Perturbation of Fuel Homeostasis Caused by Overexpression of the Glucose-6-phosphatase Catalytic Subunit in Liver of Normal Rats

Trinh, Khiet Y.; O’Doherty, Robert M.; Anderson, Paul; Lange, Alex J.; Newgard, Christopher B.

doi:10.1074/jbc.273.47.31615

Cited by 180 publications

(147 citation statements)

References 42 publications

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“…Overexpression of G6Pase is associated with diabetes mellitus in humans, and caused hyperglycemia in rats. 8 Therefore, excessive G6Pase expression would be harmful in the setting of gene therapy for GSD-Ia. The presence of only 10% of normal G6Pase levels would be therapeutic in GSD-Ia, as a patient with 8% G6Pase activity had no hypoglycemia.…”

Section: Introductionmentioning

confidence: 99%

Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia

et al. 2006

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Section: Introductionmentioning

confidence: 99%

Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia

et al. 2006

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“…Similarly, a protein detectable with an anti-FLAG antibody was immunoprecipitated and immunoblotted only in liver samples from AdCMV-G M ⌬C-injected animals. It should be noted that we expect systemic administration of AdCMV-G M ⌬C to result in expression of G M ⌬C in a largely liver-specific fashion, based on prior analysis of a wide array of tissues in rats and mice infused with this and other recombinant adenoviruses (8,10,15,16).…”

Section: Resultsmentioning

confidence: 99%

Hepatic Expression of a Targeting Subunit of Protein Phosphatase-1 in Streptozotocin-diabetic Rats Reverses Hyperglycemia and Hyperphagia Despite Depressed Glucokinase Expression

Yang

Newgard

2003

Journal of Biological Chemistry

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Glycogen-targeting subunits of protein phosphatase-1 (PP-1) are scaffolding proteins that facilitate the regulation of key enzymes of glycogen metabolism by PP-1. In the current study, we have tested the effects of hepatic expression of G M ⌬C, a truncated version of the muscle-targeting subunit isoform, in rats rendered insulin-deficient via injection of a single moderate dose of streptozotocin (STZ). Three key findings emerged. First, G M ⌬C expression in liver was sufficient to fully normalize blood glucose levels (from 335 ؎ 31 mg/dl prior to viral injection to 109 ؎ 28 mg/dl 6 days after injection) and liver glycogen content in STZ-injected rats. Second, this normalization occurred despite very low levels of liver glucokinase expression in the insulin-deficient STZ-injected rats. Finally, the hyperphagia induced by STZ injection was completely reversed by G M ⌬C expression in liver. In contrast to these findings with G M ⌬C, overexpression of another targeting subunit, G L , in STZinjected rats caused a large increase in liver glycogen stores but only a transient decrease in food intake and blood glucose levels. The surprising demonstration of a glucose-lowering effect of G M ⌬C in the background of depressed hepatic glucokinase expression suggests that controlled stimulation of liver glycogen storage may be an effective mechanism for improving glucose homeostasis, even when normal pathways of glucose disposal are impaired.

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“…Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the initial step of gluconeogenesis, whereas glucose-6-phosphatase (G6Pase) catalyzes the last committed step of this process. Hence, overexpression of G6Pase increases glucose production and causes hyperglycemia and glucose intolerance (6). The expression of both PEPCK and G6Pase is primarily regulated at the level of transcription (7).…”

mentioning

confidence: 99%

Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice

Zhang

Lee

Barrera

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

838

716

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Farnesoid X receptor (FXR) plays an important role in maintaining bile acid and cholesterol homeostasis. Here we demonstrate that FXR also regulates glucose metabolism. Activation of FXR by the synthetic agonist GW4064 or hepatic overexpression of constitutively active FXR by adenovirus-mediated gene transfer significantly lowered blood glucose levels in both diabetic db͞db and wild-type mice. Consistent with these data, FXR null mice exhibited glucose intolerance and insulin insensitivity. We further demonstrate that activation of FXR in db͞db mice repressed hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involves enhanced insulin sensitivity. In view of its central roles in coordinating regulation of both glucose and lipid metabolism, we propose that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus.glucose ͉ GW4064 ͉ farnesoid X receptor-VP16 ͉ triglyceride ͉ cholesterol

show abstract

Perturbation of Fuel Homeostasis Caused by Overexpression of the Glucose-6-phosphatase Catalytic Subunit in Liver of Normal Rats

Cited by 180 publications

References 42 publications

Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia

Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia

Hepatic Expression of a Targeting Subunit of Protein Phosphatase-1 in Streptozotocin-diabetic Rats Reverses Hyperglycemia and Hyperphagia Despite Depressed Glucokinase Expression

Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice

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