Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.9 (glucose-6-phosphatase)
3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The deficiency of glucose-6-phosphatase (G6Pase) underlies life-threatening hypoglycemia and growth retardation in glycogen storage disease type Ia (GSD-Ia). An adeno-associated virus (AAV) vector encoding G6Pase was pseudotyped as AAV8 and administered to 2-week-old GSD-Ia mice (n = 9). Median survival was prolonged to 7 months following vector administration, in contrast to untreated GSD-Ia mice that survived for only 2 weeks. Although GSD-Ia mice were initially growth-retarded, treated mice increased fourfold in weight to normal size. Blood glucose was partially corrected by 2 weeks following treatment, whereas blood cholesterol normalized. Glucose-6-phosphatase activity was partially corrected to 25% of the normal level at 7 months of age in treated mice, and blood glucose during fasting remained lower in treated, affected mice than in normal mice. Glycogen storage was partially corrected in the liver by 2 weeks following treatment, but reaccumulated to pre-treatment levels by 7 months old (m.o.). Vector genome DNA decreased between 3 days and 3 weeks in the liver following vector administration, mainly through the loss of single-stranded genomes; however, double-stranded vector genomes were more stable. Although CD8+ lymphocytic infiltrates were present in the liver, partial biochemical correction was sustained at 7 m.o. The development of efficacious AAV vector-mediated gene therapy could significantly reduce the impact of long-term complications in GSD-Ia, including hypoglycemia, hyperlipidemia and growth failure.
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PMID:Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia. 1667 83

Genetic deficiency of glucose-6-phosphatase (G6Pase) underlies glycogen storage disease type Ia (GSD-Ia, also known as von Gierke disease; MIM 232200), an autosomal recessive disorder of metabolism associated with life-threatening hypoglycemia and growth retardation. We tested whether helper-dependent adenovirus (HDAd)-mediated hepatic delivery of G6Pase would lead to prolonged survival and sustained correction of the metabolic abnormalities in G6Pase knockout (KO) mice, a model for a severe form of GSD-Ia. An HDAd vector encoding G6Pase was administered intravenously (2 or 5 x 10(12)vector particles/kg) to 2-week-old (w.o.) G6Pase-KO mice. Following HDAd vector administration survival was prolonged to a median of 7 months, in contrast to untreated affected mice that did not survive past 3 weeks of age. G6Pase levels increased more than tenfold between 3 days and 28 weeks after HDAd injection (P < 0.03). The weights of untreated 2 w.o. G6Pase-KO mice were approximately half those of their unaffected littermates, and treatment stimulated their growth to the size of wild-type mice. Severe hypoglycemia and hypercholesterolemia, which are hallmarks of GSD-Ia both in humans and in mice, were also restored to normalcy by the treatment. Glycogen accumulation in the liver was markedly reduced. The efficacy of HDAd-G6Pase treatment in reversing the physiological and biochemical abnormalities associated with GSD-Ia in affected G6Pase-KO mice justifies further preclinical evaluation in murine and canine models of GSD-Ia.
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PMID:Efficacy of helper-dependent adenovirus vector-mediated gene therapy in murine glycogen storage disease type Ia. 1750 75

Hexose-6-phosphate dehydrogenase (H6PDH) knockout (KO) mice have reduced generation of nicotinamide adenine dinucleotide phosphate (reduced) within the endoplasmic reticulum. As a consequence, 11beta-hydroxysteroid dehydrogenase type 1 enzyme activity switches from a reductase to a dehydrogenase leading to glucocorticoid inactivation. 11beta-Hydroxysteroid dehydrogenase type 1 has emerged as an important factor in regulating hepatic glucose output; therefore, we examined aspects of glucose homeostasis in KO mice. Compared with wild-type mice, KO mice reduced weight gain, displayed peripheral fasting hypoglycemia, improved glucose tolerance, and elevated plasma corticosterone concentrations. Plasma insulin levels in fed and fasted KO mice are normal; however, insulin and plasma glucose levels are reduced 4 h after fasted animals are refed, indicating improved insulin sensitivity. There is preserved induction and activity of the glucocorticoid-responsive gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in fasted KO mice. Glycogen storage is elevated in fed KO liver, with fed glycogenesis rates increased in KO mice. There is normal flux of lactate through gluconeogenesis recovered as plasma glucose, coupled with increased glycogen derived from lactate. These data suggest partial retention of glucocorticoid sensitivity at the level of the liver. We therefore postulate that increased glycogen synthesis may reflect increased flux of glucose-6-phosphate (H6PDH substrate) through to glycogen in the absence of H6PDH mediated metabolism.
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PMID:Hypoglycemia with enhanced hepatic glycogen synthesis in recombinant mice lacking hexose-6-phosphate dehydrogenase. 1782 65

Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (G6Pase) deficiency. An adeno-associated virus (AAV) containing a small human G6Pase transgene was pseudotyped with AAV8 (AAV2/8) to optimize liver tropism. Survival was prolonged in 2-week-old G6Pase (-/-) mice by 600-fold fewer AAV2/8 vector particles (vp), in comparison to previous experiments involving this model (2 x 10(9) vp; 3 x 10(11) vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 x 10(13) vp/kg). The AAV2/8 vector uniquely prevented hypoglycemia during fasting and fully corrected liver G6Pase deficiency in GSD-Ia mice and dogs. The AAV2/8 vector has prolonged survival in three GSD-Ia dogs to >11 months, which validated this strategy in the large animal model for GSD-Ia. Urinary biomarkers, including lactate and 3-hydroxybutyrate, were corrected by G6Pase expression solely in the liver. Glycogen accumulation in the liver was reduced almost to the normal level in vector-treated GSD-Ia mice and dogs, as was the hepatocyte growth factor (HGF) in GSD-Ia mice. These preclinical data demonstrated the efficacy of correcting hepatic G6Pase deficiency, and support the further preclinical development of AAV vector-mediated gene therapy for GSD-Ia.
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PMID:AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia. 1836 24

Mechanism of action of GII (100 mg/kg body weight, po for 15 days) purified from fenugreek (T. foenum-graecum) seeds was studied in the sub-diabetic and moderately diabetic rabbits. In the sub-diabetic rabbits it did not change much the content of total lipids, glycogen and proteins in the liver, muscle and heart (glycogen was not studied in the heart). However, in the moderately diabetic rabbits same treatment decreased total lipids more in the liver (21%) than those in the heart and muscle. Total protein content increased (14%) in the liver but negligible change (5-7%) was observed in heart and muscle. Glycogen increased (17%) in the liver but not in the muscle of the moderately diabetic rabbits (glycogen was not estimated in the heart). Among the enzymes of glycolysis, activity of glucokinase was not affected in the liver of both the sub-diabetic and moderately diabetic rabbits. Phosphofructokinase and pyruvate kinase activity in both sub-diabetic and moderately diabetic rabbits increased (13-50%) indicating stimulation of glycolysis. The activity of gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-diphosphatase of the sub-diabetic rabbits decreased in the liver (15-20%) but not in the kidneys. In the moderately diabetic rabbits after treatment with GII, glucokinase in the liver was not affected much (-9%) but increased well in the muscle (40%). Phosphofructokinase and pyruvate kinase were moderately increased both in the liver and the muscle (18-23%). The gluconeogenic enzyme glucose-6-phosphatase decreased reasonably well in the liver and kidneys (22, 32%). Fructose-1,6-diphosphatase decreased only slightly (10, 9%) in the moderately diabetic rabbits. Thus GII seems to decrease lipid content of liver and stimulate the enzymes of glycolysis (except glucokinase) and inhibit enzymes of gluconeogenesis in the liver of the diabetic especially moderately diabetic rabbits.
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PMID:Mechanism of anti-diabetic action, efficacy and safety profile of GII purified from fenugreek (Trigonella foenum-graceum Linn.) seeds in diabetic animals. 2111 52

