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

1982 ◽  
Vol 202 (2) ◽  
pp. 309-316 ◽  
Author(s):  
A Sener ◽  
F Malaisse-Lagae ◽  
W J Malaisse
Keyword(s):  
Environmental Factors ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Incubation Medium ◽  
Redox State ◽  
Islet Cells ◽  
Atp Content ◽  
Univalent Cations ◽  
Physiological Concentration ◽  
Stimulus Secretion Coupling

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.

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

1984 ◽  
Vol 220 (2) ◽  
pp. 433-440 ◽  
Author(s):  
A Sener ◽  
F Malaisse-Lagae ◽  
S P Dufrane ◽  
W J Malaisse
Keyword(s):  
Pancreatic Islets ◽  
Malate Dehydrogenase ◽  
Insulin Release ◽  
Pancreatic Islet ◽  
Flow Rate ◽  
Isocitrate Dehydrogenase ◽  
Malic Enzyme ◽  
Redox State ◽  
Islet Cells ◽  
Pancreatic Islet Cells

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.

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

1983 ◽  
Vol 210 (3) ◽  
pp. 921-927 ◽  
Author(s):  
W J Malaisse ◽  
A Sener ◽  
M Welsh ◽  
F Malaisse-Lagae ◽  
C Hellerström ◽  
...  
Keyword(s):  
Amino Acids ◽  
Pancreatic Islets ◽  
Glutamate Dehydrogenase ◽  
Production Rate ◽  
Insulin Release ◽  
Incubation Medium ◽  
Islet Cells ◽  
Metabolic Effects ◽  
Rat Pancreatic Islets ◽  
Endogenous Amino Acids

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.

Impairment by aminooxyacetate of ionic response to nutrients in pancreatic islets

1983 ◽  
Vol 245 (1) ◽  
pp. E38-E46
Author(s):  
P. Lebrun ◽  
W. J. Malaisse ◽  
A. Herchuelz
Keyword(s):  
Pancreatic Islets ◽  
Insulin Release ◽  
Redox State ◽  
Islet Cells ◽  
Inhibitory Effect ◽  
High Concentration ◽  
Perifused Islets ◽  
45Ca Efflux ◽  
Reduced State ◽  
Stimulation Of

Aminooxyacetate, an inhibitor of transamination reactions, was recently reported to prevent the induction of a more reduced state in the cytosolic redox couple, as normally evoked by glucose or 2-ketoisocaproate in rat pancreatic islets. The cationic effects of aminooxyacetate were examined, therefore, in perifused islets prelabeled with either 86Rb or 45Ca. Aminooxyacetate augmented the outflow of 86Rb from the islets whether in the absence or presence of an exogenous nutrient and slightly impaired the capacity of nutrients, especially 2-ketoisocaproate, to decrease 86Rb outflow. Aminooxyacetate abolished the nutrient-induced rise in 45Ca efflux that normally results from the stimulation by glucose or 2-ketoisocaproate of 40Ca influx into the islet cells. Aminooxyacetate, however, failed to suppress the early inhibitory effect of nutrients on 45Ca efflux. The alteration by aminooxyacetate of the cationic response to nutrient secretagogues coincided with a suppression of insulin release, whereas the cationic response to a nonnutrient stimulation by a high concentration of extracellular K+ was unaffected by aminooxyacetate. These findings suggest that the induction of a more reduced cytosolic redox state represents an essential link between metabolic events and both the decrease in K+ conductance and stimulation of Ca2+ inflow in the process of nutrient-induced insulin release.

scholarly journals The stimulus–secretion coupling 4-methyl-2-oxopentanoate-induced insulin release

1979 ◽  
Vol 184 (2) ◽  
pp. 303-311 ◽  
Author(s):  
J C Hutton ◽  
A Sener ◽  
W J Malaisse
Keyword(s):  
Insulin Release ◽  
Metabolic Flux ◽  
Energy Charge ◽  
Hyperbolic Function ◽  
Maximal Response ◽  
Coupling Mechanism ◽  
Adenylate Energy Charge ◽  
Atp Content ◽  
45Ca Uptake ◽  
Stimulus Secretion Coupling

