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Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in mouse liver lowers blood glucose by suppressing hepatic glucose production
Chaodong Wu, … , Christopher B. Newgard, Alex J. Lange
Chaodong Wu, … , Christopher B. Newgard, Alex J. Lange
Published January 1, 2001
Citation Information: J Clin Invest. 2001;107(1):91-98. https://doi.org/10.1172/JCI11103.
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Article

Overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in mouse liver lowers blood glucose by suppressing hepatic glucose production

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Abstract

Hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is an important regulatory enzyme of glucose metabolism. By controlling the level of fructose-2,6-bisphosphate, an allosteric activator of the glycolytic enzyme 6-phosphofructo-1-kinase and an inhibitor of the gluconeogenic enzyme fructose-1,6-bisphosphatase, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase regulates hepatic glucose output. We studied the effects of adenovirus-mediated overexpression of this enzyme on hepatic glucose metabolism in normal or diabetic mice. These animals were treated with virus encoding either wild-type or bisphosphatase activity–deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Seven days after virus injection, hepatic fructose-2,6-bisphosphate levels increased significantly in both normal and diabetic mice, with larger increases observed in animals with overexpression of the mutant enzyme. Blood glucose levels in normal mice overexpressing either enzyme were lowered, accompanied by increased plasma lactate, triglycerides, and FFAs. Blood glucose levels were markedly reduced in diabetic mice overexpressing the wild-type enzyme, and still more so in mice overexpressing the mutant form of the enzyme. The lower blood glucose levels in diabetic mice were accompanied by partially normalized plasma triglycerides and FFAs, increased plasma lactate, and increased liver glycogen levels, relative to diabetic mice treated with a control adenovirus. Our findings underscore the critical role played by hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in control of fuel homeostasis and suggest that this enzyme may be considered as a therapeutic target in diabetes.

Authors

Chaodong Wu, David A. Okar, Christopher B. Newgard, Alex J. Lange

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Figure 1

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Protocols for treatment of normal mice and STZ-induced diabetic mice wit...
Protocols for treatment of normal mice and STZ-induced diabetic mice with adenovirus. Protocol 1 was used for normal mice treated with adenovirus. Protocol 1a: Time course of overexpression of double mutant 6PF-2-K/F-2,6-P2ase in normal mice. Immunosuppressant injection (IM) started at day –2. Samples were collected (SP) on day 0 (no adenovirus infusion) and days 3, 5, and 7 (after adenovirus infusion; n = 2). Protocol 1b: Normal mice were divided into three groups (n = 6) and treated with different adenovirus. IM was started on day –2; adenovirus (AD) was infused on day 0. Samples were collected (SP) on day 7. Protocol 2 was used for diabetogenesis and adenovirus infusion. Saline control mice (n = 6) only received citrate buffer (SAL) on day –7, and samples were collected on day 7. Mice were made diabetic by STZ injection on day –7. IM started on day –2, and AD was given on day 0. Samples were collected (SP) on day 7 (n = 6).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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