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Research Article Free access | 10.1172/JCI118876

Overexpression of glutamine:fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance.

L F Hebert Jr, M C Daniels, J Zhou, E D Crook, R L Turner, S T Simmons, J L Neidigh, J S Zhu, A D Baron, and D A McClain

Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Veterans Administration Medical Center, Jackson, Mississippi, USA.

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Published August 15, 1996 - More info

Published in Volume 98, Issue 4 on August 15, 1996
J Clin Invest. 1996;98(4):930–936. https://doi.org/10.1172/JCI118876.
© 1996 The American Society for Clinical Investigation
Published August 15, 1996 - Version history
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Abstract

The hexosamine biosynthetic pathway has been hypothesized to be involved in mediating some of the toxic effects of hyperglycemia. Glutamine:fructose-6-phosphate amidotransferase (GFA), the first and rate limiting enzyme of the hexosamine biosynthetic pathway, was overexpressed in skeletal muscle and adipose tissue of transgenic mice. A 2.4-fold increase of GFA activity in muscle of the transgenic mice led to weight-dependent hyperinsulinemia in random-fed mice. The hyperinsulinemic-euglycemic clamp technique confirmed that transgenic mice develop insulin resistance, with a glucose disposal rate of 68.5 +/- 3.5 compared with 129.4 +/- 9.4 mg/kg per min (P < 0.001) for littermate controls. The decrease in the glucose disposal rate of the transgenic mice is accompanied by decreased protein but not mRNA levels of the insulin-stimulated glucose transporter (GLUT4). These data support the hypothesis that excessive flux through the hexosamine biosynthesis pathway mediates adverse regulatory and metabolic effects of hyperglycemia, specifically insulin resistance of glucose disposal. These mice can serve as a model system to study the mechanism for the regulation of glucose homeostasis by hexosamines.

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