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

1978 ◽  
Vol 176 (1) ◽  
pp. 217-232 ◽  
Author(s):  
A Sener ◽  
S Kawazu ◽  
J C Hutton ◽  
A C Boschero ◽  
G Devis ◽  
...  
Keyword(s):  
Insulin Release ◽  
Islet Cells ◽  
Close Correlation ◽  
Net Generation ◽  
Isolated Pancreatic Islets ◽  
Pyruvate Oxidation ◽  
Net Uptake ◽  
Sigmoidal Curve ◽  
Stimulus Secretion Coupling ◽  
The Relationship

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.

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.

scholarly journals Ketone bodies and islet function: 86Rb handling and metabolic data

1990 ◽  
Vol 259 (1) ◽  
pp. E123-E130 ◽  
Author(s):  
W. J. Malaisse ◽  
P. Lebrun ◽  
J. Rasschaert ◽  
F. Blachier ◽  
T. Yilmaz ◽  
...  
Keyword(s):  
Ketone Bodies ◽  
Close Correlation ◽  
Subsequent Decrease ◽  
Mitochondrial Redox State ◽  
Net Uptake ◽  
Atp Generation ◽  
Stimulus Secretion Coupling ◽  
Nadh Generation ◽  
Beta Hydroxybutyrate ◽  
Induced Changes

The metabolism of ketone bodies was investigated in rat pancreatic islets incubated in the absence or presence of D-glucose. The generation of 14CO2 from 3-14C-labeled ketone bodies, the interconversion of D-(-)-beta-hydroxybutyrate and acetoacetate (AcAc), the reciprocal effects of ketone bodies and D-glucose on their respective catabolism, and the influence of these exogenous nutrients on the output of 14CO2 from islets preincubated with either L-[U-14C]glutamine or [U-14C]palmitate provided an estimation of the nutrient-induced changes in O2 uptake that was in fair agreement with the observed modifications of islet respiration. There was a close correlation between such changes and the corresponding values for insulin output. Because the stimulation of insulin release by ketone bodies also coincided with a decrease in 86Rb outflow from prelabeled islets, these findings suggest that the insulinotropic action of ketone bodies is causally linked to their catabolism through an increase in ATP generation rate and a subsequent decrease in K+ conductance. A complementary participation of changes in mitochondrial redox state to stimulus-secretion coupling is considered, however, in the light of comparisons between the effects of D-(-)-beta-hydroxybutyrate and AcAc, respectively, on mitochondrial NADH generation, 45Ca net uptake, and D-[6-14C]glucose oxidation.

cAMP-secretion coupling is impaired in diabetic GK/Par rat β-cells: a defect counteracted by GLP-1

2011 ◽  
Vol 301 (5) ◽  
pp. E797-E806 ◽  
Author(s):  
Manuel Dolz ◽  
Jamileh Movassat ◽  
Danielle Bailbé ◽  
Hervé Le Stunff ◽  
Marie-Hélène Giroix ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Camp Accumulation ◽  
Camp Content ◽  
Camp Generation ◽  
Stimulus Secretion Coupling ◽  
Glucagon Like Peptide 1 ◽  
The Relationship

cAMP-raising agents with glucagon-like peptide-1 (GLP-1) as the first in class, exhibit multiple actions that are beneficial for the treatment of type 2 diabetic (T2D) patients, including improvement of glucose-induced insulin secretion (GIIS). To gain additional insight into the role of cAMP in the disturbed stimulus-secretion coupling within the diabetic β-cell, we examined more thoroughly the relationship between changes in islet cAMP concentration and insulin release in the GK/Par rat model of T2D. Basal cAMP content in GK/Par islets was significantly higher, whereas their basal insulin release was not significantly different from that of Wistar (W) islets. Even in the presence of IBMX or GLP-1, their insulin release did not significantly change despite further enhanced cAMP accumulation in both cases. The high basal cAMP level most likely reflects an increased cAMP generation in GK/Par compared with W islets since 1) forskolin dose-dependently induced an exaggerated cAMP accumulation; 2) adenylyl cyclase (AC)2, AC3, and Gsα proteins were overexpressed; 3) IBMX-activated cAMP accumulation was less efficient and PDE-3B and PDE-1C mRNA were decreased. Moreover, the GK/Par insulin release apparatus appears less sensitive to cAMP, since GK/Par islets released less insulin at submaximal cAMP levels and required five times more cAMP to reach a maximal secretion rate no longer different from W. GLP-1 was able to reactivate GK/Par insulin secretion so that GIIS became indistinguishable from that of W. The exaggerated cAMP production is instrumental, since GLP-1-induced GIIS reactivation was lost in the presence the AC blocker 2′,5′-dideoxyadenosine. This GLP-1 effect takes place in the absence of any improvement of the [Ca2+]i response and correlates with activation of the cAMP-dependent PKA-dependent pathway.

