Defect in glucokinase translocation in Zucker diabetic fatty rats

Abstract

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; μmol·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-glucose3H specific activity to plasma glucose3H specific activity ([3H]UDP-G/[3H]G; %), total hepatic glucose output (μmol·kg−1·min−1), and hepatic glucose cycling (μmol·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 (μmol 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 (μmol·kg−1·min−1), [3H]UDP-G/[3H]G (%), and [3H]glucose incorporation into glycogen (μmol 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.