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Diabetes Research and Training Center, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461
Glucokinase (GK) catalyzes the phosphorylation
of glucose in 
-cells and hepatocytes, and mutations in the GK gene
have been implicated in a form of human diabetes. To investigate the
relative role of partial deficiencies in the hepatic vs. pancreatic GK activity, we examined insulin secretion, glucose disposal, and hepatic
glucose production (HGP) in response to hyperglycemia in transgenic
mice 1) with one disrupted GK
allele, which manifest decreased GK activity in both liver and
-cells (GK+/
), and 2) with
decreased GK activity selectively in -cells (RIP-GKRZ). Liver GK
activity was decreased by 35-50% in the GK+/ but not in
the RIP-GKRZ compared with wild type (WT) mice. Hyperglycemic clamp
studies were performed in conscious mice with or without concomitant
pancreatic clamp. In all studies
[3-3H]glucose was
infused to measure the rate of appearance of glucose and HGP during 80 min of euglycemia (Glc ~5 mM) followed by 90 min of hyperglycemia
(Glc ~17 mM). During hyperglycemic clamp studies, steady-state plasma
insulin concentration, rate of glucose infusion, and rate of glucose
disappearance (Rd) were
decreased in both GK+/ and RIP-GKRZ compared with WT mice.
However, whereas the basal HGP (at euglycemia) averaged ~22
mg · kg
1 · min1
in all groups, during hyperglycemia HGP was suppressed by only 48% in
GK+/ compared with ~70 and 65% in the WT and RIP-GKRZ mice,
respectively. During the pancreatic clamp studies, the ability of
hyperglycemia per se to increase
Rd was similar in all groups. However, hyperglycemia inhibited HGP by only 12% in GK+/, vs. 42 and 45%, respectively, in the WT and RIP-GKRZ mice. We conclude that, although impaired glucose-induced insulin secretion is common to
both models of decreased pancreatic GK activity, the marked impairment
in the ability of hyperglycemia to inhibit HGP is due to the specific
decrease in hepatic GK activity.
transgenic mice; glucose cycling; gluconeogenesis; glycogen; maturity-onset diabetes of the young
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