Glucose 6-Phosphate Hydrolysis Is Activated by Glucagon in a Low Temperature-sensitive Manner

Ichaï, Carole; Guignot, Ludovic; El-Mir, Mohamad Y.; Nogueira, Véronique; Guigas, Bruno; Chauvin, Christiane; Fontaine, Éric; Mithieux, Gilles; Leverve, Xavier

doi:10.1074/jbc.m010186200

Cited by 21 publications

(25 citation statements)

References 52 publications

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“…At variance with these results, Ichai et al [61] observed that glucagon increased glucose production from dihydroxyacetone, but decreased the intracellular concentration of Glc-6-P, in perifused hepatocytes. Similarly, infusion of glucagon to anaesthetized rats caused a 1.8-fold increase in hepatic glucose production, but a 2.8-fold decrease in the Glc-6-P level measured after 3 h, again suggesting activation of G6Pase.…”

Section: Short-term Regulationmentioning

confidence: 44%

The glucose-6-phosphatase system

Schaftingen¹,

Gerin²

2002

Biochemical Journal

322

205

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Glucose-6-phosphatase (G6Pase), an enzyme found mainly in the liver and the kidneys, plays the important role of providing glucose during starvation. Unlike most phosphatases acting on water-soluble compounds, it is a membrane-bound enzyme, being associated with the endoplasmic reticulum. In 1975, W. Arion and co-workers proposed a model according to which G6Pase was thought to be a rather unspecific phosphatase, with its catalytic site oriented towards the lumen of the endoplasmic reticulum [Arion, Wallin, Lange and Ballas (1975) Mol. Cell. Biochem. 6, 75–83]. Substrate would be provided to this enzyme by a translocase that is specific for glucose 6-phosphate, thereby accounting for the specificity of the phosphatase for glucose 6-phosphate in intact microsomes. Distinct transporters would allow inorganic phosphate and glucose to leave the vesicles. At variance with this substrate-transport model, other models propose that conformational changes play an important role in the properties of G6Pase. The last 10 years have witnessed important progress in our knowledge of the glucose 6-phosphate hydrolysis system. The genes encoding G6Pase and the glucose 6-phosphate translocase have been cloned and shown to be mutated in glycogen storage disease type Ia and type Ib respectively. The gene encoding a G6Pase-related protein, expressed specifically in pancreatic islets, has also been cloned. Specific potent inhibitors of G6Pase and of the glucose 6-phosphate translocase have been synthesized or isolated from micro-organisms. These as well as other findings support the model initially proposed by Arion. Much progress has also been made with regard to the regulation of the expression of G6Pase by insulin, glucocorticoids, cAMP and glucose.

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Section: Short-term Regulationmentioning

confidence: 44%

The glucose-6-phosphatase system

Schaftingen¹,

Gerin²

2002

Biochemical Journal

322

205

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“…Of note, glucagon concentrations were clamped at constant levels in all experiments in order to assess the effect of insulin in the absence of a concurrent change in glucagon. Since glucagon can increase gluconeogenesis and glucose-6-phosphatase activity (34,35), it is likely that an even greater effect of insulin on EGP may have been observed if glucagon concentrations had been permitted to fall as insulin concentrations increased.…”

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confidence: 99%

Higher Insulin Concentrations Are Required to Suppress Gluconeogenesis Than Glycogenolysis in Nondiabetic Humans

et al. 2003

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To determine the mechanism(s) by which insulin inhibits endogenous glucose production (EGP) in nondiabetic humans, insulin was infused at rates of 0.25, 0.375, or 0.5 mU ⅐ kg ؊1 ⅐ min ؊1 and glucose was clamped at ϳ5.5 mmol/l. EGP, gluconeogenesis, and uridine-diphosphoglucose (UDP)-glucose flux were measured using [3-3 H]glucose, deuterated water, and the acetaminophen glucuronide methods, respectively. An increase in insulin from ϳ75 to ϳ100 to ϳ150 pmol/l (ϳ12.5 to ϳ17 to ϳ25 U/ml) resulted in progressive (ANOVA; P < 0.02) suppression of EGP (13.1 ؎ 1.3 vs. 11.7 ؎ 1.03 vs. 6.4 ؎ 2.15 mol ⅐ kg ؊1 ⅐ min ؊1 ) that was entirely due to a progressive decrease (ANOVA; P < 0.05) in the contribution of glycogenolysis to EGP (4.7 ؎ 1. The contribution of the direct (extracellular) pathway to UDP-glucose flux was minimal and constant during all insulin infusions. We conclude that higher insulin concentrations are required to suppress the contribution of gluconeogenesis of EGP than are required to suppress the contribution of glycogenolysis to EGP in healthy nondiabetic humans. Since suppression of glycogenolysis occurred without a decrease in UDP-glucose flux, this implies that insulin inhibits EGP, at least in part, by directing glucose-6-phosphate into glycogen rather than through the glucose-6-phosphatase pathway. Diabetes

