Inhibition of glucose-induced insulin secretion through inactivation of glucokinase by glyceraldehyde.
D-Glyceraldehyde irreversibly inhibited rat liver glucokinase in a concentration-dependent manner. The inactivation of glucokinase by glyceraldehyde was blocked by the presence of its substrates such as glucose and mannose. Glucokinase was highly sensitive to glyceraldehyde compared with some other glycolytic enzymes (from animal tissues) including hexokinase, glucose-6-phosphate isomerase, 6-phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase. The amino acid analysis of untreated and glyceraldehyde-treated glucokinase suggested that glyceraldehyde-induced inactivation of glucokinase is caused by glycation of Lys residues of the enzyme by the triose. Treatment of pancreatic islets with 6 mM glyceraldehyde for 1 h at 37 degrees C caused both inactivation of glucokinase and inhibition of glucose-induced insulin secretion. Another glucose-phosphorylating enzyme (hexokinase) in pancreatic islets, however, was little affected by glyceraldehyde. In addition, glyceraldehyde did not affect the insulin secretory responses of islets to nonglucose secretagogues such as glyceraldehyde and Leu. When pancreatic islets were cultured with a lower concentration (1 mM) of glyceraldehyde for a longer time (17 h) in the presence of 10 mM glucose to mimic the in vivo conditions, both glucokinase activity and glucose-induced insulin secretion were again decreased. This study demonstrates that glucose-induced insulin secretion is impaired by glyceraldehyde through the inactivation of glucokinase. The implication of this finding in the pathophysiology of type II diabetes is discussed.
Department of Clinical Biochemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
T
T
Murata
I
I
Miwa
Y
Y
Toyoda
J
J
Okuda
D000596:Amino Acids / Q000032:analysis; D000818:Animals; D005260:Female; D005941:Glucokinase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D005947:Glucose / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005985:Glyceraldehyde / Q000494:pharmacology*; D006593:Hexokinase / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D009005:Monosaccharides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013403:Sugar Phosphates / Q000494:pharmacology
D000596:Amino Acids; D007328:Insulin; D009005:Monosaccharides; D013403:Sugar Phosphates; D005985:Glyceraldehyde; D006593:Hexokinase; D005941:Glucokinase; D005947:Glucose