Cyclic Nucleotides in Pancreatic Islets: Tolbutamide- and Arginine-induced Insulin Release

Charles, M. Arthur; Lawecki, J; Steiner, Alton L.; Grodsky, Gerold M.

doi:10.2337/diab.25.4.256

Cited by 32 publications

(18 citation statements)

References 5 publications

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“…These effects may be due to elevation of intracellular Ca 2ϩ , which leads to activation of adenylcyclase. Our results are in agreement with data showing that glucose, in addition to other agents, stimulates insulin secretion through cAMP-dependent mechanisms (20).…”

Section: Fig 5 Effect Of High Glucose (A)supporting

confidence: 93%

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Differential Effects of Glucose and Glyburide on Energetics and Na+ Levels of βHC9 Cells

et al. 2003

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In the present study, noninvasive 31 P and 23 Na ؉ -nuclear magnetic resonance (NMR) technology and respirometry were used to compare the effect of high glucose (30 mmol/l) with the effect of the antidiabetic sulfonylurea (SU) compound glyburide (GLY) on energy metabolism, Na ؉ flux, insulin, and cAMP release of continuously superfused ␤-HC9 cells encapsulated in microscopic agarose beads. Both high glucose and GLY increased oxygen consumption in ␤-HC9 cells (15-30%) with a maximal effect at 8 mmol/l for glucose and at 250 nmol/l for GLY. At the same time, insulin release from ␤-cells increased by 15-and 25-fold with high glucose or GLY, respectively. The P-creatine (PCr) level was greatly increased and inorganic phosphate (P i ) was decreased with 30 mmol/l glucose in contrast to the decreased level of PCr and increased P i with GLY. ATP levels remained unchanged during both interventions. Studies on isolated mitochondria of ␤-HC9 cells showed that GLY added to mitochondria oxidizing glutamine or glutamate abolished the stimulation of respiration by ADP (state 3) meanwhile leaving state 3 respiration unchanged during oxidation of other substrates. Exposure of ␤-HC9 cells to 5 mmol/l glucose decreased intracellular Na ؉ levels monitored by 23 Na ؉ -NMR spectroscopy and 30 mmol/l glucose resulted in a further decrease in cytosolic Na ؉ . In contrast, Na ؉ increased when 1 mol/l GLY was added to the perfusate containing 5 mmol/l glucose. These data support the hypothesis that glucose activates the ␤-cell through a "push mechanism" due to substrate pressure enhancing fuel flux, energy production, and extrusion of Na ؉ from the cells in contrast to SU receptor (SUR)-1 inhibitors, which may modify intermediary and energy metabolism secondarily through a "pull mechanism" due to higher energy demand resulting from increased ion fluxes and the exocytotic work load. Diabetes 52:394 -402, 2003

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Section: Fig 5 Effect Of High Glucose (A)supporting

confidence: 93%

“…There is evidence in the literature that GLY affects respiration and ATP content in rat islets (16 -19). Through use of islet homogenates, tolbutamide (another SU) and its analogs have been shown to inhibit islet phosphodiesterase (20) and increase c-AMP levels. SUs also modulate the sodium content in rat pancreatic islets (21,22).…”

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confidence: 99%

Differential Effects of Glucose and Glyburide on Energetics and Na+ Levels of βHC9 Cells

et al. 2003

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“…cAMP concentration as earlier studies have shown that TLB and GLB can rapidly raise levels of cAMP in islets. 14,15 However, Zhang et al…”

Section: Resultsmentioning

confidence: 99%

Exchange Protein Directly Activated by Cyclic AMP Isoform 2 Is Not a Direct Target of Sulfonylurea Drugs

Tsalkova

Gribenko

Cheng

2011

ASSAY and Drug Development Technologies

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It has been reported by Zhang et al. that antidiabetic sulfonylurea drugs promote insulin secretion by directly binding to exchange protein directly activated by cyclic AMP isoform 2 (Epac2) and activating its down-stream effector Rap1. However, a critical link for an unambiguous validation of a direct interaction between Epac2 and sulfonylurea using purified individual components is missing. Our in vitro analyses using purified full-length Epac2 and Rap1 suggest that sulfonylureas are not able to directly bind to Epac2, nor are they capable of triggering Epac2-dependent Rap1 activation.

