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  • 1
    ISSN: 1432-1912
    Keywords: Pancreas Perfusion ; Insulin Release ; Cyproheptadine ; Doxepin ; Amitriptyline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Cyproheptadine and the structurally related compounds doxepin and amitriptyline inhibited the insulin release from the perfused rat pancreas. Both early and late insulin secretion induced by a high glucose stimulus (20 mM) were suppressed by cyproheptadine (0.1 and 0.01 mM). Similarly, although less efficiently doxepin (0.1 and 0.01 mM) and amitriptyline (0.1 mM) diminished both phases of secretion. 2 hrs after a single injection of cyproheptadine (20 mg/kg) the rat plasma insulin was reduced to 20% of controls. Simultaneously the blood glucose had increased 2.5 fold. The results suggest that the inhibition of insulin release is a common attribute to tricyclic compounds structurally related to cyproheptadine.
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  • 2
    ISSN: 1432-1912
    Keywords: Monoamine oxidase ; Pancreatic islets ; Exocrine pancreas ; Liver ; Amezinium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Monoamine oxidase (MAO) was characterized in tissue homogenates from pancreatic islets, exocrine pancreas, and liver from rats. Phenylethylamine was preferentially deaminated by pancreatic islet MAO while 5-hydroxytryptamine was preferentially deaminated by MAO from exocrine pancreas, and tyramine was a good substrate for both tissues. All three substrates were well deaminated by liver tissue. Clorgyline, a selective inhibitor of MAO-A, preferentially inhibited deamination of 5-hydroxytryptamine by all three tissue homogenates, while deprenyl, a selective inhibitor of MAO-B, preferentially inhibited deamination of phenylethylamine. In the case of pargyline, a less selective MAO-B inhibitor, the preference in favour of phenylethylamine was less pronounced. According to these results, MAO in pancreatic islets can be classified as predominantly type B enzyme species and MAO in exocrine pancreas as predominantly type A enzyme species while both types of the enzyme are present in the liver. Using the same three MAO substrates and compared with the effects of the selective enzyme inhibitors, clorgyline and deprenyl, tranylcypromine can be classified as a potent nonselective inhibitor of MAO in homogenates of all three tissues investigated with a slight preference in favour of the inhibition of the B-form of the enzyme, while in contrast amezinium can be classified as a weak nonselective inhibitor of MAO with a slight preference in favour of the inhibition of the A-form of the enzyme. All MAO inhibitors tested also inhibited insulin secretion by isolated incubated rat pancreatic islets, however only at IC50 which were two to three decimal powers higher than those necessary for the inhibition of the MAO activity, thus indicating that inhibition of MAO activity and inhibition of insulin secretion are apparently not closely related.
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  • 3
    ISSN: 1432-1912
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
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  • 4
    ISSN: 1432-1912
    Keywords: Glibenclamide ; ATP ; GTP ; Diazoxide ; Pancreatic islet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In microsomes obtained from mouse pancreatic islets, the Mg complex of adenosine 5′-triphosphate (MgATP) increased the dissociation constant (K D) for binding of [3H]glibenclamide by sixfold. In the presence of Mg2+, not only ATP but also adenosine 5′-0-(3-thiotriphosphate) (ATPγS), adenosine 5′-diphosphate (ADP), guanosine 5′-triphosphate (GTP), guanosine 5′-diphosphate (GDP), guanosine 5′-0-(3-thiotriphosphate) (GTPγTS) and guanosine 5′-0-(2-thiodiphosphate) (GDPβ S) inhibited binding of [3H]glibenclamide. These effects were not observed in the absence of Mg2+. Half maximally effective concentrations of the Mg complexes of ATP, ADP, ATPγS and GDP were 11.6, 19.0, 62.3 and 90.1 μmol/l, respectively. The non-hydrolyzable analogues adenosine 5′-(β,γ-imidotriphosphate) (AMP-PNP) and guanosine 5′-(β,γ-imidotriphosphate) (GMP-PNP) did not alter [3H]glibenclamide binding in the presence of Mg2+. MgADP acted much more slowly than MgATP and both MgADP and MgADP did not inhibit [3H]glibenclamide binding when the concentrations of MgATP and MgATP were kept low by the hexokinase reaction. Development of MgATP-induced inhibition of [3H]glibenclamide binding and dissociation of [3H]-glibenclamide binding occurred at similar rates. However, the reversal of MgATP-induced inhibition of [3H]glibenclamide binding was slower than the association of [3H]glibenclamide with its binding site. Exogenous alkaline phosphatase accelerated the reversal of MgATP-induced inhibition of [3H]glibenclamide binding. MgATP enhanced displacement of [3H]glibenclamide binding by diazoxide. The data suggest that sulfonylureas and diazoxide exert their effects by interaction with the same binding site at the sulfonylurea receptor and that protein phosphorylation modulates the affinity of the receptor.
