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)

Studies were performed to examine the effects of alloxan- or streptozotocin-induced diabetes on carbon tetrachloride (CCl4) liver injury. Male rats were pretreated with single i.v. injections of alloxan monohydrate (40 or 80 mg/kg) or streptozotocin (65 mg/kg). A challenging dose of CCl4 (0.1 ml/kg i.p.) was given to rats 4 days after alloxan pretreatment or 5 days after streptozotocin pretreatment, and the animals were sacrificed 24 hours later. Biochemical and morphologic evidence was obtained to show that pretreatment with the diabetogenic agents markedly enhanced CCl4-induced hepatotoxity. The challenging dose of CCl4 had no effect on the serum glutamic pyruvic transaminase (SGPT) activity in control rats. However, the administration of this dose of CCl4 to rats pretreated with 40 and 80 mg/kg of alloxan as well as to rats pretreated with streptozotocin resulted in 11-, 68-, and 32-fold increases, respectively, in SGPT activity. Hepatic triglyceride concentrations in the diabetic rats were also markedly elevated above control values after CCl4 challenge. Alloxan- or streptozotocin-pretreatment alone did not enhance these biochemical parameters of liver injury. Hepatic glucose-6-phosphatase activity, which increased in the rats given a diabetogenic agent, was lowered as a result of CCl4 injection. Insulin treatment of rats given alloxan (80 mg/kg) markedly protected against CCl4-induced hepatotoxicity. The severity of the morphologic changes in diabetic rats given CCl4 correlated with the biochemical findings.
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PMID:Potentiation of carbon tetrachloride-induced hepatotoxicity in alloxan- or strepto- zotocin-diabetic rats. 16 33

Cell fractionation, enzyme analysis, and electron microscopy were used to study the effects of streptozotocin-induced diabetes and insulin replacement on liver structure and function. In liver homogenates from diabetic rats, glucose-6-phosphatase (G-6-Pase) activity was stimulated about 2 1/2-fold over that found in normal animals. Analyses of isolated rough and smooth microsomes from diabetic rats for G-6-Pase activity showed a fourfold increase in the smooth microsomes and a small increase in enzyme activity in rough microsomes when compared with these fractions from control animals. Associated with the increased enzyme activity was a reduction in liver glycogen. Insulin treatment of the diabetic rats caused a fall in homogenate G-6-Pase levels to approximately normal values and stimulated the accumulation of hepatic glycogen. Administration of insulin to these animals also caused a decrease in G-6-Pase activity, which was most pronounced in the smooth microsomes. Studies with the electron microscope revealed ultrastructural alterations in livers of the diabetic rats, which were most striking in the periportal region of the lobule. Periportal hepatocytes from diabetic rats displayed dispersed particles of glycogen separated by cytoplasm rich in SER rather than dense masses of glycogen with little SER, as is characteristic of these cells in normal animals. Centrilobular cells from the diabetic animals displayed some disorganization of the RER and a dispersed pattern of glycogen with abundant SER, similar to the pattern found in these cells from normal animals. After insulin treatment the periportal cells appeared normal morphologically, whereas the centrilobular hepatocytes displayed regions of both dense masses and dispersed glycogen. In the glycogen masses, little SER was found; however, in the areas of dispersed glycogen particles, an abundance of this organelle was evident. We conclude from these studies that diabetes causes an increase in amount of hepatic smooth endoplasmic reticulum (SER), especially within periportal hepatocytes. The results of cell fractionation indicate that membranes of the smooth endoplasmic reticulum are enriched in G-6-pase. We interpret these results to indicate that diabetes causes hepatocytes to form additional smooth endoplasmic reticulum with specialized membranes, at least with respect to G-6-Pase. It is suggested that this cellular specialization is a response of the hepatocyte to the diabetic state, namely, a demand for increased hepatic glucose production and release into the blood stream, thus contributing to the hyperglycemia characteristic of this disease. Insulin administration to the diabetic animals reverses the above alterations.
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PMID:Hepatic glucose-6-phosphatase activities and correlated ultrastructural alterations in hepatocytes of diabetic rats. 22 Dec 99

The ten-fold increase in glucose-6-phosphatase, previously reported, in 2S FAZA hepatoma cells exposed to dexamethasone, is completely blocked by low concentrations of insulin. At 3 x 10(-10) M insulin, the activity induced by 10(-6) M dexamethasone is reduced by half. The activity of intact microsomes, which reflects translocation of cytoplasmic glucose 6-phosphate into the endoplasmic reticulum, is induced by dexamethasone, but to a lesser extent than the hydrolase. Insulin also prevents this induction.
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PMID:Effect of insulin on the induction by dexamethasone of glucose-6-phosphohydrolase and translocase activities in cultured hepatoma cells. 283 6

