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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 11 (1975), S. 49-55 
    ISSN: 1432-0428
    Keywords: Rat ; blood glucose ; plasma insulin ; pancreas perfusion ; insulin secretion ; thyroxine ; glucose ; tolbutamide ; pyruvate ; isoprenaline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Thyroxine treatment increases blood glucose and plasma insulin levels in the rat. The hypoglycemic effect of tolbutamide is more pronounced in treated animals. The immediate insulin secretory response of the isolated perfused pancreas to maximal, but not to submaximal, glucose stimuli was increased after thyroxine treatment, especially in the lower dose range. However, as thyroxine treatment reduces insulin release during the prolonged late phase, the total amount of insulin released from the pancreas is reduced. Both the early response to tolbutamide and the subsequent basal secretion were increased after thyroxine treatment. When the pancreas of treated rats was exposed to glucose plus pyruvate the inhibition of the late phase was reversed. Isoprenaline did not overcome the inhibitory effect of thyroxine treatment on the late phase of glucose-induced insulin release. Thyroxine induces a selective inhibition of glucose induced insulin release which is reversed by pyruvate; this indicates that thyroxine interferes with the glycolysis in the beta cell.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Insulin release ; glucagon release ; cyproheptadine ; tolbutamide ; arginine ; theophylline ; calcium ; perfused rat pancreas
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The tricyclic compound cyproheptadine (Periactinol®, Nuran®) inhibited glucose-induced insulin release from the perfused rat pancreas. Tolbutamide-stimulated insulin release was significantly reduced in the presence and completely suppressed in the absence of a substimulatory glucose concentration (5 mM). Arginine produced a slow rise of insulin release, which was completely abolished by cyproheptadine. Furthermore the biphasic glucagon release due to the stimulus was inhibited. Oxidation of 14C-glucose in isolated islets was unaltered in the presence of cyproheptadine, and pyruvate added to the perfusion medium failed to reverse the inhibitory effect on glucose induced insulin release, indicating that impaired glucose metabolism is not responsible for the inhibition. In addition, the inhibition remained unchanged when phentolamine was present, suggesting that the effect is not mediated by inhibitory adrenergic alpha receptors. Theophylline, in contrast, partly overcame the inhibition. When the calcium concentration of the medium was enhanced, the inhibitory effect of cyproheptadine was still visible, although the relative inhibition had become smaller. The results suggest that cyproheptadine blocks insulin release by affecting a fundamental step of the stimulus-secretion coupling common to peptide hormones. A participation of a calcium-antagonizing effect in the inhibition is discussed.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 12 (1976), S. 495-500 
    ISSN: 1432-0428
    Keywords: Rat pancreas perfusion ; insulin secretion ; thyroxine treatment ; D-glucose ; D-glyceraldehyde ; D-mannose ; tolbutamide ; L-glucose ; D-fructose ; dihydroxyacetone ; DL-glyceric acid ; pyruvate ; L-lactate ; propionic acid ; α-ketobutyrate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Thyroxine treatment did not significantly affect the immediate insulin secretory response of the perfused rat pancreas, but it inhibited the late phase of D-glucose-induced insulin secretion. Thyroxine treatment did not inhibit D-glyceraldehyde-, D-mannose-, and tolbutamide-induced insulin release from the perfused pancreas. An increase in the D-glucose concentration of the perfusion medium as well as feeding of the rats did not restore insulin secretion after thyroxine treatment. The inhibition of D-glucose-induced insulin release in response to thyroxine treatment was reversed after addition of either D-glyceraldehyde, dihydroxyacetone, DL-glyceric acid, pyruvate, or α-ketobutyrate to the perfusion medium. Tolbutamide, L-glucose, D-fructose, D-mannose, L-lactate, and propionic acid were not able to overcome the inhibition of D-glucose-induced insulin secretion. Except for α-ketobutyrate all substances which were effective in reversing the inhibition of D-glucose-induced insulin release were glycolytic intermediates. Comparing the glycolytic α-ketoacid pyruvate and the non-glycolytic ketoacid α-ketobutyrate, the only part common to both substances was the ketoacid moiety. It is concluded from these findings that the ketoacid moiety of the α-ketoacids plays an important role in reversing the effect of thyroxine on D-glucose-induced insulin release.