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)

A model of maternal lipemia without hyperglycemia, in the rat, produced by high-fat feedings, was developed to study the effects of and abnormal maternal lipid homeostasis on placental transport of nutrients and possible alterations of key enzymes of energy metabolism in the liver and brain of the fetuses. Pregnant rats fed lower concentrations of fat served as controls. All studies were carried out in dams and fetuses one day prior to delivery. The dietary treatment of the dams and fetuses produced in the fetuses ketonemia as well as lipemia. Following a bolus of 14C-3-0-methyl-D-glucose to the dams, the levels of the tracer remained higher in the blood and brain of lipemic than in control fetuses. By contrast, there was a decrease in the fluxes of 14C-alpha-amino-isobutyric acid in the fetuses of lipemic dams as compared to controls. Among enzymes of energy metabolism, fetal liver glucose-6-phosphatase and succinic dehydrogenase were enhanced by lipemia. Fetal brain glucose-6-phosphatase was depressed. Thus, lipemia, as occurring in poorly controlled maternal diabetes, may be a factor in determining the access to the fetus of essential, neutral amino acids and alter the normal activity of energy metabolism enzymes in the fetus.
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PMID:Placental permeability and energy metabolism enzymes in fetuses of lipemic rats. 710 47

The molecular basis for the beta-cell dysfunction that characterizes non-insulin-dependent diabetes mellitus (NIDDM) is unknown. The Zucker diabetic fatty (ZDF) male rat is a rodent model of NIDDM with a predictable progression from the prediabetic to the diabetic state. We are using this model to study beta-cell function during the development of diabetes with the goal of identifying genes that play a key role in regulating insulin secretion and, thus, may be potential targets for therapeutic intervention aimed at preserving or improving beta-cell function. As a first step, we have characterized morphology, insulin secretion, and pattern of gene expression in islets from prediabetic and diabetic ZDF rats. The development of diabetes was associated with changes in islet morphology, and the islets of diabetic animals were markedly hypertrophic with multiple irregular projections into the surrounding exocrine pancreas. In addition, there were multiple defects in the normal pattern of insulin secretion. The islets of prediabetic ZDF rats secreted significantly more insulin at each glucose concentration tested and showed a leftward shift in the dose-response curve relating glucose concentration and insulin secretion. Islets of prediabetic animals also demonstrated defects in the normal oscillatory pattern of insulin secretion, indicating the presence of impairment of the normal feedback control between glucose and insulin secretion. The islets from diabetic animals showed further impairment in the ability to respond to a glucose stimulus. Changes in gene expression were also evident in islets from prediabetic and diabetic ZDF rats compared with age-matched control animals. In prediabetic animals, there was no change in insulin mRNA levels. However, there was a significant 30-70% reduction in the levels of a large number of other islet mRNAs including glucokinase, mitochondrial glycerol-3-phosphate dehydrogenase, voltage-dependent Ca2+ and K+ channels, Ca(2+)-ATPase, and transcription factor Islet-1 mRNAs. In addition, there was a 40-50% increase in the levels of glucose-6-phosphatase and 12-lipoxygenase mRNAs. There were further changes in gene expression in the islets from diabetic ZDF rats, including a decrease in insulin mRNA levels that was associated with reduced islet insulin levels. Our results indicate that multiple defects in beta-cell function can be detected in islets of prediabetic animals well before the development of hyperglycemia and suggest that changes in the normal pattern of gene expression contribute to the development of beta-cell dysfunction.
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PMID:Evolution of beta-cell dysfunction in the male Zucker diabetic fatty rat. 758 53

Genetically diabetic db/db mice and their normoglycemic littermates (+/+ mice) were studied to determine plasma levels of glucose, glucagon and insulin and hepatic gluconeogenic enzyme activities. Plasma glucose levels did not differ significantly between the 5-week-old db/db and +/+ mice, but increased with age in the former until the animals were 16-week-old. Similar age-associated changes were observed in the activities of the gluconeogenic enzymes, glucose-6-phosphatase (G-6-Pase) and fructose-1,6-diphosphatase (F-1,6-DPase). While the plasma levels of insulin and glucagon that peaked at 7 weeks of age did not parallel the hyperglycemia, the plasma glucagon/insulin (G/I) ratio roughly paralleled the hyperglycemia. Analysis of individual values for the db/db mice revealed statistically significant (P < 0.001) correlations between plasma glucose levels and hepatic G-6-Pase (r = 0.78) or F-1,6-DPase (r = 0.74) activity. There were also significant correlations between the G/I ratio and plasma glucose levels (P < 0.001, r = 0.66), hepatic G-6-Pase (P < 0.01, r = 0.48) or F-1,6-DPase (P < 0.01, r = 0.57) activity. It is thus concluded that the relative predominance of glucagon over insulin action plays an important role in the age-associated development of hyperglycemia in db/db mice. Glucagon presumably activates the hepatic gluconeogenic enzymes to enhance hepatic glucose output.
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PMID:The possible role of age-related increase in the plasma glucagon/insulin ratio in the enhanced hepatic gluconeogenesis and hyperglycemia in genetically diabetic (C57BL/KsJ-db/db) mice. 786 14

