Participation of glucokinase inactivation in inhibition of glucose-induced insulin secretion by 2-cyclohexen-1-one.
We assessed our speculation that 2-cyclohexen-1-one (CHX) impairs glucose-induced insulin secretion through inactivation of glucokinase. Treatment of pancreatic islets with CHX at concentrations (0-5 mM) that caused a dose-dependent inactivation of glucokinase activity similarly inhibited glucose-induced insulin secretion. Another glucose-phosphorylating enzyme (hexokinase) in pancreatic islets was little affected by CHX. CHX-induced inactivation of glucokinase was blocked by the presence of its substrates (glucose and mannose) and an inhibitor (N-acetylglucosamine), all of which also protected against the inhibitory effect of the drug on glucose-induced insulin secretion. CHX also impaired insulin secretion induced by D-glyceraldehyde and dimethyl succinate, which are believed to stimulate the release of the hormone by being directly oxidized by glyceraldehyde-3-phosphate dehydrogenase, by entering the midstream of the glycolytic pathway as glyceraldehyde 3-phosphate, or by entering the tricarboxylic acid cycle in mitochondria after intracellular hydrolysis. The inhibitory effect of CHX on glucose-induced insulin secretion, however, was far more marked than that on insulin secretion evoked by D-glyceraldehyde and dimethyl succinate at any CHX concentrations used. Our study revealed that the inhibitory action of CHX on glucose-induced insulin secretion is exerted mainly, but not solely, through inactivation of glucokinase. This conclusion supports the view that glucokinase is a key enzyme in the recognition of glucose as an insulin secretagogue in pancreatic islets.
Department of Clinical Biochemistry, Faculty of Pharmacy, Meijo University, Japan.
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Miwa
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Murata
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Mitsuyama
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Okuda
D000818:Animals; D003512:Cyclohexanones / Q000494:pharmacology*; D005941:Glucokinase / Q000037:antagonists & inhibitors*; D006593:Hexokinase / Q000378:metabolism; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D009005:Monosaccharides / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D003512:Cyclohexanones; D009005:Monosaccharides; C028215:2-cyclohexen-1-one; D006593:Hexokinase; D005941:Glucokinase