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(1) Alkyl sugar inhibition of d-allose uptake into adipocytes has been used to explore the spatial requirements of the external sugar transport site in insulin-treated cells. α-methyl and β-methyl glucosides show low affinity indicating very little space around C-1. The high affinity of d-glucosamine (Ki = 9.05 ± 0.66 mM) is lost by N-acetylation. N-Acetyl-d-glucosamine shows no detectable affinity, indicating that a bulky group at C-2 is not accepted. Similarly 2,3-di-O-methyl-d-glucose (Ki = 42.1 ± 7.5 mM) has lower affinity than 3-O-methyl-d-glucose (Ki = 5.14 ± 0.32 mM) indicating very little space around C-2 but much more around C-3. A reduction in affinity does occur if a propyl group is introduced into the C-3 position. The Ki for 3-O-propyl-d-glucose is 11.26 ± 2.12 mM. 6-O-Methyl-d-galactose (Ki = 87.2 ± 17.9 mM) and 6-O-propyl-d-glucose (Ki = 78.07 ± 12.6 mM) show low affinity compared with d-galactose and d-glucose, indicating steric constraints around C-6. High affinity is restored in 6-O-pentyl-d-galactose (Ki = 4.66 ± 0.23 mM) possibly indicating a hydrophobic binding site around C-6). (2) In insulin treated cells 4,6-O-ethylidene-d-glucose (Ki = 6.11 ± 0.5 mM) and maltose (Ki = 23.5 ± 2.1 mM) are well accommodated by the site but trehalose shows no detectable inhibition. These results indicate that the site requires a specific orientation of the sugar as it approaches the transporter from the external solution. C-1 faces the inside while C-4 faces the external solution. (3) To determine the spatial and hydrogen bonding requirements for basal cells 40 μM 3-O-methyl-d-glucose was used as the substrate. Poor hydrogen bonding analogues and analogues with sterically hindering alkyl groups showed similar Ki values to those determined for insulin-treated cells. These results indicate that insulin does not change the specificity of the adipocyte transport system.  相似文献   

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Both d-glucose and its nonmetabolized analog 3-O-methyl-d-glucose are known to protect the pancreatic B-cell against the toxic action of alloxan, as if the protective action of hexoses were to involve a membrane-associated glucoreceptor site. In the present study, the protective actions of the two hexoses were found to differ from one another in several respects. Using the process of glucose-stimulated insulin release by rat pancreatic islets as an index of alloxan cytotoxicity, we observed that the protective action of d-glucose was suppressed by d-mannoheptulose and menadione, impaired by NH4Cl, and little affected by aminooxyacetate. These findings and the fact that d-glucose failed to decrease [2-14C]alloxan uptake by the islets suggest that the protective action of d-glucose depends on an increase in the generation rate of reducing equivalents (NADH and NADPH). The latter view is supported by the observation that the protective action of a noncarbohydrate nutrient, 2-ketoisocaproate, was also abolished by menadione. Incidentally, the protective action of 2-ketoisocaproate was apparently a mitochondrial phenomenon, it not being suppressed by aminooxyacetate. In contrast to that of glucose, the protective action of 3-O-methyl-d-glucose was unaffected by d-mannoheptulose, failed to be totally suppressed by menadione, and coincided with a decreased uptake of [2-14C]-alloxan by the islets. It is concluded that the protective action of d-glucose in linked to the metabolism of the sugar in islet cells, whereas that of 3-O-methyl-d-glucose results from inhibition of alloxan uptake. This conclusion reinforces our opinion that the presence in the B-cell of an alleged stereospecific membrane glucoreceptor represents a mythical concept.  相似文献   

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