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Pancreatic islets ; rats ; obese-hyperglycemic mice ; perifusion ; fluorescence ; reduced pyridine nucleotides ; D-glucose ; D-mannoheptulose ; L-lactate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In perifused pancreatic islets, the fluorescence of reduced pyridine nucleotides (NAD(P)H) was measured continuously. Elevation of glucose concentration in the medium from 0 – 5 mM to 20 mM led to an increase in NAD(P)H-fluorescence beginning 10–20 sec after change of medium. Perifusion with calcium-free media had no influence on this effect. It was, however, partially or completely blocked by 2-deoxy D-glucose, D-glucosamine, or D-mannoheptulose. D-mannose, but not D-fructose and L-lactate, enhanced NAD(P)H-fluorescence from pancreatic islets. Pyruvate caused but a small fluorescence increase. From these observations it is concluded that D-glucose leads to the increase of NAD(P)H-fluorescence by mediation of the phosphoglyceraldehyde dehydrogenase reaction.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0428
    Keywords: Pancreatic islets ; obese-hyperglycemic mice ; perifusion ; insulin release ; reduced pyridine nucleotides ; L-leucine ; α-ketoisocaproic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The insulinotropic effects of L-leucine and α-ketoisocaproic acid have been compared in perifused isolated pancreatic islets. In contrast to α-ketoisocaproic acid (10 mM), L-leucine (10 mM) released less insulin in the presence than in the absence of glucose (5 mM). Changes of islet cell metabolism accompanying insulin release were studied by recording the fluorescence of reduced pyridine nucleotides. The traces of L-leucine-or α-ketoisocaproic acid-induced fluorescence increase differed both in the absence and in the presence of glucose (5 mM). When the medium perif using the islets contained 30 mM L-leucine, α-ketoisocaproic acid (10 mM) still triggered a significant insulin release. These results argue against an indirect action of α-ketoisocaproic acid via transformation to L-leucine. Isocaproic acid (10 mM), L-α-hydroxyisocaproic acid (10 mM) or α-ketoisovaleric acid stimulated no remarkable insulin release, demonstrating that the strong insulinotropic effect of α-ketoisocaproic acid is coupled both to its α-ketogroup and to the length of its carbon chain.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 44 (1966), S. 713-716 
    ISSN: 1432-1440
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary 3,5-dimethylisoxazole depressed ketonaemia in starving rats. It caused a sharp decline of the elevated level ofβ-hydroxybutyric and acetoacetic acid in the blood. The concentration of unesterified fatty acids was less markedly reduced. 3,5-dimethylisoxazole also suppressed the ketonaemia induced by acute insulin deficiency. In fed rats hyperglycaemia, ketonaemia and an increase of unesterified fatty acids in the blood was produced by an infusion of guinea-pig antiinsulin-serum. 3,5-dimethylisoxazole reduced the free fatty acids, and theβ-hydroxybutyric and acetoacetic acid in the blood to control-levels. There was no effect of dimethylisoxazole on the hyperglycaemia. In man ketonaemia caused by starvation is similarily depressed by 3,5-dimethylisoxazole. As the reduction of the free fatty acids in the blood precedes the drop ofβ-hydroxybutyric and acetoacetic acid it is apparent that the primary effect of dimethylisoxazole is to reduce the supply of fatty acids to the liver. The hepatic output of theβ-hydroxybutyric and acetoacetic acids is subsequently diminished. As shown previously, in man 3,5-dimethylisoxazole has no effect on blood sugar.
