Inhibition of glucose-induced insulin release by 3-O-methyl-D-glucose: Enzymatic, metabolic and cationic determinants

The analog of D-glucose, 3-O-methyl-D-glucose, is thought to delay the equi libration of D-glucose concentration across the plasma membrane of pancreat ic islet B-cells, but not to exert any marked inhibitory action upon the la te phase of glucose-stimulated insulin release. In this study, however, 3-O -methyl-D-glucose, when tested in high concentrations (30-80 mM) was found to cause a rapid, sustained and not rapidly reversible inhibition of glucos e-induced insulin release in rat pancreatic islets. In relative terms, the inhibitory action of 3-O-methyl-D-glucose was more marked at low than high concentrations of D-glucose. It could not be attributed to hyperosmolarity and appeared specific for the insulinotropic action of D-glucose, as distin ct from non-glucidic nutrient secretagogues. Although 3-O-methyl-D-glucose and D-glucose failed to exert any reciprocal effect upon the steady-state v alue for the net uptake of these monosaccharides by the islets, the glucose analog inhibited D-[5-H-3]glucose utilization and D-[U-C-14]glucose oxidat ion. This coincided with increased Rb-86 outflow and decreased Ca-45 outflo w from prelabelled islets, as well as decreased Ca-45 net uptake. A prefere ntial effect of 3-O-methyl-D-glucose upon the first phase of glucose-stimul ated insulin release was judged compatible with an altered initial rate of D-glucose entry into islet B-cells. The long-term inhibitory action of the glucose analog upon the metabolic and secretory response to D-glucose, howe ver, may be due, in part at least, to an impaired rate of D-glucose phospho rylation. The phosphorylation of the hexose by beef heart hexokinase and hu man B-cell glucokinase, as well as by parotid and islet homogenates, was in deed inhibited by 3-O-methyl-D-glucose. The relationship between insulin re lease and D-glucose utilization or oxidation in the presence of 3-O-methyl- D-glucose was not different from that otherwise observed at increasing conc entrations of either D-glucose or D-mannoheptulose. It is concluded, theref ore, that 3-O-methyl-D-glucose adversely affects the metabolism and insulin otropic action of D-glucose by a mechanism largely unrelated to changes in the intracellular concentration of the latter hexose.