Somatostatin inhibition of glucose-induced electrical activity in cultured rat islet cells

1977 ◽  
Vol 233 (5) ◽  
pp. C164-C171 ◽  
Author(s):  
Caroline S. Pace ◽  
Mary Murphy ◽  
Susan Conant ◽  
Paul E. Lacy
Keyword(s):  
Electrical Activity ◽  
Insulin Release ◽  
Spike Activity ◽  
Inhibitory Action ◽  
Islet Cells ◽  
Secretory Response ◽  
Adrenergic Blockade ◽  
Ionic Fluxes ◽  
Electrophysiological Studies ◽  
Stimulus Secretion Coupling

Electrophysiological studies of rat islet cells in monolayer culture were undertaken to determine the role of transmembranous ionic fluxes in the inhibitory action of somatostatin on insulin release. In the presence of somatotropin release inhibiting factor (SRIF) (2.5 nM), hyperpolarization occured with or without glucose (16.6 mM) in the medium. SRIF also inhibited the incidence of glucose-induced spike activity. The inhibitory action of SRIF occurred within 5 min and was readily reversible. An increase in extracellular K+ (5–13 mM) or Ca2+ (2.3–4.6 mM) prevented SRIF inhibition of glucose-induced electrical activity. The secretory response of cultured islets to glucose (16.6 mM) was completely inhibited by SRIF (2.5 nM). The presence of high [Ca2+]0 or [K+]0, enhanced insulin release in the presence of SRIF and glucose. Although phentolamine (5.0 μg/ml) did not block the inhibition of glucose-induced electrical responses by SRIF, it prevented the inhibitory action of epinephrine (0.2 μg/ml). It is concluded that the primary action of SRIF is to alter transmembranous cationic fluxes, as manifested by hyperpolarization and a decrease in the incidence of spike activity, which may prevent glucose from eliciting a normal secretory response. insulin secretion; epinephrine; alpha-adrenergic blockade; stimulus-secretion coupling Submitted on February 14, 1977

Ketone bodies and islet function: 45Ca handling, insulin synthesis, and release

1990 ◽  
Vol 259 (1) ◽  
pp. E117-E122 ◽  
Author(s):  
W. J. Malaisse ◽  
P. Lebrun ◽  
B. Yaylali ◽  
J. Camara ◽  
I. Valverde ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Ketone Bodies ◽  
Islet Cells ◽  
Islet Function ◽  
Insulin Synthesis ◽  
Ambient Concentration ◽  
Net Uptake ◽  
Sigmoidal Curve ◽  
Beta Hydroxybutyrate ◽  
Stimulation Of

D-(-)-beta-Hydroxybutyrate and acetoacetate cause a rapid, sustained, and rapidly reversible stimulation of insulin release from rat pancreatic islets incubated in the presence, but not absence, of D-glucose. This coincides with stimulation of both proinsulin biosynthesis and 45Ca net uptake. The ketone bodies also decrease 45Ca outflow from prelabeled islets perifused in the absence of Ca2+ and, in contrast, enhance effluent radioactivity in the presence of Ca2+. In the presence of D-glucose, the secretory response to D-(-)-beta-hydroxybutyrate is concentration related in the 2.5-20 mM range, abolished in the absence of Ca2+ or presence of KCN, and enhanced by theophylline and forskolin. It corresponds grossly to a shift to the left of the sigmoidal curve relating insulin output to the ambient concentration of D-glucose. The secretory, biosynthetic, and cationic response to acetoacetate is less marked than that evoked by an equimolar concentration of D-(-)-beta-hydroxybutyrate. These features are compatible with the view that the insulinotropic action of ketone bodies would be causally linked to their metabolism in islet cells.

scholarly journals Effect of intracellular alkalinization on pancreatic islet calcium uptake and insulin secretion

1986 ◽  
Vol 239 (1) ◽  
pp. 199-204 ◽  
Author(s):  
P Lindström ◽  
J Sehlin
Keyword(s):  
Insulin Secretion ◽  
Beta Cells ◽  
Calcium Uptake ◽  
Islet Cells ◽  
Cell Interior ◽  
Experimental Conditions ◽  
Bicarbonate Buffer ◽  
Stimulus Secretion Coupling ◽  
The Relationship ◽  
Intracellular Alkalinization

