Effects of Sulfonylurea Derivatives on Pancreatic β-Cells

Hellman, Bo; Täljedal, Inge‐Bert

doi:10.1007/978-3-642-66002-3_4

Cited by 21 publications

(20 citation statements)

References 81 publications

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Section: Discussionmentioning

confidence: 99%

“…Hypoglycaemic sulphonylurea s were also able to provoke the translocation of 45Ca from one aqueous medium into another across the organic mixture [16]. The concentrations of sulphonylureas used in these experiments were not higher than those presumed to be found in the phospholipid domain of the B-cell plasma membrane when pancreatic islets are exposed to the same extracellular concentration of the drug as that used in most in vitro studies, this estimation taking into account the reported values for the uptake of hypoglycaemic sulphonylureas by isolated islets [1].…”

Section: Ionophoretic Effects Of Hypoglycaemic Sulphonylureasmentioning

confidence: 99%

“…The mechanism of such an insulinotropic effect is poorly understood [1]. Within the framework of current concepts concerning the cytophysiology of insulin release [2], three primary sites of action could be proposed to account for the insulinotropic action of sulphonylureas: a facilitation of nutrient metabolism, an interference with cyclic AMP synthesis or breakdown, or a remodelling of ionic fluxes in the B-cell.Biochemical studies, reviewed elsewhere [1, 3], do not support the first of these 3 hypotheses.Although hypoglycaemic sulphonylureas were occasionally claimed to activate adenylate cyclase [4] and repeatedly found to inhibit phosphodiesterase [5][6][7] in islet homogenates, the relevance of the latter finding may be questioned since sulphonylureas apparently do not penetrate the B-cell beyond the plasma membrane [1]. A drug-induced increase in the cyclic AMP content of intact islets could be secondary to a cytosolic accumulation of Ca 2+ [8].…”

mentioning

confidence: 99%

“…Although hypoglycaemic sulphonylureas were occasionally claimed to activate adenylate cyclase [4] and repeatedly found to inhibit phosphodiesterase [5][6][7] in islet homogenates, the relevance of the latter finding may be questioned since sulphonylureas apparently do not penetrate the B-cell beyond the plasma membrane [1]. A drug-induced increase in the cyclic AMP content of intact islets could be secondary to a cytosolic accumulation of Ca 2+ [8].…”

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confidence: 99%

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Insulinotropic effects of hypoglycaemic and hyperglycaemic sulphonamides: The ionophoretic hypothesis

Couturier¹,

Malaisse²

1980

Diabetologia

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Summary.Hypoglycaemic sulphonamides stimulate net uptake of 45Ca+ + and insulin release in isolated pancreatic islets. These effects are antagonized by organic calcium-antagonists (e.g. suloctidil). In an artificial system, hypoglycaemic sulphonamides, such as gliclazide, stimulate the translocation of calcium into or across a hydrophobic immiscible domain, a process enhanced by the antibiotic ionophore A 23187 and antagonized by suloctidil. In this artificial system, the A23187-mediated process of calcium countertransport is stimulated by gliclazide and inhibited by diazoxide. It is postulated that the insulinotropic action of hypoglycaemic and hyperglycaemic sulphonamides is primarily attributable to the ionophoretic action of these drugs.Key words: Hypoglycaemic sulphonylureas, diazoxide, calcium, insulin release, ionophores, organic calcium antagonists.Hypoglycaemic sulphonylureas stimulate insulin release from the pancreatic B-cell. The mechanism of such an insulinotropic effect is poorly understood [1]. Within the framework of current concepts concerning the cytophysiology of insulin release [2], three primary sites of action could be proposed to account for the insulinotropic action of sulphonylureas: a facilitation of nutrient metabolism, an interference with cyclic AMP synthesis or breakdown, or a remodelling of ionic fluxes in the B-cell.Biochemical studies, reviewed elsewhere [1, 3], do not support the first of these 3 hypotheses.Although hypoglycaemic sulphonylureas were occasionally claimed to activate adenylate cyclase [4] and repeatedly found to inhibit phosphodiesterase [5][6][7] in islet homogenates, the relevance of the latter finding may be questioned since sulphonylureas apparently do not penetrate the B-cell beyond the plasma membrane [1]. A drug-induced increase in the cyclic AMP content of intact islets could be secondary to a cytosolic accumulation of Ca 2+ [8].The third hypothesis, namely that of a primary action of hypoglycaemic sulphonylureas upon ionic movements, may involve two distinct mechanisms. First, sulphonylureas may cause a decrease in K § conductance [9,10] leading to subsequent cell depolarization and gating of voltage-dependent Ca 2+ channels; however, under suitable conditions, tolbutamide is able to stimulate Ca 2+ influx and insulin release without decreasing K + conductance [11]. Second, sulphonylureas may directly interfere with an ionophoretic modality of Ca transport across the B-cell plasma membrane [12][13][14][15]. This hypothesis has recently been scrutinized in great detail [16][17][18].The present report documents some selected experimental findings in support of the ionophoretic hypothesis. Methodological ConsiderationsInsulin release was measured in groups of 8 pancreatic islets, removed from fed female albino rats and incubated for 60 min at 37~ in a bicarbonate-buffered solution [19]. The net uptake of 45Ca 2+ by the islets was measured over 90 min incubation, followed by repeated washes of the islets in order to remove extracellular radioactivity [20].Two...

