Glucokinase in pancreatic B-cells and its inhibition by alloxan.
Characterization of glucokinase in pancreatic B-cells from ob/ob mice and from rat liver revealed identical characteristics. A narrow substrate specificity; high Km values for the two substrates, D-glucose and D-mannose, in the range of 10 and 20 mmol/l, respectively; higher Vmax values for D-glucose than for D-mannose; inhibition of glucokinase activities by D-mannoheptulose and by a specific glucokinase antibody. These characteristics distinguish glucokinase in soluble cytoplasmic fractions of pancreatic B-cells and liver from low Km hexokinases. Alloxan is a pancreatic B-cell cytotoxic agent, which has been widely used as a tool for the elucidation of the mechanisms of insulin secretion, because its inhibitory action on insulin secretion has been presumed to be intimately related to the mechanism of glucose-induced insulin secretion. Alloxan inhibited glucokinase but not hexokinase activity in cytoplasmic fractions of pancreatic B-cells and liver. The half maximal inhibitory concentration of alloxan was 5 mumol/l. Glucokinase activity was protected from alloxan toxicity only by D-glucose and D-mannose; the alpha anomer of D-glucose provided significantly greater protection than the beta anomer. The non-metabolizable sugar 3-O-methyl-D-glucose did not provide protection of glucokinase activity against inhibition by alloxan. Thus, inhibition of pancreatic B-cell glucokinase may contribute to the inhibition of glucose-induced insulin secretion by alloxan. These results support the contention that glucokinase regulates the metabolic flux rate through the glycolytic chain in the pancreatic B-cell and thereby generates the signal for glucose-induced insulin secretion.
Lenzen
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Tiedge
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Panten
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D000496:Alloxan / Q000494:pharmacology*; D000818:Animals; D003593:Cytoplasm / Q000201:enzymology; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D007515:Islets of Langerhans / Q000201:enzymology*; D008099:Liver / Q000201:enzymology; D008358:Mannose / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains
D000496:Alloxan; D006593:Hexokinase; D005941:Glucokinase; D005947:Glucose; D008358:Mannose