Insulin synthesis, secretory competence, and glucose utilization are sensitized by transgenic yeast hexokinase.
Glucokinase regulates insulin secretion by controlling the rate of glucose phosphorylation. In this report we utilize islets transgenic for high affinity yeast hexokinase to examine the role of glucose phosphorylation on other beta cell functions. Normal pancreatic islets responded to culture in low glucose by lowering insulin synthetic rates, becoming depleted of insulin and insulin mRNA, losing competence to respond to glucose with increased insulin secretion, and lowering glucokinase levels by one-half. In transgenic islets, increased high affinity hexokinase activity provided significant protection against reductions in all parameters of insulin synthesis and helped preserve the competence of beta cells to secrete insulin. The transgenic hexokinase also increased the rate of glucose utilization. These results demonstrate that glucose phosphorylation and presumably glucokinase mediate these glucose regulated responses. Of the parameters measured, only the change in glucokinase activity did not show an effect of the yeast hexokinase transgene. We also found that yeast hexokinase transgene expression was regulated 10-fold by glucose. This is the first demonstration of glucose inducibility of the insulin promoter in transgenic mice.
Voss-McCowan
M E
ME
Department of Pharmacology and Toxicology, University of North Dakota School of Medicine, Grand Forks 58202.
Xu
B
B
Epstein
P N
PN
D000818:Animals; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006593:Hexokinase / Q000235:genetics* / Q000378:metabolism*; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D012016:Reference Values; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics
D007328:Insulin; D012333:RNA, Messenger; D006593:Hexokinase; D005947:Glucose