Internalization of 3H-glibenclamide in pancreatic islet cells

Carpentier, Jean‐Louis; Sawano, Fumio; Ravazzola, Mariella; Malaisse, Willy

doi:10.1007/bf00454887

Cited by 64 publications

(38 citation statements)

References 9 publications

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“…Desensitization of receptor mediated processes by permanent binding of the ligand to its receptor involving distinct molecular mechanisms is well established for several hormone signaling pathways, i.e., /3-adrenergic receptors (for a review, see Benovic et al [32]). In this respect, it is interesting that internalization of glibenclamide has been reported for HIT T15 cells (Carpentier et ah [33]). If this based on endocytosis of the sulfonylurea receptor when occupied by the ligand, it may represent a mechanism for desensitization by down regulation of the number of sulfonylurea receptors at the cell surface which will be more pronounced for sulfonylureas with lower exchange rate.…”

Section: Discussionmentioning

confidence: 96%

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

Müller

Hartz

Pünter

et al. 1994

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Glimepiride is a novel sulfonylurea drug for treatment of non-insulin-dependent diabetes mellitus with higher blood sugar lowering efficacy in diabetic patients than glibenclamide raising the question whether this characteristics is in line with different binding of glimepiride and glibenclamide to the 0-cell sulfonylurea receptor. Scatchard plot analysis of [3H]sulfonylurea binding to membranes isolated from rat 0-cell tumors and (RINm5F) insulinoma cells and to RINm5F cells demonstrated that glimepiride has a 2.5-3-fold lower affinity than glibenclamide. This corresponded well to the 8-9-fold higher kof f and 2.5-3-fold higher kon rates of glimepiride compared to glibenclamide as revealed by the dissociation and association kinetics of [3H]sulfonylurea binding and the K d values calculated thereof. In agreement, the concentrations required for half-maximal displacement of [3H]sulfonylurea bound to 0-cell membranes were significantly higher for glimepiride compared to glibenclamide. However, the binding affinity of glimepiride measured by both equilibrium binding and kinetic binding studies upon solubilization of 0-cell tumor membranes and RINm5F cell membranes increased up to the value for glibenclamide. This was primarily based on a drastic decrease of the dissociation rate constant of glimepiride whereas the kinetics of glibenclamide binding remained largely unaffected upon solubilization. These data suggest that the K d value alone is not sufficient for characterization of a suifonylurea drug, since the kinetic binding parameters may also determine its acute blood sugar lowering efficacy.

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Section: Discussionmentioning

confidence: 96%

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

Müller

Hartz

Pünter

et al. 1994

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Furthermore, reports show that Ͼ90% of glibenclamide-binding sites are localized intracellularly in the ␤-cell (7,31). Interestingly, under chronic treat-ment, glibenclamide specifically and progressively accumulates in islets in association with secretory granules and mitochondria and causes long-lasting stimulation of insulin secretion (21).…”

mentioning

confidence: 99%

Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis

Lehtihet

Welsh

Berggren

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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Hypoglycemic sulfonylureas such as glibenclamide have been widely used to treat type 2 diabetic patients for 40 yr, but controversy remains about their mode of action. The widely held view is that they promote rapid insulin exocytosis by binding to and blocking pancreatic β-cell ATP-dependent K+ (KATP) channels in the plasma membrane. This event stimulates Ca2+ influx and sets in motion the exocytotic release of insulin. However, recent reports show that >90% of glibenclamide-binding sites are localized intracellularly and that the drug can stimulate insulin release independently of changes in KATP channels and cytoplasmic free Ca2+. Also, glibenclamide specifically and progressively accumulates in islets in association with secretory granules and mitochondria and causes long-lasting insulin secretion. It has been proposed that nutrient insulin secretagogues stimulate insulin release by increasing formation of malonyl-CoA, which, by blocking carnitine palmitoyltransferase 1 (CPT-1), switches fatty acid (FA) catabolism to synthesis of PKC-activating lipids. We show that glibenclamide dose-dependently inhibits β-cell CPT-1 activity, consequently suppressing FA oxidation to the same extent as glucose in cultured fetal rat islets. This is associated with enhanced diacylglycerol (DAG) formation, PKC activation, and KATP-independent glibenclamide-stimulated insulin exocytosis. The fat oxidation inhibitor etomoxir stimulated KATP-independent insulin secretion to the same extent as glibenclamide, and the action of both drugs was not additive. We propose a mechanism in which inhibition of CPT-1 activity by glibenclamide switches β-cell FA metabolism to DAG synthesis and subsequent PKC-dependent and KATP-independent insulin exocytosis. We suggest that chronic CPT inhibition, through the progressive islet accumulation of glibenclamide, may explain the prolonged stimulation of insulin secretion in some diabetic patients even after drug removal that contributes to the sustained hypoglycemia of the sulfonylurea.

