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Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats.

Publication ,  Journal Article
Trinh, KY; O'Doherty, RM; Anderson, P; Lange, AJ; Newgard, CB
Published in: J Biol Chem
November 20, 1998

The terminal step in hepatic gluconeogenesis is catalyzed by glucose-6-phosphatase, an enzyme activity residing in the endoplasmic reticulum and consisting of a catalytic subunit (glucose-6-phosphatase (G6Pase)) and putative accessory transport proteins. We show that Zucker diabetic fatty rats (fa/fa), which are known to exhibit impaired suppression of hepatic glucose output, have 2.4-fold more glucose-6-phosphatase activity in liver than lean controls. To define the potential contribution of increased hepatic G6Pase to development of diabetes, we infused recombinant adenoviruses containing the G6Pase cDNA (AdCMV-G6Pase) or the beta-galactosidase gene into normal rats. Animals were studied by one of three protocols as follows: protocol 1, fed ad libitum for 7 days; protocol 2, fed ad libitum for 5 days, fasted overnight, and subjected to an oral glucose tolerance test; protocol 3, fed ad libitum for 4 days, fasted for 48 h, subjected to oral glucose tolerance test, and then allowed to refeed overnight. Hepatic glucose-6-phosphatase enzymatic activity was increased by 1.6-3-fold in microsomes isolated from AdCMV-G6Pase-treated animals in all three protocols, and the resultant metabolic profile was similar in each case. AdCMV-G6Pase-treated animals exhibited several of the abnormalities associated with early stage non-insulin-dependent diabetes mellitus, including glucose intolerance, hyperinsulinemia, decreased hepatic glycogen content, and increased peripheral (muscle) triglyceride stores. These animals also exhibited significant decreases in circulating free fatty acids and triglycerides, changes not normally associated with the disease. Our studies show that overexpression of G6Pase in liver is sufficient to perturb whole animal glucose and lipid homeostasis, possibly contributing to the development of metabolic abnormalities associated with diabetes.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 20, 1998

Volume

273

Issue

47

Start / End Page

31615 / 31620

Location

United States

Related Subject Headings

  • Triglycerides
  • Recombinant Proteins
  • Rats, Zucker
  • Rats, Wistar
  • Rats
  • Obesity
  • Muscles
  • Microsomes, Liver
  • Male
  • Liver
 

Citation

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Trinh, K. Y., O’Doherty, R. M., Anderson, P., Lange, A. J., & Newgard, C. B. (1998). Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats. J Biol Chem, 273(47), 31615–31620. https://doi.org/10.1074/jbc.273.47.31615
Trinh, K. Y., R. M. O’Doherty, P. Anderson, A. J. Lange, and C. B. Newgard. “Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats.J Biol Chem 273, no. 47 (November 20, 1998): 31615–20. https://doi.org/10.1074/jbc.273.47.31615.
Trinh KY, O’Doherty RM, Anderson P, Lange AJ, Newgard CB. Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats. J Biol Chem. 1998 Nov 20;273(47):31615–20.
Trinh, K. Y., et al. “Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats.J Biol Chem, vol. 273, no. 47, Nov. 1998, pp. 31615–20. Pubmed, doi:10.1074/jbc.273.47.31615.
Trinh KY, O’Doherty RM, Anderson P, Lange AJ, Newgard CB. Perturbation of fuel homeostasis caused by overexpression of the glucose-6-phosphatase catalytic subunit in liver of normal rats. J Biol Chem. 1998 Nov 20;273(47):31615–31620.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

November 20, 1998

Volume

273

Issue

47

Start / End Page

31615 / 31620

Location

United States

Related Subject Headings

  • Triglycerides
  • Recombinant Proteins
  • Rats, Zucker
  • Rats, Wistar
  • Rats
  • Obesity
  • Muscles
  • Microsomes, Liver
  • Male
  • Liver