Effects of Increased Glucokinase Gene Copy Number on Glucose Homeostasis and Hepatic Glucose Metabolism

The relationship between glucokinase (GK) gene copy number and glucose homeostasis was studied in transgenic mice with additional copies of the entire GK gene locus (Niswender, K. D., Postic, C., Jetton, T. L., Bennett, B. D., Piston, D. W., Efrat, S., and Magnuson, M. A. (1997) J. Biol. Chem.272, 2...

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Published in:The Journal of biological chemistry 1997-09, Vol.272 (36), p.22570-22575
Main Authors: Niswender, Kevin D., Shiota, Masakazu, Postic, Catherine, Cherrington, Alan D., Magnuson, Mark A.
Format: Article
Language:English
Subjects:
ANIMAL TRANSGENIQUE
ANIMALES TRANSGENICOS
Animals
ARN MENSAJERO
ARN MESSAGER
AZUCAR EN SANGRE
Blood Glucose - metabolism
BLOOD SUGAR
CARBOHYDRATE METABOLISM
EXPRESION GENICA
EXPRESSION DES GENES
FOIE
GENE
GENE DOSAGE
GENE EXPRESSION
GENES
GLICOGENO
Glucokinase - genetics
GLUCOSA
GLUCOSE
Glucose Tolerance Test
GLYCOGEN
GLYCOGENE
HIGADO
HIPERGLUCEMIA
HIPOGLUCEMIA
HOMEOSTASIE
HOMEOSTASIS
HYPERGLYCAEMIA
HYPERGLYCEMIA
HYPERGLYCEMIC CLAMP
HYPERGLYCEMIE
HYPOGLYCAEMIA
HYPOGLYCEMIA
Hypoglycemia - metabolism
HYPOGLYCEMIE
Islets of Langerhans - metabolism
LIASAS
LIVER
Liver - enzymology
Liver - metabolism
LYASE
LYASES
MESSENGER RNA
METABOLISME DES GLUCIDES
METABOLISMO DE CARBOHIDRATOS
MICE
Mice, Transgenic
Phenotype
PHOSPHOENOLPYRUVATE CARBOXYKINASE
PIRUVATO QUINASA
PYRUVATE KINASE
RATON
SOURIS
SUCRE DU SANG
TRANSFERASAS
TRANSFERASE
TRANSFERASES
TRANSGENIC ANIMALS
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Summary:The relationship between glucokinase (GK) gene copy number and glucose homeostasis was studied in transgenic mice with additional copies of the entire GK gene locus (Niswender, K. D., Postic, C., Jetton, T. L., Bennett, B. D., Piston, D. W., Efrat, S., and Magnuson, M. A. (1997) J. Biol. Chem.272, 22564–22569). The plasma glucose concentration was reduced by 25 ± 3% and 37 ± 4% in mice with one or two extra copies of the gene locus, respectively. The basis for the hypoglycemic phenotype was determined using metabolic tracer techniques in chronically cannulated, conscious mice with one extra GK gene copy. Under basal conditions (6-h fasted) transgenic mice had a lower blood glucose concentration (−12 ± 1%) and a slightly higher glucose turnover rate (+8 ± 3%), resulting in a significantly higher glucose clearance rate (+21 ± 2%). Plasma insulin levels were not different, suggesting that increased glucose clearance was due to augmented hepatic, not islet, GK gene expression. Under hyperglycemic clamp conditions the transgenic mice had glucose turnover and clearance rates similar to the controls, but showed a lower plasma insulin response (−48 ± 5%). Net hepatic glycogen synthesis was markedly elevated (+360%), whereas skeletal muscle glycogen synthesis was decreased (−40%). These results indicate that increased GK gene dosage leads to increased hepatic glucose metabolism and, consequently, a lower plasma glucose concentration. Increased insulin secretion was not observed, even though the transgene is expressed in islets, because hypoglycemia causes a down-regulation in islet GK content (Niswender, K. D., Postic, C., Jetton, T. L., Bennett, B. D., Piston, D. W., Efrat, S., and Magnuson, M. A. (1997) J. Biol. Chem. 272, in press).
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.272.36.22570