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A Herchuelz

Publications and source records attributed to A Herchuelz.

At least 19 recordsLinked to original sources
PubMed1979

The stimulus-secretion coupling of glucose-induced insulin release. XXXV. The links between metabolic and cationic events.

When isolated rat islets were exposed to glucose, the concentrations of NADH and NADPH, and the NADH/NAD+ and NADPH/NADP+ ratios were increased. The dose-response curve resembled that characterising the glucose-induced secondary rise in 45Ca efflux, displaying a sigmoidal pattern with a half-maximal value at glucose 7.5 mmol/l. The glucose-induced increase in NAD(P)H was detectable within 1 min of exposure to the sugar. Except for the fall in ATP concentration and ATP/ADP ratio found at very low glucose concentrations (zero to 1.7 mmol/l) no effect of glucose (2.8-27.8 mmol/l) upon the steady-state concentration of adenine nucleotides was observed. However, a stepwise increase in glucose concentration provoked a dramatic and transient fall in the ATP concentration, followed by a sustained increase in both O2 consumption and oxidation of exogenous + endogenous nutrients. This may be essential to meet the energy requirements in the stimulated B-cell. Although no significant effect of glucose upon intracellular pH was detected by the 5,5-dimethyloxazolidine-2,4-dione method, the net release of H+ was markedly increased by glucose, with a hyperbolic dose-response curve (half-maximal response at glucose 2.9 mmol/l) similar to that characterising the glucose-induced initial fall in 45Ca efflux. It is proposed that the generation of both NAD(P)H and H+ participates in the coupling of glucose metabolism to distal events in the secretory sequence, especially the ionophoretic process of Ca2+ inward and outward transport, and that changes in these parameters occur in concert with an increased turn-over rate of high-energy phosphate intermediates.

Adenine Nucleotides↗
PubMed1979

Insulin release: the fuel hypothesis.

The immediate and direct regulation of insulin release by circulating nutrients, especially glucose, is thought to be mediated in the pancreatic B-cell by a sequence of metabolic, ionic, and motile events. On the basis of previous work, it is assumed that the process by which glucose is recognized as an insulinotropic agent entirely depends on the metabolic changes evoked by the sugar in the islet cells. Several factors are considered as possible candidates for the coupling between these metabolic changes and subsequent ionic events such as altered phosphate, chloride, sodium, potassium, and calcium handling. It is acknowledged that changes in the concentrations of glycolytic intermediates and cyclic nucleotides (adenosine- or guanosine-3', 5'-cyclic monophosphate), or both, could play a modulatory role upon stimulated insulin release. However, the initiation of insulin release seems to depend on the generation of two essential coupling factors: H+ and reduced pyridine nucleotides. The changes in H+ fluxes may account for the glucose-induced decrease in K+ and Ca2+ fractional outflow rate, all three parameters displaying hyperbolic-like dose-response curves with half-maximal values at noninsulinotropic glucose concentrations. The changes in NAD(P)H concentration may account for a glucose-induced Ca2+--Ca2+ exchange process due to a change in affinity of a native ionophoretic system. The dose-response curves for these parameters yield a sigmoidal pattern analogous to that which depicts the rate of insulin release at increasing glucose concentrations. It is proposed that such a coupling between metabolic and cationic events is operative in response to other insulinotropic nutrients and that its time course may be relevant to the phasic aspect of insulin release. Thus, the nutrient-induced release of insulin (and possibly other pancreatic hormones), which is essential for the regulation of fuel homeostasis, would depend on the capacity of circulating nutrients to act as a fuel in the islet cells. This concept raises a question as to the existence and nature of feedback mechanisms regulating the metabolic fluxes in the islet cells as a function of their energy expenditure.

Adenosine Triphosphate↗
PubMed1978

The stimulus-secretion coupling of glucose-induced insulin release. Effect of exogenous pyruvate on islet function.

