Inhibition of Glucose and Tolbutamide-Induced Insulin Release by Iodoacetate and Antimycin A1

Georg, Ralph H.; Sussman, Karl E.; Leitner, J. Wayne; Kirsch, Wolff M.

doi:10.1210/endo-89-1-169

Cited by 27 publications

(22 citation statements)

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“…Thus, it would appear that at least two sulfonylurea drugs, when administered in amounts proportional to those used in human therapy, tended to suppress three parameters of B cell function (insulin release, insulin synthesis, glucose metabolism) in one or the other of three animal species. This conclusion stands in sharp contrast ~dth that of other investigators [1,5,6,13,37,39] who found evidence of islet hyperfunetion after prolonged treatment with sulfonylureas. Differences in animal species, in the intensity and duration of therapy and the use of normal instead of alloxan diabetic animals are possible, albeit unsatisfactory, explanations for this contrast.…”

Section: Discussioncontrasting

confidence: 78%

“…In support of this conclusion, the foliowing evidence may be cited: carbutamide and glibenclamide lower the ATP [46] and the glucose-6-phosphate content of isolated islets [46,47], even as glibenclamide and tolbutamide increase their oxygen consumption and laetate production [33,48]. Thus, although there is some exddenee to the contrary [37,49], the sulfonylureas may uncouple oxidative phosphorylation in the islets, as they appear to do in liver, diaphragm and adipose tissue [50,51]. In so doing, these drugs inhibit the energy producing reactions required for the synthesis of insulin.…”

Section: Discussionmentioning

confidence: 96%

“…In addition, we have found that following prolonged treatment with sulfonylureas the pancreas, when incubated in a glucose containing medium, produced an insulin of similar or significantly lower specific activity than the pancreas of control animals. Abundant direct [32--35] and indirect [36,37] evidence demonstrates that pancreatic islets or pancreatic slices metabolize glucose in vitro. Under the conditions of our experiments, the production of t4C02 from labelled glucose by the islets of animals treated with tolbutamide was significantly depressed, although it was not affected by treatment with insulin.…”

Section: Discussionmentioning

confidence: 99%

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

Dunbar

Foà

1974

Diabetologia

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Summary. Tolbutamide and glibenelamide (glyburide) were administered to normal hamsters, mice or rats in daily doses proportional to their body weight and equivalent to those used in human therapy. The animals were sacrificed after 6 to 8 weeks of treatment. Pieces of pancreas or isolated pancreatic islets were incubated or perifused in a medium containing glucose or tolbutamide, with or without leueine-114C or glucose-U-14C. The results indicate that the B cells of sulfonylurea treated animals synthesized and released less insulin and oxidized less glucose than those of insulin or saline treated controls. Accordingly, at least in the glibenelamide treated animals, the tolerance for glucose and the insulinogenie response to a glucose load in vivo were suppressed. Although insular function tended to return.to normal after treatment was discontinued, the results reported in this paper do not support the generally aeeepted view that the lasting therapeutic effectiveness of the sulfonylureas is due to a beta-cytotrophie action.

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Section: Discussioncontrasting

confidence: 78%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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

Dunbar

Foà

1974

Diabetologia

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“…Given that this is an energy-dependent process (21), it is not surprising that metabolic inhibitors dramatically reduce insulin release (22)(23)(24)(25)(26)(27). However, such inhibitors have more profound effects on the ␤-cell, because the cell's recognition of glucose as a secretory stimulus also depends on metabolism of the glucose (28).…”