    Notes: Zusammenfassung An der Ratte hemmt 3,5-Dimethylisoxazol die Hungerketose. Die im Hunger stark erhöhte Konzentration vonβ-Hydroxybuttersäure und Acetessigsäure im Blut wurde stark, die gleichfalls erhöhte Konzentration der unveresterten Fettsäuren vergleichsweise geringer ernidrigt. 3,5-Dimethylisoxazol unterdrückt die durch einen akuten Insulinmangel ausgelöste Ketose. Bei gefütterten Ratten führte die Infusion eines Meerschweinchen-Antiinsulinserums zu einem akuten Insulinmangel mit Hyperglykämie, Anstieg der unveresterten Fettsäuren und Ketonämie. In diesen Versuchen vermochte 3,5-Dimethylisoxazol nicht den Anstieg der Blutzuckerwerte zu beeinflussen. Die starke Zunahme der freien Fettsäuren im Blut wurde durch das Isoxazolderivat verhindert, der Anstieg derβ-Hydroxybuttersäure und Acetessigsäure im Blut blieb aus. Auch am Menschen wird ebenso wie im Tierversuch die Ketonämie im Hunger durch 3,5-Dimethylisoxazol unterdrückt. Die Abnahme der Konzentration freier Fettsäuren im Blut geht hier der Erniedrigung derβ-Hydroxybuttersäure- und Acetessigsäurewerte voraus. Darin zeigt sich, daß die primäre Wirkung von 3,5-Dimethylisoxazol darin besteht, die Lipolyse zu hemmen. Erst anschließend wird die Bildung von Ketonkörpern gehemmt, und die Konzentration vonβ-Hydroxybuttersäure und Acetessigsäure im Blut sinkt ab.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 42 (1964), S. 449-454 
    ISSN: 1432-1440
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary The passage of bromsulphalein (BSP) from the blood into the liver was accelerated by tolbutamide in rabbits. When a constant level of BSP was maintained in the blood by a continuous infusion an injection of tolbutamide immediately lowered the plasma concentration of the dye. Correspondingly the gradient in concentration of BSP across the liver was increased by tolbutamide. Following a single intravenous injection of BSP the disappearance of the dye from the blood was largely accelerated by tolbutamide. This effect of tolbutamide is not caused by an increase in the secretion of BSP into the bile. There was no significant change in the amount of BSP secreted with the bile in the course of a constant infusion of BSP. Following a single intravenous injection the appearance of BSP in the bile was accelerated in animals which had received tolbutamide. The fact that tolbutamide does alleviate the passage of BSP into the liver may fully account for this observation. As tolbutamide did accelerate the disappearance of injected BSP from the blood in humans the sulfonylurea-drug may change the results of the tests of hepatic function where BSP or similar dyes are injected.
    Notes: Zusammenfassung Unter der Wirkung von Tolbutamid nimmt die Leber vermehrt Bromsulphalein aus dem Blute auf. Wenn Bromsulphalein intravenös infundiert wird, senkt Tolbutamid die Farbstoffkonzentration im Plasma. Dabei steigt das arteriovenöse Konzentrationsgefälle durch die Leber an. Wird Bromsulphalein schnell intravenös injiziert, so beschleunigt Tolbutamid den Abfall der Konzentration des injizierten Farbstoffes im Blut. Die Wirkung von Tolbutamid kann nicht damit erklärt werden, daß sich die Ausscheidung von Bromsulphalein mit der Galle erhöht. Bei einer Dauerinfusion von Bromsulphalein verändert Tolbutamid die Ausscheidung mit der Galle nicht. Nach intravenöser Injektion wird Bromsulphalein zwar schneller ausgeschieden, wenn die Tiere Tolbutamid erhalten. Die zeitliche Verschiebung kann jedoch damit erklärt werden, daß Tolbutamid die Konzentration von Bromsulphalein in der Leber erhöht. Durch das erhöhte Angebot von Bromsulphalein wird indirekt die Conjugation und Sekretion des Farbstoffes in die Galle gefördert. Die Auswirkung dieser Befunde für klinische Leberfunktionsproben wird besprochen.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1440
