Interacting Effects of Sulfonylureas and Glucose on Cyclic AMP Metabolism and Insulin Release in Pancreatic Islets of the Rat

Grill, Valdemar; Cerasi, Erol

doi:10.1172/jci109052

Cited by 26 publications

(9 citation statements)

References 22 publications

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“…However, the present study has also clarified the difference in stimulating insulin release between DG-5128 and tolbutamide. DG-5128 stimulated insulin release in vitro at any glucose concentrations tested, in contrast to tolbut¬ amide which stimulated it only at low glucose concentrations below 5.6 mM (Table 2), as reported by Grill & Cerasi (1978) and Joost & Hasselblatt (1979).…”

Section: Discussionsupporting

confidence: 68%

Insulin releasing action of 2-[2-(4,5-dihydro-1H-imadazol-2-yl)-1-phenylethyl] pyridine dihydrochloride sesquihydrate (DG-5128), a new, orally effective hypoglycaemic agent

Kameda¹,

Ono²,

Koyama³

et al. 1982

Acta Endocrinologica

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2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenyl\x=req-\ ethyl] pyridine dihydrochloride sesquihydrate is a new orally effective hypoglycaemic agent structurally unrelated to the known hypoglycaemics. DG-5128 was found to decrease blood glucose levels by stimulating insulin release, like the sulphonylurea hypoglycaemics. However, the study with the rat Langerhans islets in vitro indicated a great difference in mode of stimulation of insulin release between DG-5128 and a sulphonylurea hypoglycaemic, tolbutamide. DG-5128 significantly reversed \g=a\-adrenergic inhibition of the glucose-primed insulin release from the islets, while tolbutamide did not.From the comparison with the effects of phentolamine, yohimbine and prazosine, DG-5128 was strongly suggested to stimulate the glucose-primed insulin release through antagonizing at \g=a\2-adrenoreceptors on the B cells.In a previous report (Kameda et al., in press), we described the hypoglycaemic and antihyperglycaemic action of 2-[2-(4,5-dihydro-lH-imidazol-2-yl)-1-phenylethyl] pyridine dihydrochloride sesqui¬ hydrate in various animal species in¬ cluding mice, rats, dogs, monkeys and genetically diabetic mice of AyKK strain. Since DG-5128 hardly affected blood glucose levels in streptozotocin-induced diabetic rats, this compound was as¬ sumed to exert its hypoglycaemic action through stimulating insulin release, like the sulphonylurea hypoglycaemics. However, some difference was observed in hypo¬ glycaemic action between DG-5128 and tolbut¬ amide; the former was also effective in the geneti¬ cally diabetic AyKK mice, while the latter was not (Kameda et al., in press). In addition to the structural difference between DG-5128 and tolbut¬ amide, this difference in hypoglycaemic action between the 2 compounds has stimulated us to compare the mode of action of DG-5128 with that of tolbutamide. The present report describes the insulin releasing action of DG-5128 in rats in vivo and in vitro in comparison with that of tolbut¬ amide. Materials and MethodsDG-5128 was synthesized in this institute (Ishikawa 1980). The following chemicals were used: tolbutamide (Shinnihon Yakugyo Co., Tokyo), t-epinephrine bitartrate (Tokyo Kasei Kogyo Co., Tokyo), yohimbine hydrochloride (Nakarai Chemicals Co., Kyoto), phentolamine hydrochloride (Japan Ciba-Geigy Co., Takarazuka), prazosine hydrochloride (Taito-Pfizer Co., Tokyo), clonidine hydrochloride (C. H. Boehringer Sohn GmbH, Ingelheim), propranolol hydrochloride (Sumitomo Chemicals Co., Osaka), aprotinin (Trasylol, Bayer Co., Leverkusen), bovine serum albumin (Cohn Fraction V, Daiichi Pure Chemicals Co., Tokyo) and collagenase (Type I, Worthington Biochemical Corp., Freehold). Other chemicals used were of analytical grade.For the experiments in vivo, male Wistar:STD rats weighing 140-170 g were used after fasting overnight. DG-5128 or tolbutamide was dissolved in saline and injected into the tail vein at 2 ml/kg. Control rats received saline alone. For this purpose, tolbutamide was solubilized by the addition of a small amount of rat se...

