Respiratory, ionic, and functional effects of succinate esters in pancreatic islets

1993 ◽  
Vol 264 (3) ◽  
pp. E428-E433 ◽  
Author(s):  
W. J. Malaisse ◽  
J. Rasschaert ◽  
M. L. Villanueva-Penacarrillo ◽  
I. Valverde
Keyword(s):  
Succinic Acid ◽  
Insulin Release ◽  
Methyl Esters ◽  
O2 Uptake ◽  
Biosynthetic Activity ◽  
Insulin Secretagogues ◽  
Net Uptake ◽  
Characteristic Features ◽  
45Ca Efflux ◽  
Stimulation Of

The methyl esters of succinic acid were introduced a few years ago as new potent insulin secretagogues. In the present study, they were found to increase O2 uptake by rat islets incubated in the absence or presence of D-glucose; to decrease 86Rb outflow from prelabeled islets; to stimulate biosynthetic activity in the islets, with a preferential effect on the synthesis of proinsulin; to inhibit 45Ca efflux from prelabeled islets perifused in the absence of extracellular Ca2+ but to augment 45Ca net uptake and to cause a biphasic stimulation of 45Ca outflow in islets incubated or perifused in the presence of extracellular Ca2+; and to evoke a biphasic stimulation of insulin release. The insulinotropic action of these methyl esters coincided with a shift to the left of the sigmoidal relationship between insulin output and D-glucose concentration, was concentration related in the 2-10 mM range, failed to be duplicated by succinic acid, displayed both Ca2+ dependency and resistance to a lowering of extracellular pH, and was operative in the absence of D-glucose whether or not the islets were stimulated by non-nutrient secretagogues. It is concluded that the respiratory, cationic, biosynthetic, and secretory responses of the islets to succinate methyl esters display the characteristic features usually encountered in the process of nutrient-stimulated insulin release.

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

1983 ◽  
Vol 210 (3) ◽  
pp. 913-919 ◽  
Author(s):  
A Sener ◽  
M Welsh ◽  
P Lebrun ◽  
P Garcia-Morales ◽  
M Saceda ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cyclic Amp ◽  
Insulin Release ◽  
Inhibitory Effect ◽  
Secretory Response ◽  
Acid Transport ◽  
O2 Uptake ◽  
Net Uptake ◽  
High Concentrations ◽  
Stimulation Of

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.

Stimulation of Insulin Release In Vivo by the Methyl Esters of Succinic Acid and Glutamic Acid

1997 ◽  
pp. 231-234 ◽  
Author(s):  
Isabel Valverde ◽  
David Vicent ◽  
Marisa L. Villanueva-Peñacarrillo ◽  
Francine Malaisse-Lagae ◽  
Willy J. Malaisse
Keyword(s):  
Glutamic Acid ◽  
Succinic Acid ◽  
Insulin Release ◽  
Methyl Esters ◽  
Stimulation Of

Stimulation of insulin release from pancreatic islets by quinones

1991 ◽  
Vol 11 (3) ◽  
pp. 165-170 ◽  
Author(s):  
Michael J. MacDonald
Keyword(s):  
Insulin Release ◽  
Channel Blocker ◽  
Coenzyme Q ◽  
Quinone Reductase ◽  
Second Phase ◽  
Antimycin A ◽  
Free Medium ◽  
Insulin Secretagogues ◽  
Stimulate Insulin Release ◽  
Stimulation Of