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary As reported earlier the passage of the dye bromsulphalein (BSP) out of the blood and into the liver is accelerated by tolbutamide. The tests of hepatic function which are based on the BSP-clearance of the liver are therefore altered by sulfonylurea drugs. This effect of tolbutamide has been further investigated in vitro. Slices of hepatic tissue were incubated in serum diluted by buffer to which BSP had been added. More BSP was taken up by the tissue when tolbutamide was added to the incubation fluid. A concentration of 5 mg tolbutamide per 100 ml was sufficient to produce this effect. This result does not depend on the functional state of the incubated tissue as tolbutamide did similarily increase the uptake of BSP by dead tissue in the absence of oxygen. Tolbutamide failed, however, to stimulate the uptake of BSP when hepatic tissue was incubated in proteinfree buffer solution. In these experiments BSP was not restrained from entering the tissues by being bound to protein in the incubation fluid. As free BSP is readily taken up by the tissue the amount of dye enterning the liver slices was increased tenfold. The unrestained passage of free BSP into the tissues is not augmented by tolbutamide. These results show that tolbutamide does only act to accelerate the uptake of BSP by liver tissue when the passage of the dye into the tissue is inhibited by a binding in the incubation fluid. Tolbutamide does displace BSP from its binding sites on the plasma proteins and thus liberates BSP which readily diffuses into the tissues. Tolbutamide does increase the hepatic clearance of BSP by interfering with the binding of BSP in the blood, which is an extra hepatic effect.
    Notes: Zusammenfassung Aus früheren Versuchen war bekannt, daß Tolbutamid den Übergang von injiziertem Bromsulphalein aus dem Blut in die Leber beschleunigt. Dadurch wird der Bromsulphalein-Test, eine klinische Leberfunktionsprobe, verändert. Isoliertes Lebergewebe, das in Serum mit einem Zusatz von Bromsulphalein inkubiert wurde, nimm mehr Farbstoff aus dem Medium auf, wenn Tolbutamid zugesetzt wird. Bereits in einer Konzentration von 5 mg/100 ml erhöhte Tolbutamid die Farbstoffaufnahme signifikant. Dieser Effekt ist unabhängig von der Funktionsfähigkeit des inkubierten Gewebes; auch an Gewebsschnitten von abgestorbener Leber, die unter Ausschluß von Sauerstoff inkubiert werden, steigert Tolbutamid die Aufnahme von Bromsulphalein aus dem Inkubationsmedium. Wenn dagegen Lebergewebe in einer eiweißfreien Lösung inkubiert wird, erhöht Tolbutamid die Farbstoffaufnahme nicht. Hier wird Bromsulphalein nicht mehr durch die Bindung an Serumproteine im Inkubationsmedium zurückgehalten. Daher dringt eine zehnfach größere Farbstoffmenge in die Leber ein. Dieser Übergang von freiem Bromsulphalein in die Leber wird durch die Anwesenheit von Tolbutamid nicht beeinflußt. Eine Voraussetzung für die Wirkung von Tolbutamid auf die Farbstoffaufnahme ist, daß im Blut oder Serum Bromsulphalein an Proteine gebunden und dadurch sein Übergang in das Gewebe gehemmt wird. Tolbutamid verdrängt Bromsulphalein aus dieser Eiweißbindung und erhöht damit das Angebot an frei diffusablem Bromsulphalein. Es wirkt also außerhalb der Leber, indem es die Bindung von Bromsulphalein im Blute beeinflußt. Es kann durch diese extrahepatische Wirkung den Ausfall des Bromsulphalein-Testes verfälschen. Im gleichen Sinne wie Tolbutamid waren Carbutamid, Sulfisoxazol, Glykodiazin und Sulfathiazol wirksam. Keine Wirkung hatten Sulfanilsäure, Sulfanilamid und Sulfacetamid.
