Evidence for the Involvement of Na/Ca Exchange in Glucose-induced Insulin Release from Rat Pancreatic Islets

Siegel, E. G.; Wollheim, Claes B.; Renold, Albert E.; Sharp, Geoffrey W. G.

doi:10.1172/jci109969

Cited by 47 publications

(15 citation statements)

References 43 publications

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“…These results suggest that removal of extraplatelet Na+ may limit the amount of Ca2+ typically mobilized by these stimuli. A relationship between Na+ and Ca2+ availability in the platelet would be analogous to that observed in a number of target tissues (21)(22)(23)(24), particularly those involved in secretory phenomena (22)(23)(24). Alternatively, removal of extraplatelet Na+ may otherwise alter the liberation of arachidonic acid from the membrane, such that positive feedback effects of arachidonic acid metabolites on Ca2+ availability and platelet secretion do not occur.…”

Section: Resultsmentioning

confidence: 86%

Removal of extraplatelet Na+ eliminates indomethacin-sensitive secretion from human platelets stimulated by epinephrine, ADP, and thrombin.

Connolly¹,

Limbird²

1983

Proc. Natl. Acad. Sci. U.S.A.

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We have previously observed that removal of extraplatelet Na+ markedly diminishes human platelet aggregation and secretion in response to epinephrine. The present studies demonstrate that this effect of the removal of extraplatelet Na' on platelet function is not unique to activation of platelets by 2-adrenergic agents but represents a phenomenon also evident for other platelet stimuli. Thus, platelet aggregation and secretion in response to maximal concentrations of ADP and lower concentrations of thrombin (<0.04 unit/ml) were also markedly reduced in platelets in "Na'-free" medium, suggesting that these agents share an effector mechanism that is similarly inhibited by the removal of extraplatelet Na+. In contrast, platelet aggregation and secretion in response to higher concentrations of thrombin (20.04 unit/ml) and to 0.04-1.0 ImM (15S)-hydroxy-1la,9a-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619), an endoperoxide analog, were identical in control platelets and in those suspended in "Na'-free" medium, indicating that platelets suspended in "Na+-free" medium are functionally intact, at least in response to some stimuli. Furthermore, the observation that U46619 can elicit platelet aggregation and secretion independently of extraplatelet Na+ indicates that the loss of platelet responsiveness to epinephrine, ADP, and low concentrations of thrombin cannot be attributed to a loss of sensitivity to the stimulus-provoked secondary mediator(s) of platelet function, endoperoxides or thromboxane A2. Treatment with indomethacin to block the secondary aggregation and secretion pathways of platelets reduced the aggregatory and secretory responses of control platelets induced by epinephrine, ADP, and low concentrations of thrombin to those characteristic of platelets suspended in "Na+-free" medium. In contrast, indomethacin did not alter the functional responses induced by these agents in platelets suspended in "Na+-free" medium, suggesting that "primary" aggregation is intact but that the "secondary" aggregation and secretion mediated by arachidonic acid metabolites are eliminated by removal of extraplatelet Na+. Consistent with this interpretation is the observation that the indomethacin-insensitive aggregation and secretion induced by U46619 and higher concentrations of thrombin were retained in platelets suspended in "Na+-free" medium. Thus, the responses eliminated by removal of extraplatelet Na+ are those eliminated by treating control platelets with indomethacin, suggesting a strong link between the presence of extraplatelet Na+ and the operation of platelet function mediated by the cyclooxygenase pathway.We recently reported that human platelets in "Na+-free" medium have a diminished rate and extent of aggregation and a markedly reduced release of serotonin in response to epinephrine stimulation (1). Despite the effects of the removal of extraplatelet Na+ on epinephrine-induced aggregation and secretion, a2-adrenergic receptor-mediated attenuation of prostaglandin E1 (PGE1)-stimulated cAMP accumulation i...

