Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.9 (glucose-6-phosphatase)
 3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At variance with the current view that only liver and kidney are gluconeogenic organs, because both are the only tissues to express glucose-6-phosphatase (Glc6Pase), we have recently demonstrated that the Glc6Pase gene is expressed in the small intestine in rats and humans and that it is induced in insulinopenic states such as fasting and diabetes. We used a combination of arteriovenous balance and isotopic techniques, reverse transcription-polymerase chain reaction, Northern blot analysis, and enzymatic activity assays. We report that rat small intestine can release neosynthesized glucose in mesenteric blood in insulinopenia, contributing 20-25% of total endogenous glucose production. Like liver glucose production, small intestine glucose production is acutely suppressed by insulin infusion. In the small intestine, glutamine and, to a much lesser extent, glycerol are the precursors of glucose, whereas alanine and lactate are the main precursors in liver. Accounting for these metabolic fluxes: 1) the phosphoenolpyruvate carboxykinase gene (required for the utilization of glutamine) is strongly induced at the mRNA and enzyme levels in insulinopenia; 2) the glycerokinase gene is expressed, but not induced; 3) the pyruvate carboxylase gene (required for the utilization of alanine and lactate) is repressed by 80% at the enzyme level in insulinopenia. These studies identify small intestine as a new insulin-sensitive tissue and a third gluconeogenic organ, possibly involved in the pathophysiology of diabetes.
 ...
PMID:Rat small intestine is an insulin-sensitive gluconeogenic organ. 1128 37

Effects of acute inhibition of glucose-6-phosphatase activity by the chlorogenic acid derivative S4048 on hepatic carbohydrate fluxes were examined in isolated rat hepatocytes and in vivo in rats. Fluxes were calculated using tracer dilution techniques and mass isotopomer distribution analysis in plasma glucose and urinary paracetamol-glucuronide after infusion of [U-(13)C]glucose, [2-(13)C]glycerol, [1-(2)H]galactose, and paracetamol. In hepatocytes, glucose-6-phosphate (Glc-6-P) content, net glycogen synthesis, and lactate production from glucose and dihydroxyacetone increased strongly in the presence of S4048 (10 microm). In livers of S4048-treated rats (0.5 mg kg(-1)min(-)); 8 h) Glc-6-P content increased strongly (+440%), and massive glycogen accumulation (+1260%) was observed in periportal areas. Total glucose production was diminished by 50%. The gluconeogenic flux to Glc-6-P was unaffected (i.e. 33.3 +/- 2.0 versus 33.2 +/- 2.9 micromol kg(-1)min(-1)in control and S4048-treated rats, respectively). Newly synthesized Glc-6-P was redistributed from glucose production (62 +/- 1 versus 38 +/- 1%; p < 0.001) to glycogen synthesis (35 +/- 5% versus 65 +/- 5%; p < 0.005) by S4048. This was associated with a strong inhibition (-82%) of the flux through glucokinase and an increase (+83%) of the flux through glycogen synthase, while the flux through glycogen phosphorylase remained unaffected. In livers from S4048-treated rats, mRNA levels of genes encoding Glc-6-P hydrolase (approximately 9-fold), Glc-6-P translocase (approximately 4-fold), glycogen synthase (approximately 7-fold) and L-type pyruvate kinase (approximately 4-fold) were increased, whereas glucokinase expression was almost abolished. In accordance with unaltered gluconeogenic flux, expression of the gene encoding phosphoenolpyruvate carboxykinase was unaffected in the S4048-treated rats. Thus, acute inhibition of glucose-6-phosphatase activity by S4048 elicited 1) a repartitioning of newly synthesized Glc-6-P from glucose production into glycogen synthesis without affecting the gluconeogenic flux to Glc-6-P and 2) a cellular response aimed at maintaining cellular Glc-6-P homeostasis.
 ...
PMID:Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux toward glycogen in fasted rats. A pharmacological study with the chlorogenic acid derivative S4048. 1134 46

