Glibenclamide is exceptional among hypoglycaemic sulphonylureas in accumulating progressively in β-cell-rich pancreatic islets

Hellman, Bo; Sehlin, Janove; Täljedal, Inge‐Bert

doi:10.1530/acta.0.1050385

Cited by 58 publications

(31 citation statements)

References 13 publications

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“…The results illustrated in Figure 1 are in good agreement with those recently reported by Hellman et al [8], indicating that glibenclamide accumulates progressively in islets from ob/ob mice incubated at 37 °C in the presence of 20 I.tmol/1 3H-glibenclamide. The failure of unlabeled glibenclamide to cause a sizeable fall in 3H-glibenclamide uptake is also in good agreement with a prior observation indicating that the islet uptake of 14C-labeled glibenclamide is proportional to the concentration of the drug in the 10 ~tmol/1 to 0.1 mmol/1 range [9].…”

Section: Discussionsupporting

confidence: 92%

Internalization of 3H-glibenclamide in pancreatic islet cells

et al. 1986

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Diabetologia © Springer-Veflag 1986 Summary. As judged by autoradiographic criteria at the optical level, rat islet cells progressively accumulate 3H-glibenclamide over 1 to 30 min incubation at 24 °C. The labeled material associates with all endocrine cells, but is preferentially seen within B cells. The total uptake of 3H-glibenclamide (1.0 Ixmol/1) is little affected by the presence of unlabeled glibenclamide (0.2 mmol/1), but is significantly decreased at 4 °C (p < 0.05). At the electron microscopic level, less than 15% of the autoradiographic grains are located at the B cell plasma membrane and 72-79% of the grains found over the cytoplasm are associated with insulin secretory granules. Such a pattern is observed both after short (1 min) or prolonged (30 min) incubation, and at 4 or 24 °C. It is proposed that the insulinotropic action of glibenclamide is not necessarily attributable to primary events located solely at the cell surface.

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Section: Discussionsupporting

confidence: 92%

Internalization of 3H-glibenclamide in pancreatic islet cells

et al. 1986

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“…Thus, if TPA (the more lipophilic drug) activated PKC faster than glibenclamide (as one would expect), it would trigger insulin exocytosis more rapidly and give rise to a larger amount of insulin being released over 30 min, as was observed in this case. Glibenclamide seems to be exceptional among the sulfonylureas in that it specifically and progressively accumulates in islets and associates with secretory granules and mitochondria, causing long-lasting stimulation of insulin secretion (21). It is conceivable that the inactivation of CPT-1 may explain the K ATP -independent and PKC-dependent insulin secretion by sulfonylurea reported previously (14,35).…”

Section: Discussionmentioning

confidence: 97%

“…2). Interestingly, however, under chronic treatment, glibenclamide progressively and selectively accumulates in islets and is slowly cleared from islets on drug withdrawal (21). Additionally, there are large interindividual variations in the pharmacodynamics and pharmacokinetics of glibenclamide, which are furthermore greatly influenced by genetic polymorphisms of the cytochrome P-450 2C9 system (24).…”

Section: Discussionmentioning

confidence: 99%

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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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“…In contrast, two immunohistochemical studies in rodents have shown that SUR1 is abundantly distributed over the beta cell cytoplasm [15,16]. Moreover, studies using 3 H-labelled glibenclamide (known as glyburide in the USA and Canada) have shown that, unlike other sulfonylureas, glibenclamide is taken up by beta cells [17] and binds to an intracellular protein that is much more abundant (more than tenfold) than in the plasma membrane [18]. These conclusions were extended recently by monitoring the binding of glibenclamide labelled with fluorescent dipyrromethane boron difluoride (BODIPY-FL) to islet cells [16,19], a technique that is, however, complicated by a significant degree of non-specific binding due to the lipophilicity of the probe [20].…”

Section: Introductionmentioning

confidence: 98%

Morphological localisation of sulfonylurea receptor 1 in endocrine cells of human, mouse and rat pancreas

et al. 2007

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Aims/hypothesis Sulfonylurea receptor 1 (SUR1) is the regulatory subunit of ATP-sensitive K channels in beta cells. Morphological methods (immunohistochemistry and sulfonylurea binding) were used to establish the cellular and subcellular location of SUR1 in human and rodent islets. Results In the human, mouse and rat pancreas, all endocrine cells of the islets were immunolabelled with an anti-SUR1 antibody, whereas tissues containing SUR2 were consistently negative, as were those from Sur1 (also known as Abcc8) −/− mice. In beta cells of the three species, the plasma membrane was distinctly stained, but SUR1 was mainly present over the cytoplasm, with an intensity that varied between cells. Electron microscopy showed that SUR1 was immunolocalised in insulin, glucagon and somatostatin granules. In rat beta cells degranulated by in vivo treatment with glibenclamide (known as glyburide in the USA and Canada), the insulin and SUR1 staining intensity was similarly decreased by ∼45%, whereas SUR1 staining was not changed in non-beta cells. In all islet cells, binding of glibenclamide labelled with fluorescent dipyrromethane boron difluoride (BODIPY-FL) was punctate over the cytoplasm, compatible with the labelling of endocrine granules. A faint labelling persisted in Sur1 −/− mice, but it was not different from that obtained with BODIPY-FL alone used as negative control. Conclusions/interpretation Our study immunolocalised SUR1 in alpha, beta and delta cells of human, mouse and rat islets, and for the first time visualised it in the plasma membrane. We also show that SUR1 is abundant in endocrine granules, where its function remains to be established. No specific sulfonylurea-binding sites other than SUR1 are identified in islet cells by the glibenclamide-BODIPY-FL technique.

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Glibenclamide is exceptional among hypoglycaemic sulphonylureas in accumulating progressively in β-cell-rich pancreatic islets

Cited by 58 publications

References 13 publications

Internalization of 3H-glibenclamide in pancreatic islet cells

Internalization of 3H-glibenclamide in pancreatic islet cells

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

Morphological localisation of sulfonylurea receptor 1 in endocrine cells of human, mouse and rat pancreas

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