Search PubMed⌕ Search

Biomedical subjects

A Sener

Publications and source records attributed to A Sener.

At least 253 records · Page 14Linked to original sources
PubMed1985

Combined effects of a calcium-agonist and hypoglycemic or hyperglycemic sulfonamides upon insulin release.

The organic calcium-agonist CGP 28392 augmented insulin release evoked by D-glucose in rat pancreatic islets incubated in the presence or absence of gliclazide, but failed to stimulate insulin secretion in the absence of glucose or presence of diazoxide. Gliclazide, however, failed to augment insulin release evoked, in the presence of CGP 28392, by a high concentration of glucose (11.1 mM), and protected the B-cell against the inhibitory action of diazoxide. As judged from the relative magnitude of changes in 45Ca fractional outflow rate from prelabelled islets perifused at an intermediate glucose concentration (7.0 mM), CGP 28392 failed to affect the rapid cationic response to gliclazide, whereas this hypoglycemic sulfonylurea decreased the cationic response to CGP 28392. These results suggest that the functional response to gliclazide is attributable to a molecular mechanism distinct from the prolongation of the open time of calcium channels presumably provoked by the dihydropyridine.

Animals↗
PubMed1985

Anomeric dissociation between glucokinase activity and glycolysis in pancreatic islets.

In pancreatic islet homogenates incubated in the presence of a high glucose concentration (40 mM), the beta-anomer of D-glucose is phosphorylated at a higher rate than the alpha-anomer, whether in the absence or presence of exogenous glucose 6-phosphate. However, in intact islets also exposed to 40 mM D-glucose, the production of 3H2O from D-[5-3H] glucose, the oxidation of D-[U-14C] glucose and the glucose-induced increment in either lactate production or 45Ca net uptake, as well as the release of insulin from isolated perfused pancreases, are not higher with beta- than alpha-D-glucose. It is concluded that the rate of glucose utilization by islet cells is not regulated solely by the activity of hexokinase and/or glucokinase.

Animals↗
PubMed1985

Anomeric specificity of hexokinase in rat, human, and murine tumor cells.

In tumoral cells derived from the insulin-producing rat cell line RINm5F, both low- and high-Km glucose-phosphorylating enzymic activities were present. The hexokinase-like enzyme was inhibited by glucose 6-phosphate and displayed a greater affinity for but lower maximal velocity with alpha-D-glucose than beta-D-glucose. A comparable anomeric behavior of hexokinase was observed in breast cancer (MCF-7) and lymphocytic leukemia (P388) cells. Thus, the anomeric specificity of hexokinase in tumoral cells was not different from that recently characterized in normal mammalian cells.

Animals↗
PubMed1985

Suppression by 2-ketoisocaproate of the insulinotropic action of hypoglycemic sulfonylureas.

Tolbutamide (370 microM), gliclazide (62 microM) and glibenclamide (1 microM) failed to enhance insulin release evoked by 2-ketoisocaproate (10 mM) in rat pancreatic islets. Gliclazide also little affected insulin release evoked by 2-ketoisocaproate, whereas the hypoglycemic sulfonylurea stimulated insulin release from islets incubated in the absence of exogenous nutrient or presence of either L-glutamine, D-glucose, D-mannose, D-glyceraldehyde, L-leucine or the combination of D-glucose and pyruvate. In the presence of 2-ketoisocaproate, a modest secretory response to gliclazide was observed when the concentration of the 2-keto acid was decreased to 5 mM, or in perifused islets in which case gliclazide caused a transient increase in both 45Ca outflow and insulin output from prelabelled islets exposed to 10 mM 2-ketoisocaproate. Gliclazide and other hypoglycemic sulfonylureas failed to affect the oxidation of 2-[U-14 c]-ketoisocaproate and the latter 2-keto acid failed to affect the ionophoretic action of gliclazide in an artificial membrane model. Gliclazide increased 45Ca net uptake by islets exposed to 2-ketoisocaproate, but this effect of the sulfonylurea was much less marked than that seen in the presence of D-glucose used at a concentration of equal insulinotropic efficiency. These findings indicate that 2-ketoisocaproate impairs the cationic and secretory responses of islets to hypoglycemic sulfonylureas. It is proposed that such an impairment is compatible with the view that a remodelling of ionic fluxes in the islet cells represents a primary event in the process of sulfonylurea-stimulated insulin release.