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Section: Resultsmentioning

confidence: 86%

Removal of extraplatelet Na+ eliminates indomethacin-sensitive secretion from human platelets stimulated by epinephrine, ADP, and thrombin.

Connolly¹,

Limbird²

1983

Proc. Natl. Acad. Sci. U.S.A.

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“…Because 1 mmol/l ouabain, at which concentration Na ϩ /K ϩ -ATPase activity is maximally suppressed, is commonly used to investigate the effect of the compound on insulin secretion (7,10,12,30), we used that concentration in all experiments in the present study. In addition, 1 mmol/l ouabain does not have irreversible, cytotoxic effects, as shown by the complete recovery of insulin secretion after withdrawal of the compound.…”

Section: Discussionmentioning

confidence: 99%

Ouabain Suppresses Glucose-Induced Mitochondrial ATP Production and Insulin Release by Generating Reactive Oxygen Species in Pancreatic Islets

et al. 2002

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We examined the effects of reduced Na ؉ /K ؉ -ATPase activity on mitochondrial ATP production and insulin release from rat islets. Ouabain, an inhibitor of Na ؉ /K ؉ -ATPase, augmented 16.7 mmol/l glucose-induced insulin release in the early period but suppressed it after a delay of 20 -30 min. Unexpectedly, the ATP content in an islet decreases in the presence of 16.7 mmol/l glucose when Na ؉ /K ؉ -ATPase activity is diminished by ouabain, despite the reduced consumption of ATP by the enzyme. Ouabain also suppressed the increment of ATP content produced by glucose even in Ca 2؉ -depleted or Na ؉ -depleted conditions. That mitochondrial membrane hyperpolarization and O 2 consumption in islets exposed to 16.7 mmol/l glucose were suppressed by ouabain indicates that the glycoside inhibits mitochondrial respiration but does not produce uncoupling. Ouabain induced mitochondrial reactive oxygen species (ROS) production that was blocked by myxothiazol, an inhibitor of site III of the mitochondrial respiratory chain. An antioxidant, ␣-tocopherol, also blocked ouabain-induced ROS production as well as the suppressive effect of ouabain on ATP production and insulin release. However, ouabain did not directly affect the mitochondrial ATP production originating from succinate and ADP. These results indicate that ouabain suppresses mitochondrial ATP production by generating ROS via transduction, independently of the intracellular cationic alternation that may account in part for the suppressive effect on insulin secretion. efficacy in stimulation-secretion coupling, which also is dependent on the accelerated glucose metabolism that correlates with increments in the ATP/ADP ratio. Regulation of the ATP level in pancreatic ␤-cells, therefore, plays a crucial role in insulin secretion. Na ϩ /K ϩ -ATPase is involved in maintaining Na ϩ and K ϩ gradients across the ␤-cell plasma membrane and is thought to consume a large amount of ATP in the maintenance of homeostasis (2,3). Accordingly, the role of Na ϩ / K ϩ -ATPase in the regulation of the intracellular ATP levels in ␤-cells is of interest. We have reported that the ATP content of an islet unexpectedly decreases in the presence of glucose when Na ϩ /K ϩ -ATPase activity is diminished by ouabain, despite reduced consumption of ATP by the enzyme, whereas decrease of ATP content is not observed using thapsigargin, an inhibitor of another ATP consumer, the Ca 2ϩ -ATPase in endoplasmic reticulum (4,5). Inhibition by ouabain of glucose oxidation (6) and glucose utilization (7) has been reported previously in rat islets. However, the effect of ouabain on glucose-induced insulin release is complex. Ouabain has a stimulatory effect on glucose-induced insulin secretion in the early phase (8 -10), probably owing to increased Ca 2ϩ influx (10 -12). Such increased Ca 2ϩ influx by ouabain should be due to depolarization, since the electrogenic effect of Na ϩ /K ϩ -ATPase is to hyperpolarize the membrane potential (2). On the other hand, ouabain decreases glucoseinduced insulin release in th...

