Restoration of Hepatic Glucokinase Expression Corrects Hepatic Glucose Flux and Normalizes Plasma Glucose in Zucker Diabetic Fatty Rats
- Tracy P. Torres1,
- ReEtta L. Catlin1,
- Robert Chan1,
- Yuka Fujimoto1,
- Noriyasu Sasaki1,
- Richard L. Printz1,
- Christopher B. Newgard2 and
- Masakazu Shiota1
- 1Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
- 2Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina
- Corresponding author: Masakazu Shiota, masakazu.shiota{at}vanderbilt.edu
Abstract
OBJECTIVE—We examined in 20-week-old Zucker diabetic fatty (ZDF) rats whether restoration of hepatic glucokinase (GK) expression would alter hepatic glucose flux and improve hyperglycemia.
RESEARCH DESIGN AND METHODS—ZDF rats were treated at various doses with an adenovirus that directs the expression of rat liver GK (AdvCMV-GKL) dose dependently, and various metabolic parameters were compared with those of nondiabetic lean littermates (ZCL rats) before and during a hyperglycemic clamp. Viral infection per se did not affect hepatic GK activity, since expression of a catalytically inactive form of GK did not alter endogenous hepatic GK activity.
RESULTS—ZDF rats compared with ZCL rats have lower hepatic GK activity (11.6 ± 1.9 vs. 32.5 ± 3.2 mU/mg protein), marked hyperglycemia (23.9 ± 1.2 vs. 7.4 ± 0.3 mmol/l), higher endogenous glucose production (80 ± 3 vs. 38 ± 3 μmol · kg−1 · min−1), increased glucose-6-phosphatase flux (150 ± 11 vs. 58 ± 8 μmol · kg−1 · min−1), and during a hyperglycemic clamp, a failure to suppress endogenous glucose production (80 ± 7 vs. −7 ± 4 μmol · kg−1 · min−1) and promote glucose incorporation into glycogen (15 ± 5 vs. 43 ± 3 μmol/g liver). Treatment of ZDF rats with different doses of AdvCMV-GKL, which restored hepatic GK activity to one to two times that of ZCL rats, normalized plasma glucose levels and endogenous glucose production. During a hyperglycemic clamp, glucose production was suppressed and glucose incorporation into glycogen was normal.
CONCLUSIONS—Alteration of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux.
Footnotes
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T.P.T., R.L.C., and R.C. contributed equally to this work.
Published ahead of print at http://diabetes.diabetesjournals.org on 24 October 2008.
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See accompanying commentary, p. 18.
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- Received August 19, 2008.
- Accepted October 11, 2008.
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