Disruption of one allele of the murine glut 4 gene causes marked resistance to the action of insulin

L. Rossetti, A. E. Stenbit, E. B. Katz, Nir Barzilai, W. Chen, M. Hu, Maureen J. Charron

Research output: Contribution to journalArticle

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Abstract

The insulin-regulated type of glucose transporter, GLUT4, represents more than 90% of the glucose transporter isoforms in skeletal muscle, heart, and adipose cells. We performed insulin (I; 18 mU/kg'triin; plasma I=~600 u.U/ml) clamp studies in 6 conscious chronically catheterized mice heterozygous (+/-) for GLUT4 "knockout" (Nature 377:151, 1995) and in a group of 7 weight/age-matched controls. Glucose kinetics and total body glycolysis (conversion of [3-3H]-glucose to 'H2O) were assessed. Mice were studied at the age of 4-5 months and prior to the onset of overt hyperglycemia. Under basal (fasting) conditions, GLUT4+/- mice presented marked hyperinsulinemia, with modest decreases in the plasma glucose levels (88±8 vs 111 + 11 mg/dl) and in the rates of endogeneous glucose production (18.1±1.9 vs 25.7±3.2 mg/kgmin). During the euglycemic (100 mg/dl) insulin clamp studies, the rate of glucose infusion was markedly decreased in GLUT4+/- mice compared with control mice (17.1+2.8 vs 48.4+3.5; p<0.01). While the ability of insulin to inhibit endogeneous glucose output (EGP) was similar in the two groups (EGP=8.5±1.5 in the GLUT4 +/- vs 13.0+1.6 mg/kgmin in the controls), the rate of glucose uptake was markedly decreased in the GLUT4+/- mice (25.6±3.7 vs 61.3+3.7 mg/kg-min; p<0.01). This decrease in the rate of glucose uptake was reflected in similar declines in the raie of glycolysis (15.8+1.2 vs 40.4+3.1; p<0.01) and glycogen synthesis (10.4+4.0 vs 20.9+3.7 mg/kg-min; p<0.01). These studies demonstrate that the disruption of one allele of the GLUT4 gene causes marked insulin resistance in conscious mice. Thus, modest changes in the abundance of this transporter protein can markedly alter whole body glucose homeostasis.

Original languageEnglish (US)
JournalJournal of Investigative Medicine
Volume44
Issue number3
StatePublished - 1996

Fingerprint

Genes
Alleles
Insulin
Glucose
Facilitative Glucose Transport Proteins
Clamping devices
Glycolysis
Plasmas
Aptitude
Hyperinsulinism
Glycogen
Hyperglycemia
Muscle
Insulin Resistance
Fasting
Protein Isoforms
Skeletal Muscle
Homeostasis
Weights and Measures
Kinetics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Disruption of one allele of the murine glut 4 gene causes marked resistance to the action of insulin. / Rossetti, L.; Stenbit, A. E.; Katz, E. B.; Barzilai, Nir; Chen, W.; Hu, M.; Charron, Maureen J.

In: Journal of Investigative Medicine, Vol. 44, No. 3, 1996.

Research output: Contribution to journalArticle

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abstract = "The insulin-regulated type of glucose transporter, GLUT4, represents more than 90{\%} of the glucose transporter isoforms in skeletal muscle, heart, and adipose cells. We performed insulin (I; 18 mU/kg'triin; plasma I=~600 u.U/ml) clamp studies in 6 conscious chronically catheterized mice heterozygous (+/-) for GLUT4 {"}knockout{"} (Nature 377:151, 1995) and in a group of 7 weight/age-matched controls. Glucose kinetics and total body glycolysis (conversion of [3-3H]-glucose to 'H2O) were assessed. Mice were studied at the age of 4-5 months and prior to the onset of overt hyperglycemia. Under basal (fasting) conditions, GLUT4+/- mice presented marked hyperinsulinemia, with modest decreases in the plasma glucose levels (88±8 vs 111 + 11 mg/dl) and in the rates of endogeneous glucose production (18.1±1.9 vs 25.7±3.2 mg/kgmin). During the euglycemic (100 mg/dl) insulin clamp studies, the rate of glucose infusion was markedly decreased in GLUT4+/- mice compared with control mice (17.1+2.8 vs 48.4+3.5; p<0.01). While the ability of insulin to inhibit endogeneous glucose output (EGP) was similar in the two groups (EGP=8.5±1.5 in the GLUT4 +/- vs 13.0+1.6 mg/kgmin in the controls), the rate of glucose uptake was markedly decreased in the GLUT4+/- mice (25.6±3.7 vs 61.3+3.7 mg/kg-min; p<0.01). This decrease in the rate of glucose uptake was reflected in similar declines in the raie of glycolysis (15.8+1.2 vs 40.4+3.1; p<0.01) and glycogen synthesis (10.4+4.0 vs 20.9+3.7 mg/kg-min; p<0.01). These studies demonstrate that the disruption of one allele of the GLUT4 gene causes marked insulin resistance in conscious mice. Thus, modest changes in the abundance of this transporter protein can markedly alter whole body glucose homeostasis.",
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AU - Rossetti, L.

AU - Stenbit, A. E.

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AU - Chen, W.

AU - Hu, M.

AU - Charron, Maureen J.

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AB - The insulin-regulated type of glucose transporter, GLUT4, represents more than 90% of the glucose transporter isoforms in skeletal muscle, heart, and adipose cells. We performed insulin (I; 18 mU/kg'triin; plasma I=~600 u.U/ml) clamp studies in 6 conscious chronically catheterized mice heterozygous (+/-) for GLUT4 "knockout" (Nature 377:151, 1995) and in a group of 7 weight/age-matched controls. Glucose kinetics and total body glycolysis (conversion of [3-3H]-glucose to 'H2O) were assessed. Mice were studied at the age of 4-5 months and prior to the onset of overt hyperglycemia. Under basal (fasting) conditions, GLUT4+/- mice presented marked hyperinsulinemia, with modest decreases in the plasma glucose levels (88±8 vs 111 + 11 mg/dl) and in the rates of endogeneous glucose production (18.1±1.9 vs 25.7±3.2 mg/kgmin). During the euglycemic (100 mg/dl) insulin clamp studies, the rate of glucose infusion was markedly decreased in GLUT4+/- mice compared with control mice (17.1+2.8 vs 48.4+3.5; p<0.01). While the ability of insulin to inhibit endogeneous glucose output (EGP) was similar in the two groups (EGP=8.5±1.5 in the GLUT4 +/- vs 13.0+1.6 mg/kgmin in the controls), the rate of glucose uptake was markedly decreased in the GLUT4+/- mice (25.6±3.7 vs 61.3+3.7 mg/kg-min; p<0.01). This decrease in the rate of glucose uptake was reflected in similar declines in the raie of glycolysis (15.8+1.2 vs 40.4+3.1; p<0.01) and glycogen synthesis (10.4+4.0 vs 20.9+3.7 mg/kg-min; p<0.01). These studies demonstrate that the disruption of one allele of the GLUT4 gene causes marked insulin resistance in conscious mice. Thus, modest changes in the abundance of this transporter protein can markedly alter whole body glucose homeostasis.

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