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Section: Discussionmentioning

confidence: 99%

Section: Ionophoretic Effects Of Hypoglycaemic Sulphonylureasmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Insulinotropic effects of hypoglycaemic and hyperglycaemic sulphonamides: The ionophoretic hypothesis

Couturier¹,

Malaisse²

1980

Diabetologia

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“…The molecular mechanism responsible for the change in K § permeability is not known [7]. Radioisotopic studies of sulphonylurea uptake by isolated islets suggest that these hypoglycaemic agents are bound to the plasma membrane of pancreatic B cells [8][9][10], which could be equipped with sulphonylurea receptors [111. The cell boundary [12] could therefore represent the primary site of action of hypoglycaemic sulphonylureas.…”

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confidence: 99%

Binding of hypoglycaemic sulphonylureas to an artificial phospholipid bilayer

Deleers¹,

Malaisse²

1984

Diabetologia

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Summary.Hypoglycaemic sulphonylureas bind to multilamellar liposomes formed of egg yolk phosphatidylcholine. In this artificial model, both specific and non-specific components of the binding phenomenon can be characterized by the same criteria as those used in studies performed with natural membranes. The relative ability of distinct sulphonylureas to inhibit the binding of 3H-glibenclamide or 3H-gliquidone to the liposomes parallels their relative potency as insulin secretagogues. It is proposed that the insertion of hypoglycaemic sulphonylureas into the phospholipid domain of the B cell membrane could represent a primary event in the mechanism by which these agents stimulate insulin release.

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Sulfonylureas: Basic Aspects and Clinical Uses

Melander¹

2004

International Textbook of Diabetes Mellitus

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This chapter describes the chemistry, mechanism of action, pharmacodynamics, pharmacokinetics, kinetics–effect relations, clinically beneficial and adverse effects of sulfonylurea drugs, as well as the efficacy of these agents in randomized‐controlled clinical trials and other studies. It also compares the different sulfonylurea compounds, especially in terms of differences in potency, rate of onset, and duration of action, and how such differences may contribute to different clinical profiles of the various compounds. In addition, some important interactions with other drugs are listed. Their appropriate place in the therapeutic armamentarium concerning type 2 diabetes is thoroughly discussed.

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Effects of Sulfonylurea Derivatives on Pancreatic β-Cells

Cited by 21 publications

References 81 publications

Insulinotropic effects of hypoglycaemic and hyperglycaemic sulphonamides: The ionophoretic hypothesis

Insulinotropic effects of hypoglycaemic and hyperglycaemic sulphonamides: The ionophoretic hypothesis

Binding of hypoglycaemic sulphonylureas to an artificial phospholipid bilayer

Sulfonylureas: Basic Aspects and Clinical Uses

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