Most neoplasms are dependent on glucose as their primary fuel, and their ambient glucose levels tend to be rather low owing to wasteful aerobic glycolysis and poor perfusion. Previous attempts to starve tumors by inducing hypoglycemia have foundered on the fact that the CNS and other tissues have high glucose requirements. Burt has proposed that, inasmuch as hypoglycemia-sensitive normal tissues can make efficient use of glycerol, whereas many or most cancers cannot, hypoglycemic cancer therapy may be feasible if glycerol is concurrently infused. Unfortunately, when Burt used 3-mercaptopicolinate to inhibit gluconeogenesis and thereby induce hypoglycemia in fasted tumor-bearing subjects, infused glycerol served as gluconeogenic substrate, raising the serum glucose level. Agents which inhibit gluconeogenesis more distally - namely at the level of glucose-6-phosphatase or of fructosediphosphatase - may prevent the gluconeogenic response to glycerol, making glycerol-rescued hypoglycemic therapy of cancer feasible. In fact, certain new drugs being developed for diabetes therapy - chlorogenic acid derivatives and 'compound A' - are potent inhibitors of glucose-6-phosphatase, and both AICA riboside and 2,5-anhydro-D-mannitol have potential as clinical inhibitors of fructosediphosphatase. Insulin also can inhibit gluconeogenesis, both proximally and distally, and can potentiate hypoglycemia by promoting muscle glucose uptake; thus, coinfusion of high-dose insulin and of glycerol may represent an alternative viable strategy. Further research along these lines may enable glycerol-rescued hypoglycemia to become a feasible cancer therapy that has particular value as a complement to antiangiogenic measures.
 ...
PMID:Prospects for glycerol-rescued hypoglycemia as a cancer therapy. 1135 48

The effects of benfluorex and two of its metabolites (S 422-1 and S 1475-1) on fatty acid and glucose metabolic fluxes and specific gene expression were studied in hepatocytes isolated from 24-h fasted rats. Both benfluorex and S 422-1 (0.1 or 1 mmol/l) reduced beta-oxidation rates and ketogenesis, whereas S 1475-1 had no effect. At the same concentration, benfluorex and S 422-1 were more efficient in reducing gluconeogenesis from lactate/pyruvate than S 1475-1. Benfluorex inhibited gluconeogenesis at the level of pyruvate carboxylase (45% fall in acetyl-CoA concentration) and of glyceraldehyde-3-phosphate dehydrogenase (decrease in ATP/ADP and NAD(+)/NADH ratios). Accordingly, neither benfluorex nor S 422-1 inhibited gluconeogenesis from dihydroxyacetone, but both stimulated gluconeogenesis from glycerol. In hepatocytes cultured in the presence of benfluorex or S 422-1 (10 or 100 micromol/l), the expression of genes encoding enzymes of fatty acid oxidation (carnitine palmitoyltransferase [CPT] I), ketogenesis (hydroxymethylglutaryl-CoA synthase), and gluconeogenesis (glucose-6-phosphatase, PEPCK) was decreased, whereas mRNAs encoding glucokinase and pyruvate kinase were increased. By contrast, Glut-2, acyl-CoA synthetase, and CPT II gene expression was not affected by benfluorex or S 422-1. In conclusion, this work suggests that benfluorex mainly via S 422-1 reduces gluconeogenesis by affecting gene expression and metabolic status of hepatocytes.
 ...
PMID:Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: from metabolic fluxes to gene expression. 1214 46

The effect of postpartum supplementation with rumen undegradable protein on the activities of gluconeogenic enzymes was studied in cows with induced fatty liver. Prepartum liver and blood samples were collected at about one week before the expected date of calving and postpartum samples were collected at 10 and 20 days (d) postpartum. At 10 d postpartum, concentrations of serum nonesterified fatty acids and hepatic triacylglycerol levels were higher than at one wk before parturition. The postpartum increases in nonesterified fatty acids and hepatic triacylglycerols were significantly higher in the cows that were fed extra protein than in the control cows. There were no differences between the groups with regard to postpartum changes in the concentrations of plasma glucose, liver glycogen, and serum insulin. The postpartum increase in the activity of fructose 1-6-bisphosphatase was higher in the test group than in the control group, but the increase in the activity of glucose-6-phosphatase was lower. There were no group differences in the postpartum activities of phosphoenolpyruvate carboxykinase, pyruvate carboxylase, and propionyl-CoA carboxylase. Our results suggest that intense lipolysis released more glycerol in the protein-supplemented cows, which stimulated the activity of fructose 1-6-bisphosphatase. However, postpartum rumen undegradable protein supplementation did not affect the activities of the other enzymes of gluconeogenesis, and fatty liver was even exacerbated.
 ...
PMID:The effect of postpartum rumen undegradable protein supplementation on hepatic gluconeogenic enzyme activities in dairy cows with fatty liver. 1246 10