Animals↗
PubMed1985

Anomeric specificity of glycolysis in a non glucokinase-containing cell.

In rat erythrocyte homogenates, the phosphorylation of D-glucose measured at 30 degrees C over a wide range of glucose concentrations (50 microM to 20 mM) yielded in a double reciprocal plot a single straight line with a Km close to 0.06 mM and a maximal velocity close to 47 nmol/60 min per mg hemoglobin. At 8 degrees C, the rate of glucose phosphorylation was 60% higher in the presence of beta-D-glucose than alpha-D-glucose. Yet, in intact erythrocytes incubated at 8 degrees C in the presence of beta-D-glucose (4 or 7 mM), the glucose-induced increment in lactic acid output represented no more than 39 to 74% of that found in the presence of alpha-D-glucose. Thus, a greater rate of glycolysis in the presence of alpha-D-glucose was observed in a cell devoid of glucokinase and containing a hexokinase with preference for beta-D-glucose. These findings indicate that the anomeric specificity of glycolysis in intact cells cannot be predicted and does not necessarily depend on the anomeric preference of glucose-phosphorylating enzyme(s).

Animals↗
PubMed1984

Hexose metabolism in pancreatic islets. Inhibition of hexokinase.

In islet homogenates, hexokinase-like activity (Km 0.05 mM; Vmax. 1.5 pmol/min per islet) accounts for the major fraction of glucose phosphorylation. Yet the rate of glycolysis in intact islets incubated at low glucose concentrations (e.g. 1.7 mM) sufficient to saturate hexokinase only represents a minor fraction of the glycolytic rate observed at higher glucose concentrations. This apparent discrepancy between enzymic and metabolic data may be attributable, in part at least, to inhibition of hexokinase in intact islets. Hexokinase, which is present in both islet and purified B-cell homogenates, is indeed inhibited by glucose 6-phosphate (Ki 0.13 mM) and glucose 1,6-bisphosphate (Ki approx. 0.2 mM), but not by fructose 2,6-bisphosphate. In intact islets, the steady-state content of glucose 6-phosphate (0.26-0.79 pmol/islet) and glucose 1,6-bisphosphate (5-48 fmol/islet) increases, in a biphasic manner, at increasing concentrations of extracellular glucose (up to 27.8 mM). From these measurements and the intracellular space of the islets, it was estimated that the rate of glucose phosphorylation as catalysed by hexokinase represents, in intact islets, no more than 12-24% of its value in islet homogenates.

Animals↗
PubMed1984

Hexose metabolism in pancreatic islets. The phosphorylation of fructose.

Fructose, like glucose, rapidly equilibrates across the plasma membrane of pancreatic islet cells, but is poorly metabolized and is a weak insulin secretagogue in rat pancreatic islets. A possible explanation for such a situation was sought by investigating the modality of fructose phosphorylation in islet homogenates. Several findings indicated that the phosphorylation of fructose is catalyzed by hexokinase, but not fructokinase. First, at variance with the situation found in liver homogenates, the phosphorylation of fructose in the islet homogenate was unaffected by K+ and inhibited by glucose, mannose, glucose 6-phosphate or glucose 1,6-bisphosphate. Second, the Km for fructose was much higher in islets than in liver. Third, in islet homogenates the Km and Vmax for fructose were much higher than those for glucose or mannose phosphorylation, at low aldohexose concentrations, in good agreement with the properties of purified hexokinase. In intact islets fructose augmented the islet content in glucose 6-phosphate sufficiently to cause marked inhibition of its own rate of phosphorylation. These findings may account, in part at least, for the low rate of fructose utilization by rat pancreatic islets.

Animals↗
PubMed1984

Inhibition by mepacrine and p-bromophenacylbromide of phosphoinositide hydrolysis, glucose oxidation, calcium uptake and insulin release in rat pancreatic islets.