The in vivo effect of dehydroepiandrosterone (DHEA) on hepatic glycogen content and on glucose metabolizing enzymes was investigated in male and female Sprague-Dawley rats treated with 0.6% (w/w) DHEA in the diet for 3, 7, 14, 28 and 140 days. The glycolytic enzymes studied (glucokinase, hexokinase, pyruvate kinase) showed a significant persistent decrease in activity in both sexes after 3-7 days of treatment. Gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6-bisphosphatase) were increased after 3 days, but decreased after 7-14 days. Glycolytic enzymes showed a stronger reduction than gluconeogenic enzymes. Females were slightly more affected than males. Glucose-6-phosphate dehydrogenase was unchanged in females, but increased in males. Glycogen content and the activity of glycogen phosphorylase were reduced after 3 days of treatment. mRNA analysis of glucokinase and phosphorylase indicated that these enzyme alterations were accompanied by reduced transcriptional expression, while glucose-6-phosphate dehydrogenase mRNA levels were unchanged. Withdrawal of DHEA from 4 week-treated rats was associated with an almost complete reversibility of the enzyme alterations after 2 weeks. After long-term treatment (140 days) glucokinase, glucose-6-phosphatase and fructose-1,6-bisphosphatase activities were no longer altered. Since DHEA treatment affects the key enzymes of glucose metabolic pathways in the same sense, it is suggested that DHEA does not regulate individual enzymes but rather common regulatory factors or signalling pathways.
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PMID:Dehydroepiandrosterone reduces expression of glycolytic and gluconeogenic enzymes in the liver of male and female rats. 2154 66

Glycogen storage disease type Ia (GSD-Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), primarily found in liver and kidney, which causes life-threatening hypoglycemia. Dogs with GSD-Ia were treated with double-stranded adeno-associated virus (AAV) vectors encoding human G6Pase. Administration of an AAV9 pseudotyped (AAV2/9) vector to seven consecutive GSD-Ia neonates prevented hypoglycemia during fasting for up to 8 hr; however, efficacy eventually waned between 2 and 30 months of age, and readministration of a new pseudotype was eventually required to maintain control of hypoglycemia. Three of these dogs succumbed to acute hypoglycemia between 7 and 9 weeks of age; however, this demise could have been prevented by earlier readministration an AAV vector, as demonstrated by successful prevention of mortality of three dogs treated earlier in life. Over the course of this study, six out of nine dogs survived after readministration of an AAV vector. Of these, each dog required readministration on average every 9 months. However, two were not retreated until >34 months of age, while one with preexisting antibodies was re-treated three times in 10 months. Glycogen content was normalized in the liver following vector administration, and G6Pase activity was increased in the liver of vector-treated dogs in comparison with GSD-Ia dogs that received only with dietary treatment. G6Pase activity reached approximately 40% of normal in two female dogs following AAV2/9 vector administration. Elevated aspartate transaminase in absence of inflammation indicated that hepatocellular turnover in the liver might drive the loss of vector genomes. Survival was prolonged for up to 60 months in dogs treated by readministration, and all dogs treated by readministration continue to thrive despite the demonstrated risk for recurrent hypoglycemia and mortality from waning efficacy of the AAV2/9 vector. These preclinical data support the further translation of AAV vector-mediated gene therapy in GSD-Ia.
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PMID:Long-term efficacy following readministration of an adeno-associated virus vector in dogs with glycogen storage disease type Ia. 2218 25

The present study investigated the effect of diphenyl diselenide [(PhSe)2 ] on metabolic disorders induced by acephate acute exposure in rats. We also investigated a possible mechanism of action of (PhSe)2 against hyperglycemia induced by acephate. (PhSe)2 was administered to rats at a dose of 10 or 30 mg/kg by oral gavage (p.o.) 1 hour prior to acephate administration (140 mg/kg; p.o.). Glucose and corticosterone levels as well as the lipid status were determined in plasma of rats. Cardiovascular risk factors and the atherogenic index were calculated. Glycogen levels as well as tyrosine aminotransferase (TAT) and glucose-6-phosphatase (G6Pase) activities were determined in livers of rats. Cerebral acetylcholinesterase (AChE) activity was assayed. Acephate induced an increase in glucose and corticosterone levels as well as in TAT and G6Pase activities. AChE activity was inhibited by acephate. Triglyceride (TG) levels and the cardiovascular risk factor TG/high-density lipoprotein-cholesterol (HDL) were increased by acephate. (PhSe)2 was effective against the metabolic disorders induced by acephate acute exposure in rats.
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PMID:Diphenyl diselenide protects against metabolic disorders induced by acephate acute exposure in rats. 2277 74

