An inhibitory effect of tolbutamide and glibenclamide (glyburide) on the pancreatic islets of normal animals

Dunbar, Joseph C.; Foà, Piero P.

doi:10.1007/bf00421411

Cited by 64 publications

(37 citation statements)

References 38 publications

(30 reference statements)

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“…There is no evident reason to believe that the mechanism by which tolbutamide acutely stimulates insulin release in vivo is different from that proposed above. It is less certain whether the present demonstration of a delayed inhibition of insulin release by tolbutamide provides the sole explanation for the surprising decreased responsiveness of the islets after long-term treatment of animals with sulphonylureas [13][14][15].…”

Section: Discussionmentioning

confidence: 62%

“…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 [9][10][11]. These latter observations have been related to unexplained reports showing that after long-term treatment of animals with sulphonylureas, the in vivo and in vitro insulin response to glucose was reduced [12][13][14][15].The present study carried out with isolated rat islets, was designed to explore in detail the mechanisms underlying the secretory and related ionic changes produced in B cells by tolbutamide. …”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 62%

mentioning

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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“…Desensitization by sulfonylureas. Approximately 30 years ago a reversible impairment of insulin secretion by sulfonylureas, such as tolbutamide or glibenclamide, was noted (36). The sulfonylurea-induced desensitization was described to be selective for sulfonylureas (37,38), but in vitro experimentation showed that exposure of islets to sulfonylureas also markedly reduced glucose-induced insulin secretion (39 -41).…”

Section: Desensitization By Depolarizing Insulin Secretagoguesmentioning

confidence: 99%

Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues

et al. 2004

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Prolonged stimulation of insulin secretion by depolarization and Ca2؉ influx regularly leads to a reversible state of decreased secretory responsiveness to nutrient and nonnutrient stimuli. This state is termed "desensitization." The onset of desensitization may occur within 1 h of exposure to depolarizing stimuli. Desensitization by exposure to sulfonylureas, imidazolines, or quinine produces a marked cross-desensitization against other ATP-sensitive K ؉ channel (K ATP channel)-blocking secretagogues. However, desensitized ␤-cells do not necessarily show changes in K ATP channel activity or Ca 2؉ handling. Care has to be taken to distinguish desensitization-induced changes in signaling from effects due to the persisting presence of secretagogues. The desensitization by depolarizing secretagogues is mostly accompanied by a reduced content of immunoreactive insulin and a marked reduction of secretory granules in the ␤-cells. In vitro recovery from a desensitization by the imidazoline efaroxan was nearly complete after 4 h. At this time point the depletion of the granule content was partially reversed. Apparently, recovery from desensitization affects the whole lifespan of a granule from biogenesis to exocytosis. There is, however, no direct relation between the ␤-cell granule content and the secretory responsiveness. Even though a prolonged exposure of isolated islets to depolarizing secretagogues is often associated with the occurrence of ultrastructural damage to ␤-cells, we could not find a cogent link between depolarization and Ca 2؉ influx and apoptotic or necrotic ␤-cell death. Diabetes 53 (Suppl. 3)

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“…On the other hand, drugs such as sulfonylureas (the use of which in diabetes is currently under question [19]) have been postulated to act on insulin release through the cAMP system (20)(21)(22). The effect of these drugs on insulin production is a matter of controversy because they have been reported to stimulate (23) or to inhibit (24)(25)(26)(27) proinsulin biosynthesis in isolated islets of adult rodents.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of proinsulin and insulin in newborn rat pancreas. Interaction of glucose, cyclic AMP, somatostatin, and sulfonylureas on the (3H) leucine incorporation into immunoreactive insulin.

García¹,

Jarrousse²,

Rosselin³

1976

J. Clin. Invest.

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A B S T R A C T The purpose of the present study was to investigate the regulation of insulin biosynthesis during the perinatal period. The incorporation of [3H]leucine into total immunoreactive insulin (IRI) and into IRI fractions was measured by a specific immunoprecipitation procedure after incubation, extraction, and gel filtration in isolated 3-day-old rat pancreases without prior isolation of islets. IRI fractions were identified by their elution profile, their immunological properties, and their ability to compete with the binding of "I-insulin in rat liver plasma membranes. No specific incorporation of [3H]leucine was found in the IRI eluted in the void volume, making it unlikely that this fraction behaves as a precursor of (pro)insulin in this system. In all conditions tested, the incorporation of [8H]leucine was linearly correlated with time. Optimal concentration of glucose (11 mM cose and was not modified by any further increase in glucose concentrations up to 27.5 mM. Theophylline or dbcAMP at 10 mM concentration did not reverse the somatostatin inhibitory effect on either insulin biosynthesis or release. Somatostatin also inhibited both processes in isolated islets from the 3-day-old rat pancreas. High Ca"+ concentration in the incubation medium reversed the inhibitory effect of somatostatin on glucoseinduced insulin biosynthesis as well as release. In both systems the inhibitory effect of somatostatin on insulin biosynthesis and release correlated well. Glipizide (10-100 ,M) and tolbutamide (400 ELM) inhibited the stimulatory effect of glucose, dbcAMP, and theophylline on [8H]leucine incorporation into IRI. The concentrations of glipizide that were effective in inhibiting [3H]leucine incorporation into IRI were smaller than those required to inhibit the phosphodiesterase activity in isolated islets of 3-day-old rat pancreas.These data suggest the following conclusions: (a) the role of the cAMP-phosphodiesterase system on insulin biosynthesis is likely to be greater in newborns than in adults; (b) the greater effectiveness of glucose and the cAMP system on insulin biosynthesis than on insulin release might possibly be related to the rapid accumulation of pancreatic IRI which is observed in the perinatal period; (c) somatostatin, by direct interaction with the endocrine tissue, can inhibit glucose and cAMPinduced insulin biosynthesis as well as release; calcium reverses this inhibition; (d) sulfonylureas inhibit insulin biosynthesis in newborn rat pancreas an effect which has

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An inhibitory effect of tolbutamide and glibenclamide (glyburide) on the pancreatic islets of normal animals

Cited by 64 publications

References 38 publications

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

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

Desensitization of Insulin Secretion by Depolarizing Insulin Secretagogues

Biosynthesis of proinsulin and insulin in newborn rat pancreas. Interaction of glucose, cyclic AMP, somatostatin, and sulfonylureas on the (3H) leucine incorporation into immunoreactive insulin.

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