2,5-Anhydro-D-mannitol (AM), a putative gluconeogenesis inhibitor, completely reversed the hyperglycemia in genetically diabetic (db/db) mice that exhibited hyperinsulinemia and enhanced hepatic gluconeogenic enzyme (glucose-6-phosphatase (G-6-Pase) and fructose-1,6-diphosphatase (F-1,6-DPase)) activities compared with the control +/+ mice. In contrast, AM only partially reversed the hyperglycemia of streptozotocin (STZ)-treated +/+ mice in which the hepatic gluconeogenic enzyme activities were enhanced to the same degree as in the db/db mice, whereas the blood insulin level was depressed. In the db/db mice, the STZ-treatment attenuated the hyperinsulinemia and exaggerated the hyperglycemia as well as the hepatic gluconeogenic enzyme activities, and it greatly reduced the hypoglycemic action of AM. Not only the dose-response curve of AM but also the time-course of the blood glucose level (expressed as % of pre-treatment value) following 320 mg/kg of AM were almost identical between +/+, STZ-treated +/+ and STZ-treated db/db mice. In the STZ-treated +/+ mice, a combination treatment of insulin (320 micrograms/kg) with AM (320 mg/kg) caused hypoglycemia that was greater than that induced by AM or insulin alone. On the other hand, in vitro studies with purified F-1,6-DPase revealed that phosphorylated AM (AM-1,6-diphosphate) but not AM itself inhibited the gluconeogenic enzyme activities. These results suggest that inhibition of gluconeogenesis is responsible, at least in part, for the hypoglycemic activity of AM. AM appears to inhibit hepatic gluconeogenic enzyme activities after being phosphorylated by an insulin-dependent mechanism.
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PMID:Differential hypoglycemic effect of 2,5-anhydro-D-mannitol, a putative gluconeogenesis inhibitor, in genetically diabetic (db/db) and streptozotocin-induced diabetic mice. 786 20

We wished to determine whether the elevated glucose cycling (GC) between glucose and glucose-6-phosphate (G<-->G6P) in diabetes can be reversed with acute insulin treatment. In six insulin-deprived, anesthetized, depancreatized dogs, insulin was infused for 6-9 h at a starting dose of 45-150 pmol.kg-1.min-1 to normalize plasma glucose from 23.9 +/- 1.4 to 5.0 +/- 0.4 mmol/l and gradually decreased to and maintained at a basal rate (1.7 +/- 1.0 pmol.kg-1.min-1) during the last 3 h. GC, measured with [2-3H]- and [6-3H]glucose, fell markedly from 15.3 +/- 2.7 and normalized at 1.3 +/- 0.6 mumol.kg-1.min-1 (P < 0.001). This occurred because total hepatic glucose output fell much more (from 41.2 +/- 3.1 to 11.6 +/- 1.2) than did glucose production (from 25.9 +/- 1.9 to 10.3 +/- 1.0 mumol.kg-1.min-1) (both P < 0.01). Freeze-clamped liver biopsies were taken at timed intervals for measurements of hepatic enzymes and substrates. The elevated hepatic hexose-6-phosphate levels decreased with insulin infusion (151 +/- 24 vs. 71 +/- 13 nmol/g, P < 0.01). Maximal activities of glucose-6-phosphatase (G6Pase) (from 17.6 +/- 0.8 to 19.6 +/- 2.6 U/g) and glucokinase (from 1.1 +/- 0.2 to 1.0 +/- 0.2 U/g) did not change. Insulin infusion resulted in a threefold increase (P < 0.05) in the activity of glycogen synthase (active form), but had no effect on hepatic glycogen content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Importance of substrate changes in the decrease of hepatic glucose cycling during insulin infusion and declining glycemia in the depancreatized dog. 792 1