Coenzyme Q (CoQ0) and other quinones were shown to be potent insulin secretagogues in the isolated pancreatic islet. The order of potency was CoQ0≅benzoquinone≅hydroquinonemenadione. CoQ6 and CoQ10 (ubiquinone), duroquinone and durohydroquinone did not stimulate insulin release. CoQ0's insulinotropism was enhanced in calcium-free medium and CoQ0 appeared to stimulate only the second phase of insulin release. CoQ0 inhibited inositol mono-, bis- and trisphosphate formation. Inhibitors of mitochondrial respiration (rotenone, antimycin A, FCCP and cyanide) and the calcium channel blocker verapamil, did not inhibit CoQ0-induced insulin release. Dicumarol, an inhibitor of quinone reductase, did not inhibit CoQ0-induced insulin release, but it did inhibit glucose-induced insulin release suggesting that the enzyme and quinones play a role in glucose-induced insulin release. Quinones may stimulate insulin release by mimicking physiologically-occuring quinones, such as CoQ10, by acting on the plasma membrane or in the cytosol. Exogenous quinones may bypass the quinone reductase reaction, as well as many reactions important for exocytosis.

scholarly journals Mechanisms of the stimulation of insulin release by oxytocin in normal mouse islets

1991 ◽  
Vol 276 (1) ◽  
pp. 169-174 ◽  
Author(s):  
Z Y Gao ◽  
G Drews ◽  
J C Henquin
Keyword(s):  
B Cells ◽  
Cyclic Amp ◽  
Insulin Release ◽  
Islet Cells ◽  
Inositol Phosphate ◽  
Resting Potential ◽  
Phosphoinositide Metabolism ◽  
Mouse Islets ◽  
45Ca Efflux ◽  
Stimulation Of

Oxytocin (OT) produced a dose-dependent increase in somatostatin, glucagon and insulin release by isolated mouse islets. A small effect on somatostatin release was observed with 0.1 nM-OT, but 1-10 nM-OT was required to affect A- and B- cells significantly. The effects of OT on somatostatin and glucagon release were similar in the presence of 3 mM- and 10 mM-glucose. No change in insulin release was produced by OT in 3 mM-glucose, but a stimulation was still observed in the presence of a maximally effective concentration of glucose (30 mM). The increase in insulin release produced by OT (in 15 mM-glucose) was accompanied by small accelerations of 86Rb and 45Ca efflux from islet cells. Omission of extracellular Ca2+ accentuated the effect of OT on 86Rb efflux, attenuated that on 45Ca efflux, and abolished that on release. OT never inhibited 86Rb efflux. It did not affect the resting potential of B-cells, but slightly increased the Ca2(+)-dependent electrical activity induced by 15 mM-glucose. OT did not affect cyclic AMP levels, but increased inositol phosphate levels in islet cells. It is suggested that the amplification of glucose-induced insulin release that OT produces is due to a stimulation of phosphoinositide metabolism, and presumably an activation of protein kinase C, rather than to a change in cyclic AMP levels or a direct action on the membrane potential. Since OT is present in the pancreas, it is possible that it exerts a neuropeptidergic control of the islet function.

Nutrient-induced intracellular calcium movement in rat pancreatic B cell

1982 ◽  
Vol 243 (3) ◽  
pp. E196-E205
Author(s):  
P. Lebrun ◽  
W. J. Malaisse ◽  
A. Herchuelz
Keyword(s):  
B Cell ◽  
Intracellular Calcium ◽  
Islet Cells ◽  
Secretory Response ◽  
Nutrient Deprivation ◽  
Calmodulin Antagonist ◽  
Pancreatic B Cell ◽  
Insulin Secretagogues ◽  
45Ca Efflux ◽  
Stimulation Of

Several insulin secretagogues increase 45Ca efflux from islets prelabeled with the tracer in the presence of glucose, an effect attributable to stimulation of 40Ca entry into islet cells. When the islets are prelabeled in the absence instead of presence of glucose, the 45Ca becomes more readily releasable, and the secretory response to nutrient or ionic secretagogues is decreased. Such a decrease is more marked in response to glucose than other secretagogues because the prior nutrient deprivation also impairs the metabolism of glucose in islet cells. In the islets prelabeled in the absence of glucose, both glyceraldehyde and 2-ketoisocaprote dramatically stimulated 45Ca efflux. This effect persists in the absence of extracellular Ca2+ or presence of the calmodulin-antagonist trifluoperazine. It may correspond to a nutrient-induced intracellular Ca2+ movement, the existence of which would be unmasked in islets prelabeled in the absence of glucose. This so-far-undetected Ca2+ movement may play a role in the secretory response to nutrient secretagogues.