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“…Since these channels are responsible for the maintenance of a repolarized (negative) membrane potential in the ␤ cell, addition of sulfonylureas results in membrane depolarization that culminates in Ca -dependent insulin secretion (5). Surprisingly, the majority (90%) of the high-affinity sulfonylurea binding sites in the ␤ cell are intracellular and appear to associate with the insulin-containing secretory granules (6,7), far away from the K ATP channels in the plasma membrane. The role of these intracellular sulfonylurea receptors is not known.…”

mentioning

confidence: 99%

The stimulatory action of tolbutamide on Ca ²⁺ -dependent exocytosis in pancreatic β cells is mediated by a 65-kDa mdr-like P-glycoprotein

Barg

Renström

Berggren

et al. 1999

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

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Intracellular application of the sulfonylurea tolbutamide during whole-cell patch-clamp recordings stimulated exocytosis >5-fold when applied at a cytoplasmic Ca 2؉ concentration of 0.17 M. This effect was not detectable in the complete absence of cytoplasmic Ca 2؉ and when exocytosis was elicited by guanosine 5-O-(3-thiotriphosphate) (GTP␥S). The stimulatory action could be antagonized by the sulfonamide diazoxide, by the Cl ؊ -channel blocker 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS), by intracellular application of the antibody JSB1 [originally raised against a 170-kDa multidrug resistance (mdr) protein], and by tamoxifen (an inhibitor of the mdr-and volume-regulated Cl ؊ channels). Immunocytochemistry and Western blot analyses revealed that JSB1 recognizes a 65-kDa protein in the secretory granules. This protein exhibited no detectable binding of sulfonylureas and is distinct from the 140-kDa sulfonylurea high-affinity sulfonylurea receptors also present in the granules. We conclude that (i) tolbutamide stimulates Ca 2؉ -dependent exocytosis secondary to its binding to a 140-kDa high-affinity sulfonylurea receptor in the secretory granules; and (ii) a granular 65-kDa mdr-like protein mediates the action. The processes thus initiated culminate in the activation of a granular Cl ؊ conductance. We speculate that the activation of granular Cl ؊ f luxes promotes exocytosis (possibly by providing the energy required for membrane fusion) by inducing water uptake and an increased intragranular hydrostatic pressure.Sulfonylureas have been used in the treatment of non-insulindependent diabetes mellitus (NIDDM or type-2 diabetes) for more than 30 years (1), but it is only recently that the molecular mechanisms of their action have been elucidated. It is now clear that the principal effect of the sulfonylureas is to stimulate insulin secretion from the pancreatic ␤ cells (2). Patchclamp experiments have revealed that this stimulation is a consequence of their ability to selectively inhibit ATP-sensitive K ϩ channels (K ATP channels) in the ␤ cell plasma membrane (3). It has recently been demonstrated that the K ATP channel is composed of at least two components: a sulfonylurea receptor (SUR) and an inward rectifier potassium channel protein (KIR6.2; ref.

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Internalization of 3H-glibenclamide in pancreatic islet cells

Cited by 64 publications

References 9 publications

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis

The stimulatory action of tolbutamide on Ca ²⁺ -dependent exocytosis in pancreatic β cells is mediated by a 65-kDa mdr-like P-glycoprotein

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Internalization of 3H-glibenclamide in pancreatic islet cells

Cited by 64 publications

References 9 publications

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis

The stimulatory action of tolbutamide on Ca 2+ -dependent exocytosis in pancreatic β cells is mediated by a 65-kDa mdr-like P-glycoprotein

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The stimulatory action of tolbutamide on Ca ²⁺ -dependent exocytosis in pancreatic β cells is mediated by a 65-kDa mdr-like P-glycoprotein