Increased hepatic glucose production (HGP) is the major cause of fasting hyperglycemia in all forms of diabetes. Glucokinase (GK) and glucose-6-phosphatase (Glc-6-Pase) are the proximal and the distal enzymatic steps, respectively, in the regulation of HGP. We examined the impact of changes in GK and Glc-6-Pase activities on in vivo hepatic glucose fluxes in diabetic (D) and control (C) rats. In particular, the acute regulation by insulin was investigated using the euglycemic hyperinsulinemic clamp technique in conscious rats. In experimental diabetes (6 weeks): (a) GK mRNA was decreased by approximately 40%; (b) the Vmax of GK was markedly decreased (approximately 4 versus 9 mumol/g wet weight/min) and that of Glc-6-Pase was 2-fold increased (approximately 30 versus 15 mumol/g wet weight/min, D versus C), while (c) the Km of GK (approximately 10 mM) and Glc-6-Pase (approximately 1.5 mM) were unchanged. HGP was increased by 65% in diabetes and correlated highly with the ratio of Glc-6-Pase/GK (r = 0.81, p < 0.01). Following acute hyperinsulinemia (2 h): (a) GK mRNA increased by approximately 2-fold in both C and D; (b) GK Vmax did not change in C, but doubled to near-normal in D; (c) Glc-6-Pase Vmax decreased by 23% in C and by 34% in D; (d) the Km of GK decreased by approximately 40% (p < 0.01) in C. Acute hyperinsulinemia almost completely inhibited HGP in both C and D, and no correlation was demonstrated between HGP and the ratio of Glc-6-Pase/GK in these groups. Our data suggest that GK and Glc-6-Pase are important determinants of fasting HGP in diabetes. However, acute changes in Glc-6-Pase and GK activities can account for only a small portion of the in vivo inhibition of hepatic glucose flux by insulin, suggesting additional mechanisms for the short-term regulation of HGP.
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PMID:Role of glucokinase and glucose-6-phosphatase in the acute and chronic regulation of hepatic glucose fluxes by insulin. 822 65

The New Zealand obese mouse, a model of NIDDM, is characterized by hyperglycemia, hyperinsulinemia, and hepatic and peripheral insulin resistance. The aim of this study was to investigate the biochemical basis of hepatic insulin resistance in NZO mice. Glycolytic and gluconeogenic enzyme activities were measured in fed and overnight fasted 19- to 20-wk-old NZO and control New Zealand chocolate mice. The NZO mice were twice as heavy as the NZC mice. The activity of the glycolytic enzymes glucokinase and pyruvate kinase was higher, whereas that of the gluconeogenic enzymes PEPCK and glucose-6-phosphatase was lower in fed and fasted NZO mice. These enzyme changes are consistent with a normal response to the hyperinsulinemia in NZO mice. In contrast, the activity of the third regulated gluconeogenic enzyme, fructose-1,6-bisphosphatase, was similar in fed and fasted NZO and NZC mice despite the higher insulin and glucose levels in the NZO mouse. This enzyme is primarily regulated by the powerful inhibitor fructose-2,6-bisphosphate. The levels of this metabolite were measured and found to be increased in both the fed and fasted states in the NZO mouse, suggesting that the activity of the bifunctional enzyme that regulates the level of inhibitor (6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase) is normally regulated in the NZO mouse. We conclude that most insulin-responsive gluconeogenic and glycolytic enzymes are normally regulated in the NZO mouse, but an abnormality in the regulation of fructose-1,6-bisphosphatase may contribute to the increase hepatic glucose production in these mice.
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PMID:Impaired regulation of hepatic fructose-1,6-bisphosphatase in the New Zealand obese mouse model of NIDDM. 824 19

The specific effect of hyperglycemia on the reported decrease in liver glycogen synthase phosphatase activity was studied in STZ-induced diabetic rats with normal fasting insulinemia. Four groups of animals were investigated: control (nondiabetic), diabetic hyperglycemic (STZ), diabetic normoglycemic (STZ followed by 3-day phloridzin treatment), and a diabetic normoglycemic group injected with glucose to reinstate hyperglycemia. None of the treatments significantly altered fasting plasma insulin and glucagon concentrations. We found that hepatic synthase phosphatase activity decreased in STZ-induced diabetic rats and was further markedly reduced when glycemia was normalized in the diabetic animals. This additional decrease in phosphatase activity was almost fully reversed when hyperglycemia was restored by acute glucose infusion of the normoglycemic diabetic rats. In parallel, the levels of liver G6P and F6P were markedly reduced in the diabetic normoglycemic rats and restored with reinstatement of hyperglycemia. In contrast, liver microsomal glucose-6-phosphatase activity was enhanced and glucokinase activity was lowered in all diabetic groups, regardless of glycemia. Our results indicate that hyperglycemia per se counteracts part of the loss of hepatic synthase phosphatase in diabetic animals and provokes the stable conversion of synthase phosphatase from a less active to a more active form.
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PMID:Opposite effects of hyperglycemia and insulin deficiency on liver glycogen synthase phosphatase activity in the diabetic rat. 838 Oct 96