1. In isolated pancreatic islets, pyruvate causes a shift to the left of the sigmoidal curve relating the rate of insulin release to the ambient glucose concentration. The magnitude of this effect is related to the concentration of pyruvate (5--90 mM) and, at a 30 mM concentration, is equivalent to that evoked by 2 mM-glucose. Pyruvate also enhances insulin release in the presence of fructose, leucine and 4-methyl-2-oxopentanoate. 2. In the presence of glucose 8 mM), the secretory response to pyruvate is an immediate process, displaying a biphasic pattern. 3. The insulinotropic action of pyruvate coincides with an inhibition of 45Ca efflux and a stimulation of 45Ca net uptake. The relationship between 45Ca uptake and insulin release displays its usual pattern in the presence of pyruvate. 4. Exogenous pyruvate rapidly accumulates in the islets in amounts close to those derived from the metabolism of glucose. The oxidation of [2-14C]pyruvate represents 64% of the rate of [1-14C]pyruvate decarboxylation and, at a 30 mM concentration, is comparable with that of 8 mM-[U-14C]glucose. 5. When corrected for the conversion of pyruvate into lactate, the oxidation of 30 mM-pyruvate corresponds to a net generation of about 314 pmol of reducing equivalents/120 min per islet. 6. Pyruvate does not affect the rate of glycolysis, but inhibits the oxidation of glucose. Glucose does not affect pyruvate oxidation. 7. Pyruvate (30 mM) does not affect the concentration of ATP, ADP and AMP in the islet cells. 8. Pyruvate (30 mM) increases the concentration of reduced nicotinamide nucleotides in the presence but not in the absence of glucose. A close correlation is seen between the concentration of reduced nicotinamide nucleotides and the net uptake of 45Ca. Menadione inhibits the effect of pyruvate on insulin release, without altering its rate of oxidation. 9. Pyruvate, like glucose, modestly stimulates lipogenesis. 10. Pyruvate, in contrast with glucose, markedly inhibits the oxidation of endogenous nutrients. The latter effect accounts for the apparent discrepancy between the rate of pyruvate oxidation and the magnitude of its insulinotropic action. 11. Dichloroacetate fails to affect glucose oxidation and glucose-stimulated insulin release. 12. It is concluded that the effect of pyruvate to stimulate insulin release depends on its ability to increase the concentration of reduced nicotinamide nucleotides in the islet cells.

Animals↗
PubMed1978

Calcium antagonists and islet function: VII. Effect of calcium deprivation.

The role of extracellular Ca2+ in the regulation of islet function is investigated. Decreasing extracellular Ca2+ concentrations cause a dose-related inhibition of glucose-induced insulin release. Whereas the efflux of 45Ca from perifused islets is transiently increased on exposure to Ca2+-deprived media, it is unaffected by a partial lowering of the extracellular Ca2+ concentration. Under the latter condition, therefore, the observed reduction in the size of the islets' exchangeable calcium pool(s) appears to be due to reduced Ca2+ entry. The proper effect of glucose on Ca handling by the islets is apparently not affected by a lowering in the extracellular Ca2+ concentration. Nevertheless, in islets exposed to glucose and incubated in Ca2+-deprived media, glucose uptake and oxidation and lactate output are decreased, whereas the islet ATP level is increased, as if extracellular Ca2+ shortage were to affect not only the cellular pool of Ca regulating insulin release, but also energy-consuming processes possibly located at the cell membrane.

Adenosine Triphosphate↗
PubMed1978

Regulation of calcium fluxes in pancreatic islets: dissociation between calcium and insulin release.

1. The release of 45calcium from prelabelled pancreatic islets is rapidly and almost totally inhibited by lanthanum. 2. Glucose provokes an intitial fall followed by a secondary rise in 45calcium efflux. The latter rise occurs concomitantly with insulin release. Its magnitude is reduced whenever the secretory response to glucose is inhibited, e.g. in the absence of extracellular calcium, presence of Verapamil, or at high magnesium concentration. 3. However, under suitable conditions, the glucose-induced secondary rise in 45calcium efflux is not totally suppressed whilst insulin release is totally abolished. 4. Inversely, when calcium is replaced by barium in the perifusate, glucose increases insulin output without causing any obvious secondary rise in 45calcium efflux. 5. It is concluded that this secondary rise, which originates from a lanthanum-nondisplaceable calcium pool, does not correspond solely to an exocytotic release of 45calcium. It could represent, in part at least, a displacement of 45calcium from cellular sites and reflect a glucose-induced increase in the rate of calcium entry in islet cells.

Animals↗
PubMed1978

The stimulus-secretion coupling of glucose-induced insulin release. Metabolic and functional effects of NH4+ in rat islets.

NH4+ caused a dose-related, rapid, and reversible inhibition of glucose-stimulated insulin release by isolated rat islets. It also inhibited glyceraldehyde-, Ba2+-, and sulfonylurea-stimulated insulun secretion. NH4+ failed to affect glucose utilization and oxidation, glucose-stimulated proinsulin biosynthesis, the concentration of ATP, AD, and AMP, and the intracellular pH. NH4+ also failed to affect the ability of theophylline and cytochalasin B to augment glucose-induced insulin release. However, in the presence and absence of glucose, accumulation of NH4+ in islet cells was associated with a fall in the concentration of NADH and HADPH and a concomitant alteration of 86Rb+ and 45Ca2+ (or 133Ba2+) handling. These findings suggest that reduced pyridine nucleotides, generated by the metabolism of endogenous of exogenous nutrients, may modulate ionophoretic processes in the islet cells and by doing so, affect the net uptake of Ca2+ and subsequent release of insulin.