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  • 5
    ISSN: 1432-1912
    Keywords: Insulin secretion ; Mouse pancreatic islets ; d-Glucose ; α-Ketoisocaproic acid ; Sulfonylureas
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Isolated pancreatic islets from mice were perifused with media containing maximally effective concentrations of glibenclamide (0.1–10 μmol/l) or glipizide (1 μmol/l). In these islets an increase of the glucose concentration from 10 mmol/l to 40 mmol/l or addition of d-glyc-eraldehyde (20 mmol/1) caused a temporary decrease in insulin release which was followed by a sustained enhancement of release. α-Ketoisocaproate (3 or 20 mmol/1) did not inhibit insulin release; at high concentration it was an even stronger secretagogue than d-glucose or d-glyceraldehyde. It is concluded that high energy phosphates couple B-cell fuel metabolism and insulin release by acting both on the ATP-dependent K+ channel and on other targets not yet identified.
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  • 6
    ISSN: 1432-1912
    Keywords: ATP-dependent K+ channel ; Pancreatic B-cell ; Tolbutamide ; Diazoxide ; MgADP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The patch-clamp technique was used to examine the tolbutamide-sensitivity of the adenosine 5′-triphosphate (ATP)-dependent K+ channel in mouse pancreatic B-cells. When studied at 37°C in cell-attached membrane patches, this channel had a single-channel conductance of 88 pS and was half-maximally inhibited by 2.2 μmol/l tolbutamide in the presence of 3 mmol/l d-glucose and 10 μmol/l nifedipine. The tolbutamide-induced decrease in the amplitude of the single-channel currents indicated that the membrane potential was sufficiently depolarized for initiation of insulin release by 30 but not by 10 μmol/l of tolbutamide. Using 300 μmol/l diazoxide to open the ATP-dependent K+ channels already closed by 3 mmol/l d-glucose alone, it was demonstrated that initiation of insulin release requires closure of more than 98% of all ATP-dependent K+ channels. In excised inside-out membrane patches, the K+ channel-blocking potency of tolbutamide was maximally enhanced by 0.3 mmol/1 adenosine 5t'-diphosphate (ADP) at the cytoplasmic side. This ADP effect required the presence of Mg2+. Inhibition of K+ channel activity by ATP, ADP (Mg2+-free) or their non-hydrolyzable analogues adenylyl-imidodiphosphate (AMP-PNP) and α, β methylene adenosine 5′-diphosphate (AMP-CP) was not accompanied by enhancement of tolbutamide-sensitivity. The results suggest that cytosolic MgADP controls tolbutamide-sensitivity by interaction with a receptor site not identical with the site mediating channel closure and that this control plays a role in the intact B-cell.
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  • 7
    ISSN: 1432-2013
    Keywords: Superfusion of Tissue ; Islets of Langerhans ; Fluorescence Measurement ; Reduced Pyridine Nucleotides ; Gewebsumströmung ; Langerhanssche Inseln ; Fluorescenzmessung ; Reduzierte Pyridinnucleotide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Es wird eine Methode beschrieben, die an umströmten, mikrodissezierten Gewebsstückchen kontinuierliche Registrierung der Fluorescenz reduzierter Pyridinnucleotide ermöglicht. In einer speziellen Umströmungskammer wird eine kleine Gewebsprobe gegen 25 μ starke Haltefäden gedrückt und so für optische Messungen fixiert. Mittels eines Verteilungsventils kann das durch die Kammer fließende Medium gewechselt werden. Beispiele von Fluorescenzregistrierungen an verschiedenen Geweben werden gezeigt.