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“…However, a recent study on the kinetics of glucose synthesis from dihydroxyacetone and its secretion from rat hepatocytes showed that the accelerating effect of glucagon on glucose release was mostly suppressed at 21°C. This could not be explained by changes in the activity of the involved enzymes (8). It was suggested that, instead, the temperature-sensitive effect of glucagon was on regulating the membrane traffic-based pathway we previously described.…”

Section: Discussionmentioning

confidence: 94%

Glucose release from GLUT2-null hepatocytes: characterization of a major and a minor pathway

Hosokawa

Thorens

2002

American Journal of Physiology-Endocrinology and Metabolism

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Hosokawa, Masaya, and Bernard Thorens. Glucose release from GLUT2-null hepatocytes: characterization of a major and a minor pathway. Am J Physiol Endocrinol Metab 282: E794-E801, 2002; 10.1152/ajpendo.00374.2001.-We previously reported that glucose can be released from GLUT2-null hepatocytes through a membrane traffic-based pathway issued from the endoplasmic reticulum. Here, we further characterized this glucose release mechanism using biosynthetic labeling protocols. In continuous pulse-labeling experiments, we determined that glucose secretion proceeded linearly and with the same kinetics in control and GLUT2-null hepatocytes. In GLUT2-deficient hepatocytes, however, a fraction of newly synthesized glucose accumulated intracellularly. The linear accumulation of glucose in the medium was inhibited in mutant, but not in control, hepatocytes by progesterone and low temperature, as previously reported, but, importantly, also by microtubule disruption. The intracellular pool of glucose was shown to be present in the cytosol, and, in pulse-chase experiments, it was shown to be released at a relatively slow rate. Release was not inhibited by S-4048 (an inhibitor of glucose-6-phosphate translocase), cytochalasin B, or progesterone. It was inhibited by phloretin, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone, and low temperature. We conclude that the major release pathway segregates glucose away from the cytosol by use of a membrane traffic-based, microtubule-dependent mechanism and that the release of the cytosolic pool of newly synthesized glucose, through an as yet unidentified plasma membrane transport system, cannot account for the bulk of glucose release.gluconeogenesis; hepatic glucose output; intracellular traffic; glucose-6-phosphatase GLUCOSE RELEASE FROM HEPATOCYTES is an essential physiological function that is activated in the fasted state to prevent development of hypoglycemia. In diabetes, this function becomes progressively insensitive to inhibition by insulin and therefore contributes to increased hyperglycemia. Hepatic glucose production can result from activation of two metabolic pathways, glycogenolysis or gluconeogenesis, that converge at the level of glucose 6-phosphate (G-6-P) production. Conversion to glucose then requires G-6-P to enter the endoplasmic reticulum (ER), a process catalyzed by a glucose-6-phosphate translocase (4), followed by hydrolysis to glucose and phosphate by the membrane-associated glucose-6-phosphatase, whose catalytic site is located inside the ER lumen (9, 13). Release of glucose outside the cells has been classically viewed as involving diffusion of glucose back into the cytosol and transport across the plasma membrane by the glucose transporter GLUT2 (15). Recently, we reported that, in the absence of this transporter, glucose could, however, still be released at a normal rate, even though facilitated diffusion of 3-O-methylglucose (3-MG) across the plasma membrane was reduced by Ͼ95% (5). We presented evidence that glucose release in the absence of GLUT2 could...

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Glucose 6-Phosphate Hydrolysis Is Activated by Glucagon in a Low Temperature-sensitive Manner

Cited by 21 publications

References 52 publications

The glucose-6-phosphatase system

The glucose-6-phosphatase system

Higher Insulin Concentrations Are Required to Suppress Gluconeogenesis Than Glycogenolysis in Nondiabetic Humans

Glucose release from GLUT2-null hepatocytes: characterization of a major and a minor pathway

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