas in pancreatic islets.

Tolbutamide, gliclazide and glibenclamide failed to stimulate glucose oxidation in rat pancreatic islets. Tolbutamide also failed to stimulate pyruvate and palmitate oxidation and decreased the islet content of NAD(P)H and ATP. Tolbutamide stimulated 45Ca net uptake, inhibited 86Rb net uptake and tended to increase 22Na net uptake by the islets. The effect of theophylline upon islet function differed from that of tolbutamide by the magnitude of its insulinotropic action as a function of the glucose concentration, by its stimulant action upon the utilization of endogenous nutrients in islets deprived of glucose and by the lack of gross alteration in 45Ca and 86Rb net uptake. It is concluded that the insulinotropic effect of hypoglycemic sulfonylureas cannot be merely equated to a facilitation of nutrient metabolism or inactivation of phosphodiesterase in the islet cells. The primary action of these drugs could be to affect cations transport across the B-cell membrane.

Animals↗
PubMed1980

The stimulus-secretion coupling of glucose-induced insulin release. XLV. The anion-osmotic hypothesis for exocytosis.

Replacement of extracellular chloride by the impermeant anion isethionate, increase in extracellular osmotic strength by addition of sucrose, or exposure to the anion transport blocking agent probenecid inhibited insulin release evoked by glucose or alpha-ketoisocaproate in rat isolated islets. The inhibition of insulin release due to Cl- substitution was associated with a modest decrease in glucose oxidation, but no significant change in glucose-stimulated 45Ca net uptake by the islets. In the isolated perfused rat pancreas, the isethionate- or sucrose-induced inhibition of insulin release was a rapid and rapidly reversible phenomenon. Chloride substitution by isethionate inhibited more severely the second than the first phase of the secretory response to glucose, and failed to affect the insulin response to gliclazide. A chemosmotic mechanism for exocytosis, as proposed for epinephrine and parathyroid hormone release, may also be involved in insulin release.

Alkanesulfonates↗
PubMed1980

Stimulus-secretion coupling of glucose-induced insulin release. Effect of intracellular acidification upon calcium efflux from islet cells.

When pancreatic islets were exposed to a medium of normal pH (7.4) equilibrated with a gaz mixture containing 30% (instead of 5%) CO2, the intracellular pH of the islet cells, as judged by the apparent space of distribution of 14C-DMO, was decreased. The intracellular acidification was associated with a delayed decrease of [U-14C] glucose oxidation, but no major change in glucose-stimulated proinsulin biosynthesis, 45 calcium net uptake, or insulin release. The increase in PCO2 provoked an immediate and sustained decrease in the fractional outflow rate of 45Ca from prelabeled and perfused islets. The latter decrease was most marked under conditions associated with stimulated 40Ca-45Ca exchange (i.e., at glucose 16.7 mM and normal Ca2+ concentration), but was also present when a process of Na+-Ca2+ countertransport accounted for the major part of 45Ca efflux (e.g., in the absence of both glucose and extracellular Ca2+). These findings are compatible with the view that the generation of H+ derived from the metabolism of glucose in islet cells plays a role in the sugar-induced decrease in 45Ca fractional outflow rate.

Animals↗
PubMed1980

The stimulus-secretion coupling of glucose-induced insulin release. XLVI. Physiological role of L-glutamine as a fuel for pancreatic islets.

Exogenous L-glutamine is actively metabolized in rat pancreatic islets. The rate of L-glutamine deamidation largely exceeds the rate of glutamate conversion to gamma-aminobutyrate and alpha-ketoglutarate. The latter conversion occurs in part by oxidative deamination, and in part by transamination reactions coupled with the conversion of 2-keto acids (pyruvate, oxaloacetate), themselves derived from the metabolism of glutamine, to their corresponding amino acids (alanine, aspartate). An important fraction of malate formed from alpha-ketoglutarate leaves the Krebs cycle and is converted to pyruvate, the process being apparently associated with the induction of a more reduced state in cytosolic redox couples. L-Glutamine abolishes the oxidation of endogenous nutrients is documented by the fact that the glutamine-induced increase in O2 consumption is much lower than expected from the rate of 14CO2 output from islets exposed to L-[U-14C]glutamine, L-Glutamine, although decreasing K+ conductance, fails to stimulate insulin release both in the absence and presence of D-glucose. It is proposed that L-glutamine represents a major fuel for pancreatic islets under physiological conditions.