    Notes: Summary A method of superfusion of microdissected tissue is described, which allows the continuous recording of the fluorescence of reduced pyridine nucleotides. In a special superfusion chamber a small piece of tissue is pressed gently against holding filaments of 25μ thickness and thus is fixed for optical measurements. By means of a valve the medium flowing through the chamber can be changed. Examples of recordings of fluorescence from different tissues are shown.
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  • 8
    ISSN: 1432-1912
    Keywords: Islets of Langerhans ; Alpha-Ketomonocarboxylic acids ; Insulin release ; NAD(P)H-fluorescence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In perifused isolated pancreatic islets alpha-ketoisocaproic acid (KIC) or alpha-ketocaproic acid (KC) induced a high insulin secretion rate and a steep increase of the fluorescence of reduced pyridine nucleotides [NAD(P)H] which fell again to almost prestimulatory levels 6 min after medium change. Insulin release in response to alpha-ketooctanoic (KO) acid started slowly and was accompanied by a decrease of the NAD(P)H-fluorescence trace. Beta-phenylpyruvate which is known to initiate insulin release also caused a fluorescence decrease. Alpha-ketoisovaleric (KIV) acid or pyruvate had no significant effects upon insulin secretion or NAD(P)H-fluorescence. In contrast to L-leucine, L-norleucine or L-valine did not enhance insulin release or fluorescence of NAD(P)H. KIV, alpha-keto-beta-methylvaleric acid (KMV), KIC and KC raised the production of their corresponding amino acids by islet cells. From these results it is concluded that alpha-ketomonocarboxylic acids as such trigger insulin release by acting upon receptor sites which differ from those occupied by amino acids.
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  • 9
    ISSN: 1432-1912
    Keywords: Bay K 8644 ; Insulin secretion ; Mouse pancreatic islets
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of the dihydropyridine derivative Bay K 8644 upon insulin secretion by perifused isolated mouse pancreatic islets were examined. At a non-stimulatory glucose concentration (5 mmol/l) Bay K 8644 (1 μmol/l) did not stimulate insulin release. However, the same drug concentration enhanced the insulin secretory responses to an intermediate (15 mmol/l) or high (30 mmol/l) glucose concentration by 80 or 90%, respectively. Bay K 8644 was half maximally effective at 0.1 μmol/l and maximally effective at 1 μmol/l. The results are compatible with the view that voltage-dependent calcium channels are essential for stimulus-secretion coupling in pancreatic B-cells.
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  • 10
    ISSN: 1432-1912
    Keywords: Pancreatic B-cell ; Patch-clamp ; ATP-dependent K+ current ; Sulfonylureas ; Diazoxide ; Meglitinide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The influence of the hypoglycemic drugs tolbutamide, meglitinide, glipizide and glibenclamide on ATP-dependent K+ currents of mouse pancreatic B-cells was studied using the whole-cell configuration of the patch-clamp technique. In the absence of albumin, tolbutamide blocked the currents half maximally at 4.1 μmol/l. In the presence of 2 mg/ml albumin half maximal inhibition of the currents was observed at 2.1 μmol/l meglitinide, 6.4 nmol/l glipizide and 4.0 nmol/1 glibenclamide. The hyperglycemic sulfonamide diazoxide opened ATP-dependent K+channels. Half maximally effective concentrations of diazoxide were 20 μmol/l with 0.3 mmol/1 ATPand102 μmol/l with 1 mmol/1 ATP in the recording pipette. Thus, the action of diazoxide was dependent on the presence of ATP in the recording pipette. The free concentrations of the drugs which influenced ATP-dependent K+ currents were comparable with the free plasma concentrations in humans and the free concentrations which affected insulin secretion in vitro. The results support the view that the target for the actions of sulfonylureas and of diazoxide is the ATP-dependent K+ channel of the pancreatic B-cell or a structure closely related to this channel.
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