1. Pancreatic islet insulin secretion and 45Ca uptake showed similar responses to variation in the extracellular concentration of 4-methyl-2-oxopentanoate with a threshold at 4 mM and a maximal response at a 25 mM concentration. 2. Islet respiration, acetoacetate production and rates of substrate utilization, oxidation and amination all changed as a simple hyperbolic function of 4-methyl-2-oxopentanoate concentration and exhibited a maximal response at 25 mM. 3. The responses of ATP content, [ATP]/[ADP] ratio, adenylate energy charge and [NADH]/[NAD+] ratio were also hyperbolic in nature but were maximally elevated at lower concentrations of the secretagogue. The islet [NADPH]/[NADP+] ratio, however, was tightly correlated with parameters of metabolic flux, 45Ca uptake and insulin release. 4. NH4+ and menadione, agents that promote a more oxidized state in islet NADP, did not affect islet ATP content or the rates of [U-14C]4-methyl-2-oxopentanoate oxidation or amination, but markedly inhibited islet 45Ca uptake and insulin release. 5. It is proposed that changes in the redox state of NADP and Ca transport may serve as mediators in the stimulus-secretion coupling mechanism of insulin release induced by 4-methyl-2-oxopentanoate.

Nitric oxide donor SIN-1 inhibits insulin release

1996 ◽  
Vol 271 (4) ◽  
pp. C1098-C1102 ◽  
Author(s):  
A. Sjoholm
Keyword(s):  
Nitric Oxide ◽  
Diabetes Mellitus ◽  
Protein Kinase C ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Beta Cell ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Kinase C ◽  
Stimulus Secretion Coupling

Preceding the onset of insulin-dependent diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1 beta, which exerts cytotoxic and inhibitory actions on islet beta-cell insulin secretion through induction of nitric oxide (NO) synthesis. The influence of the NO donor 3-morpholinosydnonimine (SIN-1) on insulin secretion from isolated pancreatic islets in response to various secretagogues was investigated. Stimulation of insulin release evoked by glucose, phospholipase C activation with carbachol, and protein kinase C activation with phorbol ester were obtained by SIN-1, whereas the response to adenylyl cyclase activation or K(+)-induced depolarization was not affected. It is concluded that enzymes involved in glucose catabolism, phospholipase C or protein kinase C, may be targeted by NO. Reversal of SIN-1 inhibition of glucose-stimulated insulin release by dithiothreitol suggests that NO may inhibit insulin secretion partly by S-nitrosylation of thiol residues in key proteins in the stimulus-secretion coupling. These adverse effects of NO on the beta-cell stimulus-secretion coupling may be of importance for the development of the impaired insulin secretion characterizing diabetes mellitus.

Sensitivity to Cd2+ but resistance to Ni2+ of Ca2+ inflow into rat pancreatic islets

1990 ◽  
Vol 258 (3) ◽  
pp. E529-E533 ◽  
Author(s):  
P. O. Plasman ◽  
M. Hermann ◽  
A. Herchuelz ◽  
P. Lebrun
Keyword(s):  
Pancreatic Islets ◽  
Insulin Release ◽  
Islet Cells ◽  
Excitable Cells ◽  
45Ca Uptake ◽  
Rat Pancreatic Islets ◽  
Cell Plasma ◽  
Different Types ◽  
45Ca Efflux ◽  
Ca2 Channels

The presence of different types [long lasting (L) and transient (T)] of active voltage-operated Ca2+ channels in islet cells was investigated by comparing the effects of Cd2+, Ni2+, and 1,4-dihydropyridines on 45Ca uptake, 45Ca efflux, and insulin release in intact rat pancreatic islets. In several other excitable cells the L-channel has been shown to be modulated by 1,4-dihydropyridines and Cd2+, whereas the T-channel was reported to be sensitive to Ni2+. Nifedipine and Cd2+ inhibited whereas BAY K 8644 enhanced the glucose (11.1, 22.2 mM)-stimulated short-term 45Ca uptake, 45Ca efflux, and insulin release. In contrast, the stimulatory effects of glucose (11.1, 22.2 mM) on 45Ca uptake, 45Ca efflux, and insulin release were unaffected by Ni2+. These findings confirm that glucose provokes Ca2+ entry mainly by activating voltage-sensitive Ca2+ channels of the L-type and suggest that the B-cell plasma membrane is not equipped with active T-type Ca2+ channels.

scholarly journals Effect of perchlorate on calcium uptake and insulin secretion in mouse pancreatic islets

1987 ◽  
Vol 248 (1) ◽  
pp. 109-115 ◽  
Author(s):  
J Sehlin
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Glucose Oxidation ◽  
Calcium Uptake ◽  
Maximum Effect ◽  
Mouse Pancreatic Islets ◽  
Stimulus Secretion Coupling ◽  
Ca2 Channels