In preterm infants low plasma glucose concentrations are frequently observed. We hypothesized that the infants' ability to adapt endogenous glucose production to diminishing exogenous supply is disturbed, but will improve with increasing gestational age. Glucose production rate and gluconeogenesis were measured using stable isotope techniques with [6,6-2H2]glucose and [2-13C]glycerol in 19 preterm infants (10 < or = 30 wk and nine >30 wk gestational age) on d 5.0 +/- 1.4 of life. Exogenous glucose was administered at a rate of 33 micromol x kg-1 x min-1 followed by 22 micromol x kg-1 x min-1. In the first 2 h after the decrease in exogenous supply, plasma glucose concentration declined comparably in both groups: < or =30 wk, from 4.3 +/- 1.2 to 3.2 +/- 0.9 mM; >30 wk, from 3.7 +/- 0.7 to 3.0 +/- 0.6 mM. Thereafter, only in infants >30 wk an increase was observed, to 3.4 +/- 0.8 mM. Glucose production rate increased comparably in both groups: < or =30 wk, from 6.0 +/- 4.1 to 8.8 +/- 3.4 micromol x kg-1 x min-1; >30 wk, from 7.8 +/- 4.6 to 11.6 +/- 5.2 micromol x kg-1 x min-1. This increase was equivalent to approximately 30% of the decline in exogenous glucose. Gluconeogenesis increased comparably in both groups: <30 wk, from 3.2 +/- 1.2 to 4.5 +/- 1.3 micromol x kg-1 x min-1; >30 wk, from 4.3 +/- 1.9 to 6.8 +/- 2.9 micromol x kg-1 x min-1. We conclude that preterm infants can only partly compensate a decline in exogenous glucose supply by increasing endogenous glucose production rate, probably because of limitations in the final common pathway of intracellular glucose metabolism (i.e. glucose-6-phosphatase). The ability to maintain the plasma glucose concentration after a decrease in exogenous supply is better preserved in infants >30 wk owing to more efficient adaptation of peripheral glucose utilization.
 ...
PMID:Adaptation of glucose production and gluconeogenesis to diminishing glucose infusion in preterm infants at varying gestational ages. 1261 12

We studied in rats the expression of genes involved in gluconeogenesis from glutamine and glycerol in the small intestine (SI) during fasting and diabetes. From Northern blot and enzymatic studies, we report that only phosphoenolpyruvate carboxykinase (PEPCK) activity is induced at 24 h of fasting, whereas glucose-6-phosphatase (G-6-Pase) activity is induced only from 48 h. Both genes then plateau, whereas glutaminase and glycerokinase strikingly rebound between 48 and 72 h. The two latter genes are fully expressed in streptozotocin-diabetic rats. From arteriovenous balance and isotopic techniques, we show that the SI does not release glucose at 24 h of fasting and that SI gluconeogenesis contributes to 35% of total glucose production in 72-h-fasted rats. The new findings are that 1) the SI can quantitatively account for up to one-third of glucose production in prolonged fasting; 2) the induction of PEPCK is not sufficient by itself to trigger SI gluconeogenesis; 3) G-6-Pase likely plays a crucial role in this process; and 4) glutaminase and glycerokinase may play a key potentiating role in the latest times of fasting and in diabetes.
 ...
PMID:Induction of control genes in intestinal gluconeogenesis is sequential during fasting and maximal in diabetes. 1455 23

Tetrahymena pyriformis contains platelet-activating factor (PAF) as a minor lipid, which is biosynthesized de novo. A dithiothreitol-insensitive CDP-choline:cholinephosphotransferase (AAG-CPT), which utilizes alkyl-acetyl-glycerol as a substrate, had been detected in both the mitochondrial and microsomal fractions of the protozoan. In the present report, localization of this enzyme in submitochondrial fractions was studied. Cell fractionation was evaluated with enzyme and morphological markers. In this respect, succinate dehydrogenase, NADPH:cytochrome c reductase, glucose-6-phosphatase, alkaline phosphatase, monoaminoxidase, and cytochrome c oxidase activities were investigated. In the presence of antimycin A, mitochondrial activity of NADPH-cytochrome c reductase, was increased, while the microsomal one was reduced. Cardiolipin was distributed in the inner mitochondrial membrane. Alkaline phosphatase was found exclusively in the cytosol of the protozoan. The main portion of the dithiothreitol-insensitive AAG-CPT was localized in the inner mitochondrial membrane. Our data indicate that mitochondria are able to produce PAF, which might be associated with their function.
 ...
PMID:Localization of an alkyl-acetyl-glycerol-CDP-choline: cholinephosphotransferase activity in submitochondrial fractions of Tetrahymena pyriformis. 1470 14

