Defect in glucokinase translocation in Zucker diabetic fatty rats.
Hepatic glucose fluxes and intracellular movement of glucokinase (GK) in response to increased plasma glucose and insulin were examined in 10-wk-old, 6-h-fasted, conscious Zucker diabetic fatty (ZDF) rats and lean littermates. Under basal conditions, plasma glucose (mmol/l) and glucose turnover rate (GTR; micromol.kg(-1).min(-1)) were slightly higher in ZDF (8.4 +/- 0.3 and 53 +/- 7, respectively) than in lean rats (6.2 +/- 0.2 and 45 +/- 4, respectively), whereas plasma insulin (pmol/l) was higher in ZDF (1,800 +/- 350) than in lean rats (150 +/- 14). The ratio of hepatic uridine 5'-diphosphate-glucose 3H specific activity to plasma glucose 3H specific activity ([3H]UDP-G/[3H]G; %), total hepatic glucose output (micromol.kg(-1).min(-1)), and hepatic glucose cycling (micromol.kg(-1).min(-1)) were higher in ZDF (35 +/- 5, 87 +/- 16, and 33 +/- 10, respectively) compared with lean rats (18 +/- 3, 56 +/- 6, and 11 +/- 2, respectively). [3H]glucose incorporation into glycogen (micromol glucose/g liver) was similar in lean (1.0 +/- 0.7) and ZDF (1.6 +/- 0.8) rats. GK was predominantly located in the nucleus in both rats. With elevated plasma glucose and insulin, GTR (micromol.kg(-1).min(-1)), [3H]UDP-G/[3H]G (%), and [3H]glucose incorporation into glycogen (micromol glucose/g liver) were markedly higher in lean (191 +/- 22, 62 +/- 3, and 5.0 +/- 1.4, respectively) but similar in ZDF rats (100 +/- 6, 37 +/- 3, and 1.4 +/- 0.4, respectively) compared with basal conditions. GK translocation from the nucleus to the cytoplasm occurred in lean but not in ZDF rats. The unresponsiveness of hepatic glucose flux to the rise in plasma glucose and insulin seen in prediabetic ZDF rats was associated with impaired GK translocation.
Fujimoto
Yuka
Y
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA.
Donahue
E Patrick
EP
Shiota
Masakazu
M
D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000032:analysis; D002352:Carrier Proteins / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005934:Glucagon / Q000097:blood; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007425:Intracellular Membranes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity; D051381:Rats; D011924:Rats, Zucker / Q000378:metabolism*; D013851:Thinness / Q000378:metabolism; D014018:Tissue Distribution
D001786:Blood Glucose; D002352:Carrier Proteins; C499484:Gckr protein, rat; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C080906:glucokinase regulatory protein; D019298:Glucose-6-Phosphate; D006003:Glycogen; D005934:Glucagon; D005941:Glucokinase; D005947:Glucose