Mepacrine and p-bromophenacylbromide were both found to impair 3H-inositol phosphate production in response to both nutrient and hormone-neurotransmitter stimuli in islets prelabelled with 3H-inositol. Both drugs also inhibited net 45Ca uptake in response to glucose or glibenclamide and considerably modified the patterns of 45Ca and 86Rb efflux from perifused islets under both basal and glucose-stimulated conditions. In addition, the oxidation of [U-14C] glucose in islets was impaired by either mepacrine or p-bromophenacylbromide. These inhibitory effects were found to be concentration-related for both mepacrine (0.01-1.0 mM) and p-bromophenacylbromide (0.03-0.3 mM) and were accompanied, in general, by a similar degree of inhibition of insulin secretion. These results suggest that both mepacrine and p-bromophenacylbromide can inhibit phospholipase C activity in intact islets, but also impair 45Ca and 86Rb fluxes and oxidation of nutrients. The diversity of these drugs' inhibitory actions makes them unsuitable tools for examining the role of specific cellular processes in the regulation of islet function.

Acetophenones↗
PubMed1984

Effects of glucose and glucagon on the fructose 2,6-bisphosphate content of pancreatic islets and purified pancreatic B-cells. A comparison with isolated hepatocytes.

Glucose caused a sustained and dose-related increase in the fructose 2,6-bisphosphate content of isolated pancreatic islets, as well as of purified pancreatic B-cells. With isolated B-cells, the glucose saturation curve was sigmoidal and superimposable on that obtained with hepatocytes isolated from unfed rats. However, the response to glucose was notably faster in purified B-cells than in isolated hepatocytes. In contrast again with the situation prevailing in the liver, glucagon failed to decrease significantly the concentration of fructose 2,6-bisphosphate in either islets or purified B-cells. It is proposed that, in the process of glucose-stimulated insulin secretion, an early increase in fructose 2,6-bisphosphate formation may, by causing activation of 6-phosphofructo-1-kinase, allow glycolysis to keep pace with the rate of glucose phosphorylation.

Animals↗
PubMed1984

The coupling of metabolic to secretory events in pancreatic islets. The cytosolic redox state.

NADP-linked isocitrate dehydrogenase and malic enzyme [malate dehydrogenase (decarboxylating) (NADP)] activities were characterized in the cytosol of pancreatic islet cells. D-Glucose and L-leucine augmented the cytosolic NADPH/NADP+ ratio, as judged from the isocitrate/2-oxoglutarate and malate/pyruvate islet contents. The flow rate through the malic enzyme was judged from the output of labelled pyruvate by islets exposed to either L-[U-14C]glutamine or L-[U-14C]leucine. The cytosolic generation of NADPH, e.g. at the level of the malic enzyme, may play a role in the coupling of metabolic to secretory events in the process of nutrient-stimulated insulin release.

Animals↗
PubMed1984

Activation of protein kinase C by a tumor-promoting phorbol ester in pancreatic islets.

Rat pancreatic islet homogenates display protein kinase C activity. This phospholipid-dependent and calcium-sensitive enzyme is activated by diacylglycerol or the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). In the presence of TPA, the Ka for Ca2+ is close to 5 microM. TPA does not affect phosphoinositide turnover but stimulates [32P]- and [3H]choline-labelling of phosphatidylcholine in intact islets. Exogenous phospholipase C stimulates insulin release, in a sustained and glucose-independent fashion. The secretory response to phospholipase C persists in media deprived of CaCl2. It is proposed that protein kinase C participates in the coupling of stimulus recognition to insulin release evoked by TPA, phospholipase C and, possibly, those secretatogues causing phosphoinositide breakdown in pancreatic islets.

Animals↗
PubMed1984

Fasting-induced impairment of glucose-1,6-bisphosphate synthesis in pancreatic islets.

In pancreatic islets removed from rats fasted for 48 hours, the insulin secretory response to glucose is decreased. Although the activity of phosphoglucomutase is unaffected by fasting, the decrease in glucose-stimulated insulin release coincides with a suppression of the glucose-induced increment in both glucose-1,6-P2 content and lactate or pyruvate output. These findings are compatible with a regulatory role of glucose-1,6-P2 in the control of glycolysis in pancreatic islets.