Animals↗
PubMed1980

The stimulus-secretion coupling of glucose-induced insulin release. XLII. Effects of extracellular pH on insulin release: their dependency on nutrient concentration.

Changes in extracellular pH affected insulin output from pancreatic islets stimulated with either glucose or alpha-ketoisocaproate. The extracellular pH at which the highest secretory response occurred was not identical in all cases, being shifted to alkaline values as the concentration of the nutrient secretagogue was increased. The output of insulin correlated with the nutrient-induced increment in 45Ca net uptake, but not with the rate of nutrient oxidation. By reference to changes in intracellular pH observed in islets exposed to either acidic media or increasing concentrations of alpha-ketoisocaproate, and taking into account a titration curve for the buffering capacity of islet homogenates, the optimal intracellular pH for insulin release was found to approximate a value of 0.09 pH unit below basal pH. It is postulated that, in the process of nutrient-induced insulin release, modest changes in intracellular pH participate in the multifactorial coupling between metabolic, ionic and secretory events.

Animals↗
PubMed1980

Similarities in the stimulus-secretion coupling mechanisms of glucose- and 2-keto acid-induced insulin release.

The stimulus-secretion coupling of 2-keto acid-induced insulin release was investigated using 2-ketoisocaproate (4-methyl-2-oxopentanoate) as the principal model secretagogue. 2-Ketoisocaproate and 2-ketocaproate (2-oxo-, hexanoate) provoked changes in B cell electrical behavior characterized by an initial depolarization of the membrane potential, followed by rapid spike activity, which appeared either in a bursting pattern or as continuous activity. The onset of spike activity induced by 2-ketoisocaproate (5 mM) was biphasic in nature. The dynamic pattern of 2-ketoisocaproate-induced insulin release was also biphasic. 2-[U-14C]Ketoisocaproate (10 mM) was oxidized in islet tissue at a rate equivalent to that of [U-14C]glucose (17 mM) and a t a higher rate than 2-ketoisovalerate (3-methyl-2-oxobutyrate) and 2-keto-3-methyl-valerate, which were poor secretagogues. Like glucose, 2-ketoisocaproate provoked characteristic changes in 86Rb and 45Ca efflux from prelabeled islets and stimulated 45Ca net uptake. Proinsulin synthesis was stimulated by 2-ketoisocaproate through both a general effect on protein synthesis and a specific effect on hormonal biosynthesis. 2-Ketoisocaproate and 2-ketocaproate reproduced the effect of glucose on the islet content of ATP, ADP, AMP, NAD+, NADH, NADP+, and NADPH. These findings together with a series of observations on the effects upon the above parameters of site-specific inhibitors, e.g. respiratory inhibitors, suloctidil, theophylline, and epinephrine, suggested that the stimulus-secretion-coupling mechanisms for 2-ketoisocaproate- and glucose-induced release are similar. It is postulated that glucose- and 2-keto acid-induced insulin release may be initiated by a common signal.

Adenine Nucleotides↗
PubMed1980

The stimulus-secretion coupling of glucose-induced insulin release. XXXIX. Long term effects of K+ deprivation upon insulin biosynthesis and release.

A decrease in the extracellular concentration of K+ provokes a dose-related, progressive, and persistent inhibition of insulin release evoked by high concentrations of glucose or alpha-ketoisocaproate. The biosynthesis of proinsulin and other peptides is severely decreased in the K+-deprived islets. The functional situation found in the K+-deprived islets can be mimicked, to a limited extent, by exposing the islets to inhibitors of protein biosynthesis and is reminiscent of that found in glucose-deprived islets. It is postulated that the intracellular concentration of K+ in islet cells participates in the long term regulation of insulin release by glucose.

Animals↗
PubMed1980

Regulation of calcium fluxes in pancreatic islets: the role of membrane depolarization.

