Contrasting modes of action of D-glucose and 3-O-methyl-D-glucose as protectors of the rat pancreatic B-cell against alloxan.

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.