Animals↗
PubMed1984

The stimulus-secretion coupling of amino acid-induced insulin release: metabolism of L-asparagine in pancreatic islets.

The metabolism of L-asparagine in pancreatic islets was investigated. The deamidation of L-asparagine and the conversion of aspartate to oxalacetate, by transamination, may occur in both the cytosol and mitochondria. Oxalacetate is then converted to pyruvate in part via phosphoenolpyruvate and in part via malate. The latter modality, by consuming NADH and generating NADPH, may lead to changes in the redox state of the cytosolic NADH/NAD+ and NADPH/NADP+ couples. Such changes may in turn account, in part at least, for the capacity of L-asparagine to augment insulin release induced by certain nutrient secretagogues.

Acetyl Coenzyme A↗
PubMed1984

The stimulus-secretion coupling of amino acid-induced insulin release metabolic interaction of L-asparagine and L-leucine in pancreatic islets.

Because L-asparagine augments insulin release evoked by L-leucine, the metabolism of these two amino acids was investigated in rat pancreatic islets. L-Leucine inhibited the uptake and deamidation of L-asparagine, but failed to exert any obvious primary effect upon the further catabolism of aspartate derived from exogenous asparagine. L-Asparagine augmented the oxidation of L-leucine, an effect possibly attributable to activation of 2-ketoisocaproate dehydrogenase. The association of L-asparagine and L-leucine exerted a sparing action on the utilization of endogenous amino acids, so that the integrated rate of nutrients oxidation was virtually identical in the sole presence of L-leucine and simultaneous presence of L-asparagine and L-leucine, respectively. It is proposed that the enhancing action of L-asparagine upon insulin release evoked by L-leucine is attributable to an increased generation rate of cytosolic NADPH rather than any increase in nutrients oxidation.

Animals↗
PubMed1984

Metabolic and secretory effects of methylamine in pancreatic islets.

The metabolic and secretory effects of methylamine in rat pancreatic islets were investigated. Methylamine accumulated in islet cells, was incorporated into endogenous islet proteins, and inhibited the incorporation of [2,5-3H] histamine into either N,N-dimethylcasein or endogenous islet proteins. Methylamine (2 mM) did not affect the oxidation of glucose or endogenous nutrients or the intracellular pH in islet cells. Glucose did not affect the activity of transglutaminase in islet homogenates, the uptake of 14C-methylamine by intact islets or its incorporation into endogenous islet proteins. Methylamine inhibited insulin release evoked by glucose, other nutrient secretagogues, and non-nutrient insulinotropic agents such as L-arginine or gliclazide. The inhibitory effect of methylamine upon insulin release was diminished in the presence of cytochalasin B or at low extracellular pH. Methylamine retarded the conversion of proinsulin to insulin. Trimethylamine (0.7 mM) was more efficiently taken up by islet cells than methylamine (2.0 mM), and yet caused only a modest inhibition of insulin release. These findings suggest that methylamine interferes with a late step in the secretory sequence, possibly by inhibiting the access of secretory granules to their exocytotic site.

Acyltransferases↗
PubMed1984

The stimulus-secretion coupling of amino acid-induced insulin release. Inhibition of islet respiration and insulin release by aminooxyacetate.

Aminooxyacetate, an inhibitor of cytosolic transamination reactions, inhibited insulin release evoked by either 2-ketoisocaproate or L-leucine in rat pancreatic islets incubated in the presence of L-glutamine or L-asparagine. As a rule, aminooxyacetate also inhibited the oxidation of these nutrient secretagogues and impaired the respiratory response of the islets to the combinations of nutrients. However, the oxidative and secretory response to the combination of L-leucine and L-glutamine was less severely affected by aminooxyacetate than that evoked by the three other combinations of exogenous nutrients. These findings reinforce the view that the stimulus-secretion coupling of insulin release in response to L-leucine and 2-ketoisocaproate in association with either L-glutamine or L-asparagine tightly depends on the oxidation of these nutrient secretagogues, on their effect upon O2 uptake and, within limits, on the intracellular site of generation of reducing equivalents in the pancreatic islet cells.

Acetates↗