Section: Discussionmentioning

confidence: 99%

Glucose Metabolism and Pulsatile Insulin Release From Isolated Islets

Westerlund

Bergsten²

2001

Diabetes

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T he circulating insulin concentration displays regular oscillations in normal human subjects (1). Disturbances of these oscillations are an early sign in the development of type 2 diabetes (2,3). Such alterations may lead to insulin resistance and glucose intolerance by downregulation of insulin receptors (4). The plasma insulin oscillations have been attributed to the pulsatile release of the hormone from the pancreas (5), a process that requires coordinated secretion from the pancreatic islets (6).When the ambient glucose concentration is raised, ␤-cell metabolism is stimulated (7). The resulting increase in the ATP/ADP ratio decreases the permeability of the ATP-sensitive K ϩ (K ATP ) channels and depolarizes the cell (8). Subsequent influx of Ca 2ϩ through voltage-dependent channels triggers the exocytosis of insulin granules (9). ATP produced by metabolism also plays an important role in providing energy for secretion by recruitment and priming of insulin granules for exocytosis (10). Impaired glucose metabolism in pancreatic ␤-cells has been implicated in the development of the disturbed plasma insulin pattern seen in type 2 diabetes (11). Support for this idea has been obtained from altered plasma insulin patterns in patients with mutations in genes coding for glycolytic enzymes, such as phosphofructokinase and glucokinase and mitochondrial tRNA (12)(13)(14)(15)(16)(17).In the present study, we attempted to determine the importance of glycolytic and mitochondrial metabolism for pulsatile insulin release by measuring insulin secretion and [Ca 2ϩ ] i from individual pancreatic islets exposed to metabolic inhibitors at basal and stimulatory glucose concentrations. RESEARCH DESIGN AND METHODS Materials.Reagents of analytical grade and deionized water were used. Collagenase, HEPES, and bovine serum albumin (fraction V) were obtained from Boehringer Mannheim (Mannheim, Germany). Antimycin A, iodoacetamide (IAA), 2,4-dinitrophenol (DNP), tetramethylbenzidine, and insulinperoxidase were obtained from Sigma (St. Louis, MO). The rat insulin standard was obtained from Novo Nordisk (Bagsvaerd, Denmark). IgGcertified microtiter plates were purchased from Nunc (Roskilde, Denmark). The insulin antibodies were raised in guinea pigs. Preparation and culture of islets. Pancreatic islets were collagenaseisolated from ob/ob mice taken from a local colony (18). For the insulin experiments, freshly isolated islets were perifused in a medium supplemented with 1 mg/ml albumin and containing (in mmol/l) 125 NaCl, 5.9 KCl, 1.2 MgCl 2 , 1.3 CaCl 2 , and 25 HEPES, titrated to pH 7.4 with NaOH. For the [Ca 2ϩ ] i experiments, the islets were cultured overnight in the presence of 5.5 mmol/l glucose in RPMI 1640 supplemented with 10% fetal calf serum, and the Ca 2ϩ concentration of the perifusion medium was 2.6 mmol/l. Measurements of insulin release. The kinetics of insulin release were studied essentially as described previously (6). A single islet was placed in a temperature-controlled (37°C) 10-l chamber and perifused with med...

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“…The thiol reagent, iodoacetate, is a potent inhibitor of glycolysis in many tissues (Webb, 1966), including pancreatic islets (Hellerstr6m, Westman, Marsden & Turner, 1970;Hellman, Sehlin & T&ijedal, 1971 a) which show a corresponding reduction in insulin release (Georg, Sussman, Leitner & Kirsch, 1971;Kanazawat Orci & Lambert, 1971 (Matthews & Sakamoto, 1975 a) remains functional. In some ISLET CELL INHIBITORS experiments the islet cells were exposed simultaneously to iodoacetate, 5 mm and either D-glucose, 28 mm or tolbutamide, 0-7 mM; both stimulants induced depolarization and electrical activity but whereas the glucose-induced electrical activity appeared only transiently and ceased abruptly within 2 or 3 min, tolbutamide-induced activity continued for 30-40 min before block developed and the cells did not repolarize (cf.…”

Section: Effects Of Iodoacetatementioning

confidence: 99%

Pancreatic islet cells: effects of monosaccharides, glycolytic intermediates and metabolic inhibitors on membrane potential and electrical activity.

Dean¹,

Matthews²,

Sakamoto³

1975

The Journal of Physiology

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SUMMARY1. The effects of monosaccharides, glycolytic intermediates, metabolic inhibitors and anoxia, have been studied on the membrane electrical activity of mouse pancreatic islet cells in vitro using a single intracellular micro-electrode for both voltage recording and current injection. 4. Electrical activity induced by D-glucose 28 mm, was progressively inhibited by phloridzin, 10 mm, if the cells were exposed to D-glucose and inhibitor simultaneously, and abolished on pretreatment with inhibitor for 30-60 min. Phloridzin also caused depolarization of the islet cells which was independent of extracellular glucose.5. Anoxia completely blocked the electrical activity induced by glucose but not that evoked by D-glyceraldehyde, L-leucine, tolbutamide or glibenclamide.6. Jodoacetic acid, 5 mm, rapidly blocked glucose-induced electrical activity whilst that elicited by tolbutamide was relatively resistant to inhibition. 7. The nature and possible location of the glucoreceptor in pancreatic

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Inhibition of Glucose and Tolbutamide-Induced Insulin Release by Iodoacetate and Antimycin A1

Cited by 27 publications

References 0 publications

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

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

Glucose Metabolism and Pulsatile Insulin Release From Isolated Islets

Pancreatic islet cells: effects of monosaccharides, glycolytic intermediates and metabolic inhibitors on membrane potential and electrical activity.

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