Microdissected beta-cell-rich pancreatic islets of non-inbred ob/ob mice were used in studies of how perchlorate (CIO4-) affects stimulus-secretion coupling in beta-cells. CIO4- at 16 mM potentiated D-glucose-induced insulin release, without inducing secretion at non-stimulatory glucose concentrations. The potentiation mainly applied to the first phase of stimulated insulin release. In the presence of 20 mM-glucose, the half-maximum effect of CIO4- was reached at 5.5 mM and maximum effect at 12 mM of the anion. The potentiation was reversible and inhibitable by D-mannoheptulose (20 mM) or Ca2+ deficiency. CIO4- at 1-8 mM did not affect glucose oxidation. The effects on secretion were paralleled by a potentiation of glucose-induced 45Ca2+ influx during 3 min. K+-induced insulin secretion and 45Ca2+ uptake were potentiated by 8-16 mM-CIO4-. The spontaneous inactivation of K+-induced (20.9 mM-K+) insulin release was delayed by 8 mM-CIO4-. The anion potentiated the 45Ca2+ uptake induced by glibenclamide, which is known to depolarize the beta-cell. Insulin release was not affected by 1-10 mM-trichloroacetate. It is suggested that CIO4- stimulates the beta-cell by affecting the gating of voltage-controlled Ca2+ channels.

The Stimulus-Secretion Coupling of Amino Acid-induced Insulin Release: Secretory and Oxidative Response of Pancreatic Islets to L-Asparagine

Diabetes ◽  
1984 ◽  
Vol 33 (5) ◽  
pp. 464-469 ◽  
Author(s):  
F. Malaisse-Lagae ◽  
M. Welsh ◽  
P. Lebrun ◽  
A. Herchuelz ◽  
A. Sener ◽  
...  
Keyword(s):  
Amino Acid ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Oxidative Response ◽  
Stimulus Secretion Coupling

Stimulus-secretion coupling of arginine-induced insulin release. Metabolism of l-arginine and l-ornithine in pancreatic islets

1989 ◽  
Vol 1013 (2) ◽  
pp. 133-143 ◽  
Author(s):  
Willy J. Malaisse ◽  
François Blachier ◽  
Ali Mourtada ◽  
Javier Camara ◽  
Amador Albor ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Insulin Release ◽  
Stimulus Secretion Coupling

scholarly journals Effects of trifluoperazine and pimozide on stimulus–secretion coupling in pancreatic B-cells Suggestion for a role of calmodulin?

1981 ◽  
Vol 196 (3) ◽  
pp. 771-780 ◽  
Author(s):  
Jean-Claude Henquin
Keyword(s):  
Cyclic Amp ◽  
Insulin Release ◽  
Islet Cells ◽  
Antipsychotic Agents ◽  
Secretory Process ◽  
Dependent Inhibition ◽  
Net Uptake ◽  
Stimulus Secretion Coupling ◽  
Two Phases

The possible involvement of calmodulin in insulin release was evaluated by studying the effects on intact islets of trifluoperazine and pimozide, two antipsychotic agents known to bind strongly to calmodulin in cell-free systems. Trifluoperazine (10–100μm) produced a dose- and time-dependent inhibition of the two phases of glucose-stimulated insulin release. The effect was not reversible by simple washing of the drug, but could be prevented by cytochalasin B or theophylline. Trifluoperazine also inhibited the release induced by glyceraldehyde, oxoisocaproate, tolbutamide or barium, but not that stimulated by 10mm-theophylline or 1mm-3-isobutyl-1-methylxanthine. Pimozide (0.5–10μm) also produced a dose-dependent inhibition of insulin release triggered by glucose, leucine or barium, but did not affect the release induced by methylxanthines. Glucose utilization by islet cells was not modified by trifluoperazine (25μm), which slightly increased cyclic AMP concentration in islets incubated without glucose. The drug did not prevent the increase in cyclic AMP concentration observed after 10min of glucose stimulation, but suppressed it after 60min. Basal or glucose-stimulated Ca2+ influx (5min) was unaffected by 25μm-trifluoperazine, whereas Ca2+net uptake (60min) was inhibited by 20%. Glucose-stimulated Ca2+ uptake was almost unaffected by pimozide. In a Ca2+-free medium, trifluoperazine decreased Ca2+ efflux from the islets and did not prevent the further decrease by glucose; in the presence of Ca2+, the drug again decreased Ca2+ efflux and inhibited the stimulation normally produced by glucose. In the absence of glucose, trifluoperazine lowered the rate of Rb+ efflux from the islets, decreased Rb+ influx (10min), but did not affect Rb+ net uptake (60min). It did not interfere with the ability of glucose to decrease Rb+ efflux rate further and to increase Rb+ net uptake. The results show thus that trifluoperazine does not alter the initial key events of the stimulus–secretion coupling. Its inhibition of insulin release suggests a role of calmodulin at late stages of the secretory process.

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