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.

Glucose-stimulated elevation of cytoplasmic calcium is defective in the diabetic Chinese hamster islet B cell

1996 ◽  
Vol 134 (5) ◽  
pp. 617-625 ◽  
Author(s):  
Per Lindström ◽  
Janove Sehlin ◽  
Barbara J Frankel
Keyword(s):  
B Cell ◽  
Insulin Release ◽  
Cell Biology ◽  
Glucose Utilization ◽  
Islet Cells ◽  
Insulin Response ◽  
Chinese Hamster ◽  
Cytoplasmic Calcium ◽  
Essentially Normal ◽  
Channel Agonist

Lindström P. Sehlin J, Frankel BJ. Glucose-stimulated elevation of cytoplasmic calcium is defective in the diabetic Chinese hamster islet B cell. Eur J Endocrinol 1996:134:617–25. ISSN 0804–4643 To characterize insulin release and cytoplasmic free Ca2+ [Ca2+]i) levels in the diabetic Chinese hamster islet B cell, islets from genetically normal subline M) and diabetic (subline L) hamsters were collagenase isolated. Insulin release and glucose utilization (conversion of D-[5-3H]glucose to 3H2O) were measured in whole islets; [Ca2+]i levels were measured in single islet cells using fura-2, The Ca2+ channel agonist, 12 mmol/l perchlorate, ClO4−, increased the subnormal insulin response during 20 mmol/l glucose perifusion, but did not normalize it. Glucose utilization measured over a 2-h period was normal. Glucose induced an initial decrease and then a rise in [Ca2+]i in 85% of the normal (presumably B) cells. In diabetic cells, the [Ca2+]i response was delayed, subnormal and only observed in 23% of the cells. When perchlorate or another Ca2+ channel agonist, 10 μmol/l CGP 28392, was added with glucose, a larger proportion of the diabetic cells (61–67%) showed increased [Ca2+]i and the mean [Ca2+]i response was not different from normal. However, neither perchlorate nor CGP 28392 could normalize glucose-stimulated insulin release, and K+-induced insulin release was decreased in diabetic islets. The K+ -induced [Ca2+]i rise was essentially normal in all the diabetic islet cells. Therefore, the diabetic hamster islet appears to metabolize glucose normally, but has a diminished insulin response to glucose and K+. The Ca2+ channel agonists markedly improve the subnormal [Ca2+]i response but not the insulin response. Glucose-induced elevation of [Ca2−]i and exocytosis appear defective in the diabetic Chinese hamster B cell. Per Lindström, Department of Histology and Cell Biology, Umea University, S-901 87 Umea, Sweden

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 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 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.

Depolarization-independent net uptake of calcium into clonal insulin-releasing cells exposed to glucose

1983 ◽  
Vol 3 (10) ◽  
pp. 927-937 ◽  
Author(s):  
Erik Gylfe ◽  
Tommy Andersson ◽  
Patrik Rorsman ◽  
Håkan Abrahamsson ◽  
Per Arkhammar ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Insulin Release ◽  
Oxidative Degradation ◽  
Glycolytic Flux ◽  
Glucose Effect ◽  
Clonal Cell Line ◽  
Left Hand ◽  
Net Uptake ◽  
Secretory Pattern ◽  
Net Fluxes

Insulin release, net fluxes of Ca2+, and glucose metabolism were studied in a clonal cell line (RINmSF) established from a transplantable rat islet tumor. The insulin content amounted to only 0.03% of that of the total protein and decreased even further with subsequent passages. The insulin secretion was as high as 10 to 20% of the total hormone content per hour. Insulin release was stimulated by K+ depolarization but not by exposure to glucose. In contrast to this secretory pattern, glucose but not K+ stimulated the net uptake of Ca2+ at micromolar concentrations of the ion. The glucose effect was not mimicked by 20 mM 3-O-methylglucose. It was as pronounced at 1 mM as at 20 mM of the sugar and corresponded to an uptake of 119 fmol cm−2 s−1. Glucose metabolism was typical for tumor cells with a high glycolytic flux and an oxidationtoutilization ratio as low as 0.05–0.15. Maximal oxidative degradation was attained already at l mM. This concentration was also equivalent to the Km for glucose utilization, indicating a substantial left-hand shift of the normal dose-response curve. It is suggested that glucose induces a depolarizationindependent net uptake of Ca2+ by favouring intracellular buffering of the cation.