scholarly journals The stimulus-secretion coupling of glucose-induced insulin release. Insulin release due to glycogenolysis in glucose-deprived islets

1977 ◽  
Vol 164 (2) ◽  
pp. 447-454 ◽  
Author(s):  
W J Malaisse ◽  
A Sener ◽  
M Koser ◽  
M Ravazzola ◽  
F Malaisse-Lagae
Keyword(s):  
Insulin Release ◽  
Glucose Concentration ◽  
Essential Feature ◽  
Free Medium ◽  
Exogenous Glucose ◽  
Extracellular Glucose ◽  
Net Uptake ◽  
Low Glucose ◽  
Stimulus Secretion Coupling ◽  
Stimulation Of

1. When pancreatic islets are preincubated for 20h in the presence of glucose (83.3mM) and thereafter transferred to a glucose-free medium, theophylline (1.4mM) provokes a dramatic stimulation of insulin release. This phenomenon does not occur when the islets are preincubated for either 20h at low glucose concentration (5.6mM) or only 30 min at the high glucose concentration (83.3mM). 2. The insulinotropic action of theophylline cannot be attributed to contamination of the islets with exogenous glucose and is not suppressed by mannoheptulose. 3. The secretory response to theophylline is an immediate phenomenon, but disappears after 60min of exposure to the drug. 4. The release of insulin evoked by theophylline is abolished in calcium-depleted media containing EGTA. Theophylline enhances the net uptake of 45Ca by the islets. 5. Glycogen accumulates in the islets during the preincubation period, as judged by both ultrastructural and biochemical criteria. Theophylline significantly increases the rate of glycogenolysis during the final incubation in the glucose-free medium. 6. The theophylline-induced increase in glycogenolysis coincides with a higher rate of both lactate output and oxidation of endogenous 14C-labelled substrates. 7. These data suggest that stimulation of glycolysis from endogenous stores of glycogen is sufficient to provoke insulin release even in glucose-deprived islets, as if the binding of extracellular glucose to hypothetical plasma-membrane glucoreceptors is not an essential feature of the stimulus-secretion coupling process.

Metabolic effects and fate of succinate esters in pancreatic islets

1993 ◽  
Vol 264 (3) ◽  
pp. E434-E440 ◽  
Author(s):  
W. J. Malaisse ◽  
A. Sener
Keyword(s):  
Amino Acids ◽  
Pancreatic Islets ◽  
Methyl Esters ◽  
Dimethyl Ester ◽  
Krebs Cycle ◽  
Metabolic Effects ◽  
Insulin Biosynthesis ◽  
O2 Uptake ◽  
14Co2 Production ◽  
Stimulation Of

The metabolic effects and the catabolism of succinate methyl esters were examined in rat pancreatic islets. The esters augmented 14CO2 production from islets prelabeled with L-[U-14C]-glutamine but inhibited NH4+ output, suggesting that they do not activate glutamate dehydrogenase. They decreased 14CO2 output from islets prelabeled with [U-14C]palmitate. They had little effect on the oxidation of exogenous D-[3,4-14C]glucose, D-[2-14C]glucose, D-[6-14C]glucose, or D-[1-14C]glucose, suggesting unaltered ratio between the input of acetyl residues and four- or five-carbon metabolites, such as succinate, into the Krebs cycle. By following the fate of both [1,4-14C]succinate dimethyl ester and [2,3-14C]succinate dimethyl ester, data were obtained to indicate that succinate is efficiently formed from the ester and further metabolized, leading to the generation of 14C-labeled acidic metabolites including pyruvate and L-lactic acid, CO2, and amino acids. It is proposed that a concerted increase of both succinate and acetyl residue influx into the Krebs cycle accounts for the increase in O2 uptake caused by the succinate methyl esters and, hence, for stimulation of both pro-insulin biosynthesis and insulin release.

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