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Section: Discussionsupporting

confidence: 68%

Insulin releasing action of 2-[2-(4,5-dihydro-1H-imadazol-2-yl)-1-phenylethyl] pyridine dihydrochloride sesquihydrate (DG-5128), a new, orally effective hypoglycaemic agent

Kameda¹,

Ono²,

Koyama³

et al. 1982

Acta Endocrinologica

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“…The concentrations of 8-pCPT-29-O-Me-cAMP-AM used in this study are very likely to be selective for activation of EPAC over PKA because even 1 mM 8-pCPT-29-O-Me-cAMP activated ,25% of PKA activity at physiologic concentrations of the enzyme (Christensen et al, 2003). However, sulfonylurea stimulation of pancreatic b-cells has been reported to stimulate adenylyl cyclase activity (Grill and Cerasi, 1978). Therefore, endogenously produced cAMP, and activation of PKA, could potentially contribute to the activities of tolbutamide and gliclazide observed in this study.…”

Section: Discussionmentioning

confidence: 72%

Potentiation of Sulfonylurea Action by an EPAC-selective cAMP Analog in INS-1 Cells: Comparison of Tolbutamide and Gliclazide and a Potential Role for EPAC Activation of a 2-APB-sensitive Ca2+ Influx

Jarrard

Wang

Salyer

et al. 2013

Molecular Pharmacology

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Tolbutamide and gliclazide block the K ATP channel K ir 6.2/Sur1, causing membrane depolarization and stimulating insulin secretion in pancreatic beta cells. We examined the ability of the EPAC-selective cAMP analog 8-pCPT-29-O-Me-cAMP-AM to potentiate the action of these drugs and the mechanism that might account for it. Insulin secretion stimulated by both 200 mM tolbutamide and 20 mM gliclazide, concentrations that had equivalent effects on membrane potential, was inhibited by thapsigargin (1 mM) or the L-type Ca 21 channel blocker nicardipine (2 mM) and was potentiated by 8-pCPT-29-O-MecAMP-AM at concentrations $2 mM in INS-1 cells. Ca 21 transients stimulated by either tolbutamide or gliclazide were inhibited by thapsigargin or nicardipine and were significantly potentiated by 8-pCPT-29-O-Me-cAMP-AM at 5 mM but not 1 mM. Both tolbutamide and gliclazide stimulated phospholipase C activity; however, only gliclazide did so independently of its activity at K ATP channels, and this activity was partially inhibited by pertussis toxin. 8-pCPT-29-O-Me-cAMP-AM alone (5 mM) did not stimulate insulin secretion, but did increase intracellular Ca 21 concentration significantly, and this activity was inhibited by 25 mM 2-aminoethoxydiphenylborate (2-APB) or the removal of extracellular Ca 21 . 8-pCPT-29-OMe-cAMP-AM potentiation of insulin secretion stimulated by tolbutamide was markedly inhibited by 2-APB (25 mM) and enhanced by the PKC inhibitor bisindolylmaleimide I (1 mM). Our data demonstrate that the actions of both tolbutamide and gliclazide are strongly potentiated by 8-pCPT-29-O-MecAMP-AM, that gliclazide can stimulate phospholipase C activity via a partially pertussis toxin-sensitive mechanism, and that 8-pCPT-29-O-Me-cAMP-AM potentiation of tolbutamide action may involve activation of a 2-APB-sensitive Ca 21 influx.

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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%

“…It is therefore unlikely that the inhibition of phosphodiesterase (if it occurs in intact islet cells) is of major importance for the releasing effect of tolbutamide. Moreover, the observation that sulphonylureas do not increase cyclic-AMP levels in islet cells when extracellular calcium has been omitted [37] raises the possibility that the increase in cellular cyclic-AMP levels is secondary to the changes in calcium influx.…”

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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Interacting Effects of Sulfonylureas and Glucose on Cyclic AMP Metabolism and Insulin Release in Pancreatic Islets of the Rat

Abstract: A B S T R A C T The effects of tolbutamide and glibenclamide on the metabolism of cyclic AMP were investigated in pancreatic islets of the rat. Changes in cyclic AMP were assessed by measuring

Cited by 26 publications

References 22 publications

Insulin releasing action of 2-[2-(4,5-dihydro-1H-imadazol-2-yl)-1-phenylethyl] pyridine dihydrochloride sesquihydrate (DG-5128), a new, orally effective hypoglycaemic agent

Insulin releasing action of 2-[2-(4,5-dihydro-1H-imadazol-2-yl)-1-phenylethyl] pyridine dihydrochloride sesquihydrate (DG-5128), a new, orally effective hypoglycaemic agent

Potentiation of Sulfonylurea Action by an EPAC-selective cAMP Analog in INS-1 Cells: Comparison of Tolbutamide and Gliclazide and a Potential Role for EPAC Activation of a 2-APB-sensitive Ca2+ Influx

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

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