In vitro studies suggest that the mitochondrial glycerol-3-phosphate acyltransferase-1 (mtGPAT1) isoform catalyzes the initial and rate-controlling step in glycerolipid synthesis and aids in partitioning acyl-CoAs toward triacylglycerol synthesis and away from degradative pathways. To determine whether the absence of mtGPAT1 would increase oxidation of acyl-CoAs and restrict the development of hepatic steatosis, we fed wild type and mtGPAT1-/- mice a diet high in fat and sucrose (HH) for 4 months to induce the development of obesity and a fatty liver. Control mice were fed a diet low in fat and sucrose (LL). With the HH diet, absence of mtGPAT1 resulted in increased partitioning of acyl-CoAs toward oxidative pathways, demonstrated by 60% lower hepatic triacylglycerol content and 2-fold increases in plasma beta-hydroxybutyrate, acylcarnitines, and hepatic mRNA expression of mitochondrial HMG-CoA synthase. Despite the increase in fatty acid oxidation, liver acyl-CoA levels were 3-fold higher in the mtGPAT1-/- mice fed both diets. A lack of difference in CPT1 and FAS mRNA expression between genotypes suggested that the increased acyl-CoA content was not because of increased de novo synthesis, but instead, to an impaired ability to use long-chain acyl-CoAs derived from the diet, even when the dietary fat content was low. Hyperinsulinemia and reduced glucose tolerance on the HH diet was greater in the mtGPAT1-/- mice, which did not suppress the expression of the gluconeogenic genes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This study demonstrates that mtGPAT1 is essential for normal acyl-CoA metabolism, and that the absence of hepatic mtGPAT1 results in the partitioning of fatty acids away from triacylglycerol synthesis and toward oxidation and ketogenesis.
 ...
PMID:Mitochondrial glycerol-3-phosphate acyltransferase-1 is essential in liver for the metabolism of excess acyl-CoAs. 1587 74

Recent studies indicate that renal gluconeogenesis is substantially stimulated in patients with type 2 diabetes, but the mechanism that is responsible for such stimulation remains unknown. Therefore, this study tested the hypothesis that renal gluconeogenesis is intrinsically elevated in the Zucker diabetic fatty rat, which is considered to be an excellent model of type 2 diabetes. For this, isolated renal proximal tubules from diabetic rats and from their lean nondiabetic littermates were incubated in the presence of physiologic gluconeogenic precursors. Although there was no increase in substrate removal and despite a reduced cellular ATP level, a marked stimulation of gluconeogenesis was observed in diabetic relative to nondiabetic rats, with near-physiologic concentrations of lactate (38%), glutamine (51%) and glycerol (66%). This stimulation was caused by a change in the fate of the substrate carbon skeletons resulting from an increase in the activities and mRNA levels of the key gluconeogenic enzymes that are common to lactate, glutamine, and glycerol metabolism, i.e., mainly of phosphoenolpyruvate carboxykinase and, to a lesser extent, of glucose-6-phosphatase and fructose-1,6-bisphosphatase. Experimental evidence suggests that glucocorticoids and cAMP were two factors that were responsible for the long-term stimulation of renal gluconeogenesis observed in the diabetic rats. These data provide the first demonstration in an animal model that renal gluconeogenesis is upregulated by a long-term mechanism during type 2 diabetes. Together with the increased renal mass (38%) observed, they lend support to the view so far based only on in vivo studies performed in humans that renal gluconeogenesis may be stimulated by and crucially contribute to the hyperglycemia of type 2 diabetes.
 ...
PMID:Intrinsic gluconeogenesis is enhanced in renal proximal tubules of Zucker diabetic fatty rats. 1639 63


<< Previous 1 2 3 4 5 6 7 Next >>