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“…The suggestion that cyclic-AMP is involved in the stimulation of insulin release by sulphonylureas is based on the evidence that these drugs transiently increase cyclic-AMP levels in islet cells [36,37] by stimulating adenylate cyclase [16] or inhibiting phosphodiesterase [38,39], two observations made in homogenates of islet cells. In the present experiments, inhibition of the phosphodiesterase by theophylline was able to increase the rate of insulin release when the stimulating effect of tolbutamide had declined.…”

Section: Discussionmentioning

confidence: 99%

Tolbutamide stimulation and inhibition of insulin release: Studies of the underlying ionic mechanisms in isolated rat islets

Henquin

1980

Diabetologia

166

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Summary. The effects of tolbutamide on insulin release, 45Ca2+ uptake and 86Rb+ efflux were studied in isolated rat islets. At a low glucose concentration (75 mg/dl), tolbutamide (20-500 ~tg/ml) produced a rapid, dose-dependent increase in insulin release from perifused islets. After 30-40 min however, the rate of secretion as well as the potentiating effect of theophylline were inversely related to the concentration of sulphonylurea. The monophasic release of insulin triggered by tolbutamide (100 ,ug/ml) at low glucose could be evoked again by removing and reintroducing the drug, or by temporarily withdrawing calcium or adding cobalt to the medium. Tolbutamide (20 ,ug/ml) accelerated and potentiated the biphasic insulin release in response to a secondary stimulation by glucose (150mg/dl). By contrast, 100 gg/ml tolbutamide reduced the releasing effect of glucose to a slow increase in secretion rates. Theophylline normalized the second phase of release, but did not restore the rapid phase. Tolbutamide stimulated 45Ca 2+ influx (2 rain-uptake) in islet cells; this effect was maximum immediately after addition of the drug and decreased later on, exhibiting a monophasic pattern. Glucose stimulation of Ca 2+ uptake (5 min) was reduced in the presence of 100 ~g/ml tolbutamide. At a low glucose concentration, tolbutamide reversibly reduced 86Rb+ efflux (tracer of K +) from islet cells, without altering the further inhibition of this efflux by a later glucose increase. It is suggested that tolbutamide depolarizes B cells partially by reducing their K § permeability. This depolarization leads to opening of voltagedependent calcium channels and the resulting Ca 2 § influx triggers insulin release. The important and maintained depolarization by high concentrations of tolbutamide may secondarily inactivate these channels and cause a decrease in Ca 2+ influx. This could explain the monophasic release of insulin and the refractoriness of B cells to subsequent glucose stimulation.Key words: Isolated rat islets, tolbutamide, insulin release, glucose metabolism, rubidium efflux, calcium uptake, glucose, theophylline, cobalt, potassium.Sulphonylureas have been used for more than twenty years to treat diabetic patients, but, despite intensive investigation, the mechanisms by which they decrease blood glucose levels are not completely understood. The role of the pancreas in the hypoglycaemic action of sulphonylureas has been established by the pioneer work of Loubati6res [1] and was confirmed by the demonstration that these drugs stimulate insulin release in man [2] and animals [3] by a direct effect on B cells demonstrated in vitro [4]. This insulinotropic action of acute administration of sulphonylureas has since been extensively studied; its characteristics and possible mechanisms have been the subject of several reviews [5][6][7][8]. Many clinical investigations have failed, however, to show a correlation between the lowering of blood glucose and an increase in plasma insulin levels after chronic treatment with sulphonylureas ...

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Cyclic Nucleotides in Pancreatic Islets: Tolbutamide- and Arginine-induced Insulin Release

Cited by 32 publications

References 5 publications

Differential Effects of Glucose and Glyburide on Energetics and Na+ Levels of βHC9 Cells

Differential Effects of Glucose and Glyburide on Energetics and Na+ Levels of βHC9 Cells

Exchange Protein Directly Activated by Cyclic AMP Isoform 2 Is Not a Direct Target of Sulfonylurea Drugs

Tolbutamide stimulation and inhibition of insulin release: Studies of the underlying ionic mechanisms in isolated rat islets

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