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“…A rise in cytoplasmatic free calcium concentration is the trigger mechanism o f the first phase o f glucose-stimu-lated insulin release [36,37] and it is mainly related to C a 2+ mobilization from intracellular stores [36,38] and inhibition o fC a 2+ efflux ratherthan to increment o f C a 2+ influx from the extracellular environment [39]. Calcitriol may act at the genomic level, inducing the synthesis o f calbindin and other cytoplasmatic proteins that regulate intracellular calcium concentration and fluxes [12,13,40].…”

Section: Discussionmentioning

confidence: 99%

Glucose-Induced Insulin Secretion in Uremia: Role of 1α,25(HO)<sub>2</sub>-Vitamin D<sub>3</sub>

Allegra¹,

Luisetto²,

Mengozzi³

et al. 1994

Nephron

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To evaluate the role and mechanism of action of calcitriol on glucose-induced insulin secretion in uremia, 17 patients with severe chronic renal failure were studied. Glucose metabolism was investigated by the intravenous glucose tolerance test (IVGTT) before and after treatment for 21 days with 0.5 µg/day of calcitriol and 500 mg/day of calcium (C + Ca) (6 cases) or 0.5 µg/day of calcitriol alone (C) (11 cases). After these evaluations the patients on C + Ca were shifted to C and 6 patients on C were shifted to C + Ca, and IVGTT was repeated 21 days after the shift. For each test plasma glucose (G), immunoreactive insulin (IRI) and C-peptide (C-p) were measured at -30,0,2,5,15,30,45,60 min, and baseline plasma values of 1α,25(HO)₂-vitamin D₃, C-terminal parathyroid hormone (PTH-C), intact parathyroid hormone (PTH-I), calcitonin, and serum values of total and ionized calcium were dosed. Also, glucose constant decay (K-G), insulin response (IRI area), C-p production (C-p area), insulinogenic index (IGI) and insulin resistance index (RI) were calculated. A historical group of 21 healthy volunteers formed the normal controls. 1α,25(HO)₂-vitamin D₃ plasma levels in uremic patients before treatment were significantly lower than normal range. As compared to controls, uremic patients showed significantly lower K-G, IRI area and IGI values and significantly higher RI values. After treatment with C or C + Ca, the insulin response improved significantly at 2 and 5 min and G decrement was more marked at 30,45 and 60 min. K-G and 0-15 min IRI area, 0-15 min IGI and 0-15 min C-p area values increased significantly but did not reach the normal values. Serum calcium and plasma 1α,25(HO)₂-vitamin D₃ levels significantly increased after treatment but no correlations were found between changes in glucose metabolism parameters and changes in total or ionized serum calcium or changes in 1α,25(HO)₂-vitamin D₃ plasma levels. Serum calcium values significantly decreased after shift from C + Ca to C and significantly increased after shift from C to C + Ca, but glucose metabolism parameters showed no further changes. From these data we inferred that 1α,25(HO)₂-vitamin D₃ deficiency may contribute to the inhibition of glucose-induced insulin secretion in uremia. Calcitriol mainly influences the first phase of insulin release and its effect may be due to a direct action on the pancreatic β-cell.

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Evidence for the Involvement of Na/Ca Exchange in Glucose-induced Insulin Release from Rat Pancreatic Islets

Cited by 47 publications

References 43 publications

Removal of extraplatelet Na+ eliminates indomethacin-sensitive secretion from human platelets stimulated by epinephrine, ADP, and thrombin.

Removal of extraplatelet Na+ eliminates indomethacin-sensitive secretion from human platelets stimulated by epinephrine, ADP, and thrombin.

Ouabain Suppresses Glucose-Induced Mitochondrial ATP Production and Insulin Release by Generating Reactive Oxygen Species in Pancreatic Islets

Glucose-Induced Insulin Secretion in Uremia: Role of 1α,25(HO)<sub>2</sub>-Vitamin D<sub>3</sub>

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