TY - JOUR
T1 - Abnormal regulation of HGP by hyperglycemia in mice with a disrupted glucokinase allele
AU - Rossetti, Luciano
AU - Chen, Wei
AU - Hu, Meizhu
AU - Hawkins, Meredith
AU - Barzilai, Nir
AU - Efrat, Shimon
PY - 1997
Y1 - 1997
N2 - Glucokinase (GK) catalyzes the phosphorylation of glucose in β-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 β-cells (GK+/-), and 2) with decreased GK activity selectively in β-cells (RIP-GKRZ). Liver GK activity was decreased by 35-59% 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 (R(d)) were decreased in both GK+/- and RIP-GKRZ compared with WT mice. However, whereas the basal HGP (at euglycemia) averaged ~22 mg·kg-1·min-1 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 R(d) 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.
AB - Glucokinase (GK) catalyzes the phosphorylation of glucose in β-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 β-cells (GK+/-), and 2) with decreased GK activity selectively in β-cells (RIP-GKRZ). Liver GK activity was decreased by 35-59% 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 (R(d)) were decreased in both GK+/- and RIP-GKRZ compared with WT mice. However, whereas the basal HGP (at euglycemia) averaged ~22 mg·kg-1·min-1 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 R(d) 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.
KW - Gluconeogenesis
KW - Glucose cycling
KW - Glycogen
KW - Maturity-onset diabetes of the young
KW - Transgenic mice
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U2 - 10.1152/ajpendo.1997.273.4.e743
DO - 10.1152/ajpendo.1997.273.4.e743
M3 - Article
C2 - 9357804
AN - SCOPUS:0030666933
SN - 0193-1849
VL - 273
SP - E743-E750
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 4 36-4
ER -