To examine the relationship between the plasma glucose concentration (PG) and the pathways of hepatic glucose production (HGP), five groups of conscious rats were studied after a 6-h fast: (a) control rats (PG = 8.0 +/- 0.2 mM); (b) control rats (PG = 7.9 +/- 0.2 mM) with somatostatin and insulin replaced at the basal level; (c) control rats (PG = 18.1 +/- 0.2 mM) with somatostatin, insulin replaced at the basal level, and glucose infused to acutely raise plasma glucose by 10 mM; (d) control rats (PG = 18.0 +/- 0.2 mM) with somatostatin and glucose infusions to acutely reproduce the metabolic conditions of diabetic rats, i.e., hyperglycemia and moderate hypoinsulinemia; (e) diabetic rats (PG = 18.4 +/- 2.3 mM). All rats received an infusion of [3-3H]glucose and [U-14C]lactate. The ratio between hepatic [14C]UDP-glucose sp act (SA) and 2X [14C]-phosphoenolpyruvate (PEP) SA (the former reflecting glucose-6-phosphate SA) measured the portion of total glucose output derived from PEP-gluconeogenesis. In control rats, HGP was decreased by 58% in hyperglycemic compared to euglycemic conditions (4.5 +/- 0.3 vs. 10.6 +/- 0.2 mg/kg.min; P < 0.01). When evaluated under identical glycemic conditions, HGP was significantly increased in diabetic rats (18.9 +/- 1.4 vs. 6.2 +/- 0.4 mg/kg.min; P < 0.01). In control rats, hyperglycemia increased glucose cycling (by 2.5-fold) and the contribution of gluconeogenesis to HGP (91% vs. 45%), while decreasing that of glycogenolysis (9% vs. 55%). Under identical plasma glucose and insulin concentrations, glucose cycling in diabetic rats was decreased (by 21%) and the percent contribution of gluconeogenesis to HGP (73%) was similar to that of controls (84%). These data indicate that: (a) hyperglycemia causes a marked inhibition of HGP mainly through the suppression of glycogenolysis and the increase in glucokinase flux, with no apparent changes in the fluxes through gluconeogenesis and glucose-6-phosphatase; under similar hyperglycemic hypoinsulinemic conditions: (b) HGP is markedly increased in diabetic rats; however, (c) the contribution of glycogenolysis and gluconeogenesis to HGP is similar to control animals.
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PMID:Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes. 839 19

It has been suggested that regulation of glucose-6-phosphatase by insulin plays a role in the suppression of hepatic glucose production during feeding. We used hepatic glucose production (measured with the D-[3-3H]glucose infusion method) as an indicator of substrate flux through glucose-6-phosphatase in vivo. Compared with saline controls, insulin (7 mU.min-1 x kg-1, euglycemic clamp) suppressed hepatic glucose production virtually completely in both fasted (32.4 +/- 2.4 vs. -6.1 +/- 14 mumol.min-1 x kg-1) and fed (64.6 +/- 6.4 vs. 5.5 +/- 5.2 mumol.min-1 x kg-1) rats. Whereas hepatic glucose production was totally suppressed, [glucose-6-phosphate] in liver cytosol declined by only 27 and 35% in fasted and fed rats, respectively. Addition of hyperglycemia (10 mM) to the insulin infusion likewise fully suppressed hepatic glucose production (26.9 +/- 1.4 vs. -9 +/- 10 mumol.min-1 x kg-1 and 80.8 +/- 10.1 vs. -3.6 +/- 12.6 mumol.min-1 x kg-1 in fasted and fed rats, respectively), but [glucose-6-phosphate] again declined only modestly (21 and 27% in fasted and fed rats, respectively). This disproportionate suppression of hepatic glucose production could not be explained by cooperative substrate effects inasmuch as microsomal glucose-6-phosphatase isolated from saline- and insulin-treated rats followed Michaelis-Menten kinetics (Hill coefficient approximated 1). Acute insulin treatment of fasted rats in vivo did not reproducibly inhibit glucose-6-phosphatase activity assayed subsequently in isolated microsomes incubated in the absence of insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of glucose-6-phosphatase in the action of insulin on hepatic glucose production in the rat. 840 3


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