Microdissected beta-cell-rich pancreatic islets of ob/ob mice were used in studies of the relationship between intracellular pH (pHi) and 45Ca2+ uptake and insulin release. Stepwise increases in extracellular pH (pHo) from 6.80 to 8.00 resulted in a parallel, although less pronounced, elevation of pHi from 7.24 to 7.69. Experimental conditions that alkalinize the islet cell interior, i.e. addition of 5 mM-NH4+, sudden withdrawal of extracellular bicarbonate buffer or increase in pHo, induced insulin secretion in the absence of other types of secretory stimulation (1 mM-D-glucose). Intracellular acidification by lowering pHo below 7.40 or sudden addition of bicarbonate buffer did not induce insulin secretion. The removal of extracellular bicarbonate buffer, increase in pHo from 7.40 to 8.00, or the addition of 5 mM-L-5-hydroxytryptophan or 5 mM-NH4+, which all alkalinize the islet cells and induce insulin secretion, also increased the La3+-non-displaceable 45Ca2+ uptake in the presence of 1 mM-D-glucose. The results suggest that intracellular alkalinization in beta-cells can trigger insulin secretion. Taken together with the fact that D-glucose increases pHi in the islet cells, the results also point to the possibility that alkalinization may be a link in the stimulus-secretion coupling sequence in beta-cells.

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.

scholarly journals The stimulus-secretion coupling of glucose-induced insulin release. Does glycolysis control calcium transport in the B-cell?

1976 ◽  
Vol 156 (3) ◽  
pp. 521-525 ◽  
Author(s):  
A Sener ◽  
J Levy ◽  
W J Malaisse
Keyword(s):  
B Cell ◽  
Insulin Release ◽  
Glucose Utilization ◽  
Tight Control ◽  
Glucose Residue ◽  
Experimental Conditions ◽  
Lactate Output ◽  
Net Uptake ◽  
Stimulus Secretion Coupling ◽  
Secretory Pattern

1. The metabolism of glucose and the exchangeable Ca2+ pool were measured in rat pancreatic islets, in order to assess the possible significance of glycolysis in the process of glucose-induced insulin release. 2. At high glucose concentration (16.7 mM), glucose was metabolized at the following rate (pmol of glucose residue/h per islet +/- S.E.M.): 131 +/- 11 for glucose uptake, 129+/-8 for glucose utilization, as judged by the conversion of [5-3H]glucose into 3H2O,60+/-2 for lactate output and 25+/-2 for glucose oxidation. 3. The secretory pattern usually correlated with the metabolic data. For instance, the ability of different sugars (glucose, mannose, fructose, galactose, D-glyceraldehyde) to stimulate lactate output closely paralleled their relative insulinotropic capacity. A disparity between metabolic and secretory responses was, however, encountered in the presence of dibutyryl cyclic AMP and theophylline. 4. Despite this contrasting behaviour, the size of the Ca2+- exchangeable pool (net uptake of 45Ca2+) was invariably proportional to the rate of lactate output under all experimental conditions examined. It is concluded that glycolysis usually exerts a tight control on the rate constant for Ca2+ transport across the B-cell membrane.

Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice

2014 ◽  
Vol 395 (4) ◽  
pp. 453-464 ◽  
Author(s):  
Brian M. Moran ◽  
Yasser H.A. Abdel-Wahab ◽  
Peter R. Flatt ◽  
Aine M. McKillop
Keyword(s):  
Glucose Tolerance ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Islet Cells ◽  
Isolated Pancreatic Islets ◽  
Beneficial Effects ◽  
Secondary Messenger ◽  
Intracellular Ca ◽  
Mouse Pancreatic Islets

Abstract G-protein coupled receptor 119 (GPR119) is emerging as a potential target for the treatment of type 2 diabetes with beneficial effects on glucose homeostasis. This study assessed the insulin-secreting properties of various GPR119 agonists and the distribution of GPR119 in pancreatic islets. Endogenous ligands [oleoylethanolamide (OEA), palmitoylethanolamine (PEA)] and chemically synthetic analogues (AS-1269574, PSN-375963) were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Secondary messenger assays such as intracellular Ca2+ and cAMP in response to agonists at normoglycaemic and hyperglycaemic conditions were assessed. Cytotoxicity was assessed by LDH release. AS-1269574 was the most potent and selective agonist tested in isolated islets, with an EC50 value of 9.7×10-7 mol/l, enhancing insulin release maximally by 63.2%. Stimulation was also observed with GPR119 ligands; OEA (3.0×10-6 mol/l; 37.5%), PSN-375963 (2.4×10-6 mol/l; 28.7%) and PEA (1.2×10-6 mol/l; 22.2%). Results were corroborated by studies using BRIN-BD11 cells, which revealed augmentation of intracellular Ca2+ and cAMP. Both OEA and AS-1269574 enhanced insulin release and improved glucose tolerance in vivo in NIH Swiss mice. These results demonstrate the cellular localisation of GPR119 on islet cells (β and pancreatic polypeptide cells), its activation of the β-cell stimulus-secretion coupling pathway and glucose lowering effects in vivo.

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