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Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia.

Publication ,  Journal Article
O'Doherty, RM; Lehman, DL; Télémaque-Potts, S; Newgard, CB
Published in: Diabetes
October 1999

The balance between hepatic glucose uptake and production is perturbed in both major forms of diabetes. It has been suggested that pharmacologic or genetic methods for enhancing glucokinase (GK) enzymatic activity in liver might be a means of increasing glucose disposal and lowering blood glucose in diabetic patients. To better evaluate this possibility, we used a recombinant adenovirus containing the cDNA encoding GK (AdCMV-GKL) to achieve overexpression of the enzyme at different levels in liver of normal rats. In a first set of experiments, in rats fasted for 18 h, AdCMV-GKL infusion caused a 211% increase in hepatic GK activity relative to animals infused with a control virus (AdCMV-betaGAL). AdCMV-GKL-treated fasted rats exhibited no significant changes in circulating glucose, free fatty acids (FFAs), lactate, beta-hydroxybutyrate, or insulin levels relative to controls, whereas triglyceride (TG) levels were slightly increased (53%). In a second set of studies, in rats fed ad libitum, GK was overexpressed in liver by 3- and 6.4-fold. Animals with the lower degree of GK overexpression exhibited no significant changes in circulating glucose, FFAs, insulin, TG, or lactate levels relative to controls that received a virus encoding a catalytically inactive mutant GK (AdCMV-GK203), but did show a modest increase in lactate (58%) relative to AdCMV-betaGAL-infused controls. In contrast, the higher level of GK overexpression caused a 38% decrease in blood glucose levels and a 67% decrease in circulating insulin levels relative to AdCMV-GK203-infused animals. The decline in glucose levels was accompanied by a 190% increase in circulating TG and a 310% increase in circulating FFAs; total plasma cholesterol was unaffected. Finally, fasted animals treated with AdCMV-GKL had 5.4 times as much liver glycogen as AdCMV-betaGAL-treated controls; no significant increases in liver glycogen were observed at either level of GK overexpression in ad libitum-fed rats relative to fed controls. In sum, levels of hepatic GK overexpression associated with a decline in blood glucose are accompanied by equally dramatic increases in FFAs and TG, raising concerns about manipulation of liver GK activity as a viable strategy for treatment of diabetes.

Duke Scholars

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Published In

Diabetes

DOI

ISSN

0012-1797

Publication Date

October 1999

Volume

48

Issue

10

Start / End Page

2022 / 2027

Location

United States

Related Subject Headings

  • Rats
  • Liver Glycogen
  • Liver
  • Lactic Acid
  • Hyperlipidemias
  • Glucokinase
  • Fatty Acids, Nonesterified
  • Fasting
  • Endocrinology & Metabolism
  • DNA, Recombinant
 

Citation

APA
Chicago
ICMJE
MLA
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O’Doherty, R. M., Lehman, D. L., Télémaque-Potts, S., & Newgard, C. B. (1999). Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia. Diabetes, 48(10), 2022–2027. https://doi.org/10.2337/diabetes.48.10.2022
O’Doherty, R. M., D. L. Lehman, S. Télémaque-Potts, and C. B. Newgard. “Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia.Diabetes 48, no. 10 (October 1999): 2022–27. https://doi.org/10.2337/diabetes.48.10.2022.
O’Doherty RM, Lehman DL, Télémaque-Potts S, Newgard CB. Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia. Diabetes. 1999 Oct;48(10):2022–7.
O’Doherty, R. M., et al. “Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia.Diabetes, vol. 48, no. 10, Oct. 1999, pp. 2022–27. Pubmed, doi:10.2337/diabetes.48.10.2022.
O’Doherty RM, Lehman DL, Télémaque-Potts S, Newgard CB. Metabolic impact of glucokinase overexpression in liver: lowering of blood glucose in fed rats is accompanied by hyperlipidemia. Diabetes. 1999 Oct;48(10):2022–2027.

Published In

Diabetes

DOI

ISSN

0012-1797

Publication Date

October 1999

Volume

48

Issue

10

Start / End Page

2022 / 2027

Location

United States

Related Subject Headings

  • Rats
  • Liver Glycogen
  • Liver
  • Lactic Acid
  • Hyperlipidemias
  • Glucokinase
  • Fatty Acids, Nonesterified
  • Fasting
  • Endocrinology & Metabolism
  • DNA, Recombinant