A Potential New Role for Muscle in Blood Glucose Homeostasis

Shieh, Jeng-Jer; Pan, Chi-Jiunn; Mansfield, Brian C.; Chou, Janice Y.

doi:10.1074/jbc.m402036200

Cited by 28 publications

(33 citation statements)

References 26 publications

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“…These results also bear on the functional significance of the newly discovered glucose-6-phosphatase ␤ in muscle (19). The presence of this phosphatase would seem to allow glucose release in the circulation from skeletal muscle glycogen.…”

Section: Discussionmentioning

confidence: 92%

Evidence for reverse flux through pyruvate kinase in skeletal muscle

Jin¹,

Sherry²,

Malloy³

2009

American Journal of Physiology-Endocrinology and Metabolism

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Section: Discussionmentioning

confidence: 92%

Evidence for reverse flux through pyruvate kinase in skeletal muscle

Jin¹,

Sherry²,

Malloy³

2009

American Journal of Physiology-Endocrinology and Metabolism

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“…45 Glutamine is a highly abundant amino acid in the blood, largely synthesized in the skeletal muscle by glutamine synthetase from glutamate, ammonia, and ATP. 46,48 The G6Pase-␤/G6PT complex is also expressed in high levels in the skeletal muscle, and generates endogenous glucose, 49 a precursor of ATP. In G6PC3 deficiency, inactivation of G6Pase-␤ could hamper muscle glucose production, leading to reduced glutamine in both the muscle and the blood.…”

Section: Org Frommentioning

confidence: 99%

Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-β–deficient neutrophils in a congenital neutropenia syndrome

Jun

Lee

Cheung

et al. 2010

Blood

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137

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G6PC3 deficiency, characterized by neutropenia and neutrophil dysfunction, is caused by deficiencies in the endoplasmic reticulum (ER) enzyme glucose-6-phosphatase-␤ (G6Pase-␤ or G6PC3) that converts glucose-6-phosphate (G6P) into glucose, the primary energy source of neutrophils. Enhanced neutrophil ER stress and apoptosis underlie neutropenia in G6PC3 deficiency, but the exact functional role of G6Pase-␤ in neutrophils remains unknown. We hypothesized that the ER recycles G6Pase-␤-generated glucose to the cytoplasm, thus regulating the amount of available cytoplasmic glucose/ G6P in neutrophils. Accordingly, a G6Pase-␤ deficiency would impair glycolysis and hexose monophosphate shunt activities leading to reductions in lactate production, adenosine-5-triphosphate (ATP) production, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Using annexin V-depleted neutrophils, we show that glucose transporter-1 translocation is impaired in neutrophils from G6pc3 ؊/؊ mice and G6PC3-deficient patients along with impaired glucose uptake in G6pc3 ؊/؊ neutrophils. Moreover, levels of G6P, lactate, and ATP are markedly lower in murine and human G6PC3-deficient neutrophils, compared with their respective controls. In parallel, the expression of NADPH oxidase subunits and membrane translocation of p47 phox are down-regulated in murine and human G6PC3-deficient neutrophils. The results establish that in nonapoptotic neutrophils, G6Pase-␤ is essential for normal energy homeostasis. A G6Pase-␤ deficiency prevents recycling of ER glucose to the cytoplasm, leading to neutrophil dysfunction. (Blood. 2010;116(15):2783-2792) IntroductionThere are 2 enzymatically active glucose-6-phosphatases (G6Pases), the liver/kidney/intestine-restricted G6Pase-␣ (or G6PC) 1,2 and the ubiquitously expressed G6Pase-␤ (also known as G6PC3). 3,4 Both enzymes are transmembrane endoplasmic reticulum (ER) proteins, with a similar topology, that places their active site on the luminal side of the ER membrane. 5,6 Both have similar kinetic properties 2,4 and hydrolyze glucose-6-phosphate (G6P) to glucose and phosphate when coupled with the ubiquitously expressed G6P transporter (G6PT) that translocates G6P from the cytoplasm into the lumen of the ER. 7,8 The primary role of the G6Pase/G6PT complex is to provide glucose and phosphate to the ER lumen. The G6Pase-␣/G6PT complex maintains blood glucose homeostasis between meals by hydrolyzing G6P to glucose in the terminal step of gluconeogenesis and glycogenolysis. 1,2 Deficiencies in G6Pase-␣ cause glycogen storage disease type Ia (GSD-Ia) and deficiencies in G6PT result in GSD type Ib (GSD-Ib). 1,2,9 Both GSD-Ia and GSD-Ib patients manifest a phenotype of disturbed blood glucose homeostasis with GSD-Ib patients also suffering neutropenia and neutrophil dysfunction, 1,9 reflecting a role of G6PT in tissues beyond the liver and kidney.The biologic roles of G6Pase-␤ and the G6Pase-␤/G6PT complex are poorly defined. Neutrophils, which express both G6Pase-␤ and G6PT, 10 are capable ...

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“…This has raised a possibility of contribution of the skeletal muscle to mammalian glucose homeostasis by releasing glucose into circulation (Shieh et al, 2003;Shieh et al, 2004). We speculate from the data of G6Pase mRNA (Fig.…”

Section: Skeletal Musclementioning

confidence: 96%

“…In mammals, a catalytic subunit gene of G6Pase was proved to be ubiquitously expressed including in the muscle (Martin et al, 2002;Guionie et al, 2003;Shieh et al, 2003;Shieh et al, 2004), and G6Pase protein and enzyme activity were proved in the muscle (Hirose et al, 1986;Shieh et al, 2004). This has raised a possibility of contribution of the skeletal muscle to mammalian glucose homeostasis by releasing glucose into circulation (Shieh et al, 2003;Shieh et al, 2004).…”

Section: Skeletal Musclementioning

confidence: 99%

Ontogenic Profile of Gluconeogenic Key Enzyme Gene Expressions in Embryonic Chicken Liver and Muscle

et al. 2013

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To elucidate biochemical mechanisms underlining high plasma glucose in chicken embryo, gene expression profile of gluconeogenic key enzymes were characterized. The liver and skeletal muscle were collected from 13-to 21-day embryos (E) (n＝8) of layer chicken and the mRNA of pyruvate carboxylase (PC), cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), muscle-type fructose-1,6-bisphosphatase (mFBPase), liver-type fructose-1,6-bisphosphatase (lFBPase) and glucose-6-phosphatase (G6Pase) were measured by real-time PCR. All the enzymes were expressed in the liver, whereas in the skeletal muscle, only mFBPase and G6Pase were detected. In the liver, all the enzymes except for G6Pase peaked either on E13 or E15. G6Pase expression was the highest between E15 and E19. In the skeletal muscle, mFBPase peaked on E19 and G6Pase peaked on E15. These results suggest that gluconeogenesis is active in chicken embryos but regulations of mRNA expressions of the gluconeogenic key enzymes are different between liver and muscle. The results also suggest that the skeletal muscle, which is generally not regarded as a tissue conducting an active gluconeogenesis, may contribute to the regulation of embryonic plasma glucose to some extent, and warrant further investigations of the presence of enzyme activities.

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A Potential New Role for Muscle in Blood Glucose Homeostasis

Cited by 28 publications

References 26 publications

Evidence for reverse flux through pyruvate kinase in skeletal muscle

Evidence for reverse flux through pyruvate kinase in skeletal muscle

Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-β–deficient neutrophils in a congenital neutropenia syndrome

Ontogenic Profile of Gluconeogenic Key Enzyme Gene Expressions in Embryonic Chicken Liver and Muscle

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