The effect of K+-induced depolarization on calcium fluxes and insulin release from isolated islets were investigated in order to elucidate the mechanism by which glucose initially reduces and later increases 45Ca efflux from prelabeled and perifused rat pancreatic islets. Raising the extracellular K+ concentration from 5.0 to 20.0 mM produced a 2- to 3-fold increase in 45Ca net uptake and efflux from isolated islets. The latter effect was dependent on the presence of extracellular Ca2+, suggesting that it resulted from the entry of calcium into the islet cells. In the presence of 20 mM K+, 16.7 mM glucose failed to stimulate 45Ca efflux, while 20 mM K+ further enhanced 45Ca efflux from islets perifused in the presence of the high concentration of glucose. These findings suggest that the effect of glucose to stimulate 45Ca efflux from perifused islets depends mainly on the glucose-induced depolarization of the cell membrane. In the absence of extracellular calcium, 20 mM K+ failed to mimick the effect of glucose to reduce 45Ca efflux. Glucose (16.7 mM) decreased 45Ca efflux from islets perifused in the presence of 20 mM K+ and antagonized the effect of 20 mM K+ to stimulate 45Ca efflux from perifused islets. It is concluded that K+-induced plasma membrane depolarization reproduces the effect of glucose to stimulate but not to inhibit 45Ca efflux from perifused islets.

Animals↗
PubMed1980

The stimulus-secretion coupling of amino acid-induced insulin release: metabolism and cationic effects of leucine.

When isolated rat pancreatic islets are exposed to L-leucine (20 mM), the rate of NH4 production is close to the summed rates of L-[1-14C] leucine decarboxylation and alpha-ketoisocarproate production, whereas the rates of acetoacetate production and L-[U-14C]-leucine oxidation are compatible with conversion of each mole of the amino acid to one mole of acetoacetate and three moles of CO2. ATP content, ATP/ADP ratio, and adenylate charge are maintained at normal values by L-leucine, whereas the NADH/NAD+ ratio (but not the NADPH/NADP+ ratio) is significantly increased. The release of insulin evoked by L-leucine is potentiated by 2-ketoisovalerate, unaffected by L-valine, and inhibited by menadione. L-leucine mimicks the effect of D-glucose on 86Rb+ and 45Ca2+ handling by the islets. However, relative to its rate of oxidation, the insulinotropic effect of L-leucine is less marked than that of D-glucose. This may be due, in part at least, to a decrease in the oxidation of endogenous nutrients. It is concluded that the metabolic, cationic, and secretory effects of L-leucine in isolated islets are not incompatible with the fuel hypothesis for insulin release.

Acetoacetates↗
PubMed1980

Insulinotropic effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in rat pancreatic islets.

In isolated rat pancreatic islets, the tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA), when used in the 2.10(-9) to 2.10(-7) M range, was found to stimulate insulin release both in the absence and presence of glucose. The non-tumor-promoting agent 4-methylphorbol-12,13-didecanoate failed to stimulate insulin release. The insulinotropic capacity of TPA was enhanced by glucose in a dose-related fashion. In the absence of glucose, the TPA-stimulated release of insulin was a slowly induced and not rapidly reversible phenomenon. It was inhibited by antimycin A, by epinephrine, at low temperatures, and in the absence of extracellular Ca2+ or the presence of cytochalasin B, was unaffected by the organic calcium antagonist D600 or indomethacin, and was potentiated by theophylline. No obvious effect of TPA upon 86Rb or 32P efflux and 45Ca net uptake could be detected in the isolated islets. However, TPA caused a progressive increase in both 45Ca fractional outflow rate and cyclic adenosine 3':5'-monophosphate content in the islets. It is proposed that the insulinotropic action of TPA may be due, in part at least, to interference with the transport of calcium by native ionophores.

Animals↗
PubMed1980

The stimulus-secretion coupling of amino acid-induced insulin release. II. Sensitivity to K+, NH4+ and H+ of leucine-stimulated islets.

The insulinotropic action of L-leucine is thought to be tightly coupled with the metabolism of this amino acid in pancreatic islet cells. Consistent with such a view, the removal of extracellular K+ severely impaired L-leucine deamination and oxidation and L-leucine-stimulated insulin release. L-leucine increased the NH4+ content of islet cells. Exogenous NH4+ inhibited more markedly 45Ca net uptake and insulin release in islets exposed to L-leucine than in islets stimulated by D-glucose, D-glyceraldehyde or alpha-ketoisocaproate, all nutrients being used at concentrations of equal insulinotropic capacity. The islets exposed to L-leucine also differed from those stimulated with D-glucose by a somewhat higher 45Ca net uptake relative to insulin output, and an increased secretory activity in response to extracellular or intracellular acidification. It is proposed that in the islets exposed to L-leucine, an alteration in the islet content of NH4+ and possibly H+ interferes with the normal coupling between metabolic and secretory events.

Ammonia↗