Characterization of the Uptake of the Methylxanthines Theophylline and Caffeine in Isolated Pancreatic Islets and their Effect on D-Glucose Transport<sup>1</sup>

McDaniel, Michael L.; Weaver, Daniel C.; Roth, C.; Fink, Christoph; Swanson, Jean; Lacy, Paul E.

doi:10.1210/endo-101-6-1701

Cited by 20 publications

(7 citation statements)

References 18 publications

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“…In confirmation of a previous study [lo] we find that the uptake of sugars into HIT-T15 B-cells is slow, in marked contrast to normal rat or mouse islet cells [ 1, 13,14]. Direct measurement of glucose in HIT cells also showed that the intracellular concentration remained lower than extracellular after 30 min incubation with 1 or 10 mM glucose [lo].…”

Section: Discussionsupporting

confidence: 90%

The glucose sensor in HIT cells is the glucose transporter

Ashcroft¹,

Stubbs²

1987

FEBS Letters

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The nature of the rate-limiting step for glucose utilization by the clonal insulin-producing cell line HIT-T 15 has been investigated. In contrast to the situation in islets of Langerhans, we find that the HIT cell glucose metabolism is limited by the rate of entry of glucose into the cell. This is evidenced by the low rate of sugar transport and by the marked reduction in the rate of glucose utilization elicited by inhibitors of the glucose transporter. As judged by competition with glucose, the HIT cell glucose transporter also transports mannose, 2-deoxyglucose and 3-0-methylglucose but not L-glucose or N-acetylglucosamine. The K,,, for glucose of the glucose transporter, measured as the concentration of glucose required for a half-maximal rate of glucose utilization, is 4.3 mM, similar to the concentration reported to give half-maximal insulin release. Glucose-stimulated insulin release from HIT cells is inhibited by phloretin or cytochalasin B but not by mannoheptulose. We conclude that the secretory responses of HIT cells are consistent with the substrate-site hypothesis, but that, in contrast to normal B-cells, the glucose sensor which confers concentration-dependence and specificity to sugar-stimulated insulin release, is the glucose transporter.

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Section: Discussionsupporting

confidence: 90%

The glucose sensor in HIT cells is the glucose transporter

Ashcroft¹,

Stubbs²

1987

FEBS Letters

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“…Theophylline is a strong protector against alloxan in B-cells (Lacy et al, 1975;Grankvist et al, 1979a). This discrepancy may be resolved by the fact that theophylline is an effective substrate for the hexose transport system (McDaniel et al, 1977).…”

Section: Discussionmentioning

confidence: 99%

Alloxan-induced luminol luminescence as a tool for investigating mechanisms of radical-mediated diabetogenicity

Grankvist¹

1981

Biochemical Journal

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Chemiluminescence of luminol in a cell-free system was used to investigate the mechanism of alloxan-dependent free-radical generation. In the presence of alloxan and reduced glutathione (GSH), luminescence was greatly stimulated by FeSO4. Replacing GSH by oxidized glutathione or NAD(P)(H), or replacing FeSO4 by CuSO4, ZNSO4 or FeCl3, did not yield chemiluminescence. The chemiluminescence of a mixture of alloxan. GSH, FeSO4 and luminol was inhibited by catalase, superoxide dismutase, scavengers of hydroxyl radicals (sodium benzoate, n-butanol, D-mannitol, dimethyl sulphoxide) or metal-ion chelators (EDTA, diethylenetriaminepenta-acetic acid, diethyldithiocarbamate. desferroxamine), D-glucose, L-glucose, D-mannose, D-fructose, 3-O-methyl-D-glucose, NAD+, NADH, NADP+ or NADPH, but not by urea or enzymically inactive superoxide dismutase. The results support the hypothesis that the diabetogenic action of alloxan is mediated by hydroxyl radicals generated in an iron-catalysed reaction. Protection against alloxan in vivo depends both on the chemical reactivity of protector with radicals or radical-generating systems and on the stereospecific requirement of some strategic site in the B-cell.

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“…Firstly, phloretin was found to be a potent inhibitor of islet N-acetylglucosamine utilization and of N-acetylglucosamine-stimulated insulin release and biosynthesis [16,23,24,30]. Secondly, caffeine inhibits the oxidation of N-acetylglucosamine by islets [23,24]; the site of this effect is believed to be transport into the cell since it has been found that caffeine impairs islet sugar transport [44]. This action may underlie the paradoxical inhibitory action of methylxanthines on N-acetylglucosaminestimulated release and biosynthesis of insulin [23,24].…”

Section: Islet Metabolism and The Release And Biosynthesis Of Insulinmentioning

confidence: 99%

Glucoreceptor mechanisms and the control of insulin release and biosynthesis

1980

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The models proposed for the means whereby the B-cell recognises glucose and related compounds as signals for insulin release and biosynthesis are discussed. The observed correlations between rates of metabolism and insulin release and biosynthesis are consistent with the substrate-site hypothesis. For glucose itself, the enzymes catalysing the phosphorylation of the sugar provide an explanation for the major characteristics of the islet responses, but for N-acetylglucosamine evidence is presented that the sugar transport system fulfils this discriminatory role. Possible mechanisms whereby sugar metabolism may be linked to changes in Ca2+-handling are considered and evidence is given supporting a role for the cytosolic NADPH/NADP+ ratio and the islet content of phosphoenolpyruvate. The nature of the targets for cyclic AMP and Ca2+ is discussed and some properties of islet cAMP-dependent protein kinase are summarised. Evidence is presented for the presence of calmodulin in islets and the possible involvement of calmodulin in stimulus-secretion coupling. On the basis of these considerations a speculative hypothesis for the mechanisms involved in the B-cell responses to glucose is outlined.

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Characterization of the Uptake of the Methylxanthines Theophylline and Caffeine in Isolated Pancreatic Islets and their Effect on D-Glucose Transport¹

Cited by 20 publications

References 18 publications

The glucose sensor in HIT cells is the glucose transporter

The glucose sensor in HIT cells is the glucose transporter

Alloxan-induced luminol luminescence as a tool for investigating mechanisms of radical-mediated diabetogenicity

Glucoreceptor mechanisms and the control of insulin release and biosynthesis

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Characterization of the Uptake of the Methylxanthines Theophylline and Caffeine in Isolated Pancreatic Islets and their Effect on D-Glucose Transport1

Cited by 20 publications

References 18 publications

The glucose sensor in HIT cells is the glucose transporter

The glucose sensor in HIT cells is the glucose transporter

Alloxan-induced luminol luminescence as a tool for investigating mechanisms of radical-mediated diabetogenicity

Glucoreceptor mechanisms and the control of insulin release and biosynthesis

Contact Info

Product

Resources

About

Characterization of the Uptake of the Methylxanthines Theophylline and Caffeine in Isolated Pancreatic Islets and their Effect on D-Glucose Transport¹