scholarly journals 2-Oxocarboxylic acids and function of pancreatic islets in obese–hyperglycaemic mice. Insulin secretion in relation to 45Ca uptake and metabolism

1980 ◽  
Vol 186 (1) ◽  
pp. 135-144 ◽  
Author(s):  
Sigurd Lenzen ◽  
Uwe Panten
Keyword(s):  
Pancreatic Islets ◽  
Insulin Release ◽  
Β Cells ◽  
45Ca Uptake ◽  
Insulin Secretagogue ◽  
Stimulus Secretion Coupling ◽  
And Function ◽  
Secretory Pattern ◽  
Oxocarboxylic Acids ◽  
Uptake And Metabolism

The effects of aliphatic 2-oxocarboxylic acids, at concentrations of up to 40mm, on the function of pancreatic islets from ob/ob (obese–hyperglycaemic) mice were investigated. 1. 2-Oxopentanoate, dl-3-methyl-2-oxopentanoate, 4-methyl-2-oxopentanoate and 2-oxohexanoate all induced insulin release by isolated incubated islets and a biphasic insulin-secretory pattern in perfused mouse pancreas. The last two substances were similar in potency to glucose. Pyruvate, 2-oxobutyrate, 3-methyl-2-oxobutyrate and 2-oxo-octanoate did not induce insulin release significantly. 2. 2-Oxocarboxylic acids with significant insulin-secretory potency also induced significant 45Ca uptake by isolated incubated islets. 3. The rates of decarboxylation of [1-14C]pyruvate, 3-methyl-2-oxo[1-14C]butyrate and 4-methyl-2-oxo[1-14C]pentanoate were twice as high as the rates of oxidation of the corresponding U-14C-labelled compounds. However, whereas the rates of metabolism of labelled pyruvate and 3-methyl-2-oxobutyrate steadily increased over the concentration range 1–40mm, those of labelled 4-methyl-2-oxopentanoate and d-[U-14C]glucose levelled off at concentrations above 10mm. 4. Omission of 40CaCl2 from the incubation medium reduced the rate of oxidation of the insulin secretagogue [U-14C]4-methyl-2-oxopentanoate, but left that of the non-(insulin secretagogue) [U-14C]3-methyl-2-oxobutyrate unaffected. 5. Only glucose, and not pyruvate, 3-methyl-2-oxobutyrate and 4-methyl-2-oxopentanoate, significantly inhibited oxidation of endogenous fatty acids. 6. It is suggested that stimulus–secretion coupling and the resulting exocytosis of insulin in pancreatic β-cells may modulate both fuel oxidation and 45Ca uptake.

Stimulus-secretion coupling of amino acid-induced insulin release VII. The B-cell memory for L-glutamine

Metabolism ◽  
1982 ◽  
Vol 31 (3) ◽  
pp. 229-237 ◽  
Author(s):  
G. Somers ◽  
A.R. Carpinelli ◽  
G. Devis ◽  
A. Sener ◽  
W.J. Malaisse
Keyword(s):  
Amino Acid ◽  
B Cell ◽  
Insulin Release ◽  
Cell Memory ◽  
B Cell Memory ◽  
Stimulus Secretion Coupling

The stimulus-secretion coupling of amino acid-induced insulin release: metabolism and cationic effects of leucine

Diabetes ◽  
1980 ◽  
Vol 29 (6) ◽  
pp. 431-437 ◽  
Author(s):  
W. J. Malaisse ◽  
J. C. Hutton ◽  
A. R. Carpinelli ◽  
A. Herchuelz ◽  
A. Sener
Keyword(s):  
Amino Acid ◽  
Insulin Release ◽  
Stimulus Secretion Coupling
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