Ammonia↗
PubMed1976

Stimulus-secretion coupling of glucose-induced insulin release. Metabolism of alpha- and beta-D-glucose in isolated islets.

Alpha-D-Glucose is known to exert more marked insulinotropic action than B-D-glucose. Both anomers are phosphorylated at the same rate by rat islet homogenates. The islet glucose-6-phosphate dehydrogenase displays a preferential affinity towards beta-D-glucose-6-phosphate, and this coincides with a higher sorbitol content in the islets exposed to beta-D-glucose. On the contrary, the islet phosphoglucose isomerase is stereospecific for alpha-D-glucose 6-phosphate and, hence, the concentration of glucose 6-phosphate is lower and that of the alpha-anomer to lactate and CO2 is also higher than that of beta-D-glucose. This increased glycolytic flux is associated with a more marked inhibitory action on 14Ca efflux, a more pronounced stimulation of 45Ca net uptake and a higher rate of insulin release in the islets exposed to alpha-D-glucose. The more marked insulinotropic action of alpha- as a distinct from beta-D-glucose is thus compatible with the view that glycolysis represents the key component of the sensor device through which glucose is identified in the pancreatic B-cell as a stimulus for insulin release.

Animals↗
PubMed1976

The stimulus-secretion coupling of glucose-induced insulin release. XX. fasting: a model for altered glucose recognition by the B-cell.

The rate of glucose uptake and oxidation, the output of lactate, the net uptake of calcium, the release of preformed or newly synthesized insulin and, possibly to a lesser extent, the biosynthesis of proinsulin are all diminished in islets removed from fasted rats and exposed to glucose. Theophylline and dibutyryl-adenosine-3',5'-cyclic monophosphate fail to fully restore a normal secretory response to glucose, despite the fact that they increase lactate production by the islets from fasted animals. The insulinotropic action of other secretagogues, including glyceraldehyde, leucine, beta-hydroxybutyrate, and sulfonylurea is unaffected by prior fasting of the donor rats. The islets metabolism of glyceraldehyde is also unaffected by fasting. These data indicate that fasting is associated with a block in glucose metabolism in the early steps of glycolysis, prior to the triose-phosphate level, and suggest that the insulin secretory response to glucose may be closely dependent on the rate at which the hexose is metabolized by islet tissue.

Animals↗
PubMed1976

Cytochalasin B-induced impariment of glucose metabolism in islets of Langerhans.

Cytochalasin B (10 mug/ml) facilitated glucose-, glyceraldehyde-, and leucine-induced insulin release. It inhibited glucose uptake, utilization, and oxidation, as well as lactate output in islets exposed to glucose (16.7 mM). However, it failed to affect lactate output in the presence of glyceraldehyde, and leucine oxidation. Cytochalasin B also caused a partial inhibition of 45calcium uptake and proinsulin synthesis evoked by glucose in low concentration (5.6 mM), these findings being compatible with a modest impairment of the process of glucose recognition by the beta-cell. At a higher glucose level (16.7 mM), cytochalasin B failed to affect proinsulin synthesis, the immediate inhibitory effect of glucose upon 45calcium efflux, and the subsequent accumulation of 45calcium in the islets. In the presence of cytochalasin B, mannoheptulose further reduced glucose utilization and lactate production and suppressed glucose-induced insulin release. These data suggest that, although insulin release in the presence of cytochalasin B apparently remains dependent on a sufficient glycolytic flux, the facilitating effect of the drug upon insulin secretion cannot be ascribed to any favorable influence on glucose handling by islet tissue. It is suggested that cytochalasin B, possibly through its effect on the microfilamentous web which is part of the cell boundary, may both facilitate insulin release and inhibit glucose transport across the cell membrane, although no direct cause and effect relationship would exist between the two phenomena.

Animals↗
PubMed1976

Calcium antagonists and islet function. VIII. The effect of magnesium.

Mg2+ in high concentration (10 to 20 mEq/l) caused a dose-related inhibition of glucose-induced 45calcium net uptake and subsequent insulin release in isolated islets. Experiments performed with the isolated perfused pancreas indicated that the inhibitory effect of Mg2+ upon insulin secretion was rapid and reversible. Although excess Mg2+ reduced lactate production by the islets, the process of glucose recognition by the B-cell was apparently unaltered as judged by the inhibitory effect of the hexose upon 45calcium efflux from perifused islets and the resultant accumulation of 45calcium in the islets. Mg2+ in high concentration failed to facilitate 45calcium efflux from the islets, whether in the presence or absence of glucose. These data suggest that the major effect of Mg2+ upon islet function is to inhibit Ca2+ entry in the B-cell.

Animals↗