In this study we evaluated the hyperglycemic and hyperlipidemic effects of chlorpyrifos (CPF) after an acute exposure in rats. The mechanisms involved in hyperglycemia induced by CPF were studied. A single dose of CPF (50 mg kg(-1), subcutaneous, s.c.) was administered to overnight-fasted rats. Glucose and corticosterone levels, lipid status and paraoxonase (PON1) activity were determined in plasma of rats. Cardiovascular risk factors and the atherogenic index were calculated. Glycogen levels, tyrosine aminotransferase (TAT) and glucose-6-phosphatase (G6Pase) activities were determined in livers of rats. Cerebral acetylcholinesterase (AChE) activity was also determined. CPF caused an increase in glucose and glycogen levels as well as in TAT and G6Pase activities. The CPF exposure caused an increase in corticosterone levels, an inhibition of AChE activity and a reduction of PON1 activity. Regarding the lipid status, CPF induced an increase in triglycerides (TG) and low-density lipoprotein-cholesterol (LDL) levels and a decrease in high-density lipoprotein (HDL) levels associated with an increase of cardiovascular risk factors and the atherogenic index. The present study demonstrated that a single CPF administration caused hyperglycemia and hyperlipidemia in rats. The activation of the gluconeogenesis pathway, probably elicited by hypercorticosteronemia, is involved in the hyperglycemic effect of CPF in rats.
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PMID:Chlorpyrifos acute exposure induces hyperglycemia and hyperlipidemia in rats. 2283 37

We evaluated effects of chronic intracerebroventricular infusion of angiotensin (Ang)-(1-7) on cardiovascular and metabolic parameters in fructose-fed (FF) rats. After 6 weeks of fructose intake (10% in drinking water), Sprague-Dawley rats were subjected to intracerebroventricular infusion of Ang-(1-7) (200 ng/h; FF+A7 group) or 0.9% sterile saline (FF group) for 4 weeks with continued access to fructose. Compared with control rats, FF rats had increased mean arterial pressure and cardiac sympathetic tone with impaired baroreflex sensitivity. FF rats also presented increased circulating triglycerides, leptin, insulin, and glucose with impaired glucose tolerance. Furthermore, relative weights of liver and retroperitoneal adipose tissue were increased in FF rats. Glycogen content was reduced in liver, but increased in muscle. In contrast, fructose-fed rats subjected to chronic intracerebroventricular infusion of Ang-(1-7) presented reduced cardiac sympathetic tone with normalized mean arterial pressure, baroreflex sensitivity, glucose and insulin levels, and improved glucose tolerance. Relative weight of liver, and hepatic and muscle glycogen contents were also normalized in FF+A7 rats. In addition, FF+A7 rats had reduced mRNA expression for neuronal nitric oxide synthase and NR1 subunit of N-methyl-d-aspartate receptor in hypothalamus and dorsomedial medulla. Ang-(1-7) infusion did not alter fructose-induced hyperleptinemia and increased relative weight of retroperitoneal adipose tissue. There were no differences in body weights, neither in liver mRNA expression of phosphoenolpyruvate carboxykinase or glucose-6-phosphatase among the groups. These data indicate that chronic increase in Ang-(1-7) levels in the brain may have a beneficial role in fructose-fed rats by ameliorating cardiovascular and metabolic disorders.
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PMID:Increasing angiotensin-(1-7) levels in the brain attenuates metabolic syndrome-related risks in fructose-fed rats. 2451 6


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