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 44 (1966), S. 707-713 
    ISSN: 1432-1440
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary The effects of 3,5-dimethylisoxazole and of insulin on blood glucose, plasma unesterified fatty acids (UFA), and plasma glycerol were investigated in rats. 3,5-dimethylisoxazole, being less effective than insulin in producing hypoglycaemia, was more potent in lowering plasma UFA and plasma glycerol. Although blood glucose of eviscerated rats was not affected by 3,5-dimethylisoxazole it was capable to depress plasma UFA and plasma glycerol. Insulin lowered blood glucose and plasma UFA but not plasma glycerol in eviscerated rats. In rats receiving palmitate-1-14C by infusion both, insulin and 3,5-dimethylisoxazole gave rise to an increase in concentration of labelled esterified fatty acids in adipose tissue. The amount of unesterified labelled fatty acids in the tissue was reduced by either treatment. Despite of this similarity a profound difference in the action of 3,5-dimethylisoxazole and insulin on adipose tissue metabolism was found when the incorporation of glucose-U-14C was measured. While 3,5-dimethylisoxazole failed to stimulate the incorporation of glucose into lipids insulin gave rise to a sevenfold increase. Thus insulin stimulates esterification of fatty acids by promoting glucose utilisation. The effect of 3,5-dimethylisoxazole on plasma UFA is apparently not depending on glucose utilisation and is most likely due to an inhibition of lipolysis in adipose tissue. In man 3,5-dimethylisoxazole in a low oral dose of 0,2 mg/kg depressed plasma UFA by 40% within 30 minutes, this low level was sustained for more than 3 hours. Like in the experiments on animals the drop in plasma glycerol was less pronounced. Blood glucose was not effected by 3,5-dimethylisoxazol in man.
    Notes: Zusammenfassung Die Wirkung von 3,5-Dimethylisoxazol und Insulin auf die Blutglucose, die unveresterten Fettsäuren (UFS) und das Glycerin im Plasma wurde an Ratten untersucht. Im Vergleich zum Insulin hat 3,5-Dimethylisoxazol nur eine schwache Blutzuckerwirkung, aber einen starken Effekt auf die UFS und das Glycerin. Am eviscerierten Tier senkt 3,5-Dimethylisoxazol den Blutzucker nicht mehr, wohl aber die UFS und das Glycerin. Insulin wirkt unter diesen Bedingungen noch auf den Blutzucker und die UFS, dagegen nicht mehr auf das Glycerin. Nach Infusion von Palmitinsäure-1-14C erhöhen 3,5-Dimethylisoxazol und Insulin die Konzentration von veresterten markierten Fettsäuren im Fettgewebe und vermindern gleichzeitig die unveresterten markierten Fettsäuren. Die Wirkungen beider Stoffe beruhen aber auf verschiedenen Vorgängen, da der Einbau von Glucose-U-14C in die Lipide des Fettgewebes durch 3,5-Dimethylisoxazol nicht verändert, durch Insulin aber um das Siebenfache gesteigert wird. Es wird daher angenommen, daß Insulin die Veresterung von Fettsäuren anregt, weil es die Glucoseutilisation fördert, während der Fettsäureeffekt vom 3,5-Dimethylisoxazol unabhängig von einer Wirkung auf den Glucosestoffwechsel ist und wahrscheinlich auf einer Lipolysehemmung beruht. Auch am Menschen löst 3,5-Dimethylisoxazol in geringer Dosierung (0,2 mg/kg oral) einen starken Abfall des UFS-Spiegels im Plasma aus, der nach 30 min schon 40% erreicht und länger als 3 Std anhält. Das Plasmaglycerin nimmt ähnlich wie im Tierversuch weniger stark ab, der Blutzucker wird überhaupt nicht beeinflußt.
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  • 10
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Analytical Biochemistry 82 (1977), S. 317-326 
    ISSN: 0003-2697
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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