Insulin resistance has been measured in man by nonsteady state tracer methodology. Increase in overall glucose utilization and suppression of glucose production was measured when hyperglycemia was achieved either by infusing glucagon or glucose. With the first method, insulin resistance was assessed in obese man and in lean hypertriglyceridemic patients. With the second method, insulin resistance was assessed in lean mild type II diabetics. These methodologies can only assess deficiences in overall glucose utilization and glucose production, but cannot delineate the defect in glucose uptake by the liver. However, if a given metabolic event is essentially characteristic of only one organ, metabolic abnormalities specific to that organ can be detected in vivo provided there is a probe specific to that metabolic pathway. Therefore, in lean mild type II diabetics the liver glucose futile cycle was assessed by a double tracer method. Previously it was shown that liver glucose futile cycling is increased in diabetic dogs. In healthy control subjects in basal state and during glucose infusion, the futile cycle could not be detected, but it represented a major part of glucose metabolism in liver of type II diabetics. It appears, therefore, that most of the glucose taken up by the liver during the glucose challenge in diabetics reenters the blood stream without being oxidized or polymerized. On the basis of these studies, it was concluded that excessive hyperglycemia in the diabetics during glucose infusion is due to a decrease in irreversible glucose uptake (impaired phosphorylation and futile cycling) and to a decrease in suppression of glucose production. The relative contribution of the liver and periphery to hyperglycemia seems to be almost equivalent. The mechanism behind the increased glucose cycle activity is not clear. It may be due to a relative decrease of glycogen synthase or increase in glucose-6-phosphatase or both. These observations in mild lean type II diabetics may have implications also in some other types of diabetes, since we have observed that futile cycling is even more marked in obese type II diabetics and that it could account in part for the diabetogenic effect of growth hormone in acromegalics.
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PMID:New probes to study insulin resistance in men; futile cycle and glucose turnover. 389 64

This study examines the early hepatic biochemical and ultrastructural responses to insulin replacement in streptozotocin-diabetic rats and insulin withdrawal from insulin-maintained diabetic rats. Insulin administration rapidly lowered plasma glucose and the elevated glucose-6-phosphatase (G-6-Pase) specific activity of the diabetic rats. However, hepatic glycogen did not increase until after 3 hr of insulin treatment. Hepatic ultrastructure responded to insulin replacement after the decline in glucose and G-6-Pase. This was seen in periportal hepatocytes as a reduction in the close association between smooth endoplasmic reticulum (SER) and glycogen particles in the diabetic animals. The treated rats showed hepatic SER restricted to the periphery of glycogen masses, as is characteristic of these cells from normal rats, in many cells by 6 hr and all cells by 18 hr. Insulin withdrawal from insulin-treated diabetic rats elicited nearly a total reversal of the above events. Plasma insulin declined to a value half that of the normal rats by 6 hr after withdrawal; concurrently, plasma glucose rose sharply to hyperglycemic values as hepatic glycogen content dropped. Following the rise in plasma glucose and fall in glycogen content, G-6-Pase specific activity increased and by 16 hr reached the high values characteristic of the diabetic animal. Hepatic ultrastructure was also changed as evidenced by an intrusion of elements of the SER into the dense glycogen masses; the result was dispersed glycogen closely associated with SER as seen in the diabetic animal. It is concluded that the hepatic response to insulin replacement in diabetic animals and diabetic onset in insulin-withdrawn animals is rapid and occurs through defined stages.
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PMID:The effects of insulin replacement and withdrawal on hepatic ultrastructure and biochemistry. 623 42

In diabetic rats transplanted with fetal pancreata we measured the activities of six important enzymes to assess the return of liver metabolism to normal. Comparison was made among the responses of transplanted rats with and without renal-portal vein shunts and of those not transplanted and injected with insulin in varying doses. Insulin supply was not limited since three or four fetal pancreata were first grown in normal rats before transfer into the diabetic animals. Transplantation normalized blood and urine glucose and the rate of disappearance of intravenous glucose. Glucokinase and pyruvate kinase activities in liver rose toward normal at 7 days after transplantation and reached normal levels at 30 and 90 days. The response of the other four enzymes, glucose-6-phosphate dehydrogenase, citric lyase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase, was more rapidly restored to normal at 7 days and remained normal at 30 and 90 days. No difference was observed in the enzyme activities of transplanted-shunted rats to nonshunted animals. Glucokinase activity was restored to normal after 1 wk of daily injections of 1 U of PZI; pyruvate kinase restoration required 3 U/day. Glucose-6-phosphate dehydrogenase and citric lyase required 2 U/day to be restored to normal; 3 U daily resulted in temporary supernormal activities. The gluconeogenic enzymes, fructose-1,6-bisphosphatase and glucose-6-phosphatase, were only partially suppressed toward normal by insulin even with 3 U daily for 3 wk. These findings indicate that pancreas transplantation is a more effective regulator of liver metabolism in diabetes than insulin injections.
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PMID:Normalization of six key hepatic enzymes after fetal pancreas transplantation in diabetic rats. 630 89

Although the activity of glucose-6-phosphatase in rat liver is altered markedly following the administration of a variety of hormones in vivo, it is not certain whether the hormones act directly on the hepatocyte. To study this problem hepatocytes were isolated by a collagenase-perfusion technique and cultured on collagen gel/nylon mesh membranes. The activity of glucose 6-phosphatase in cells cultured with fetal calf serum and with Dulbecco's modified Eagle's medium or Leibovitz L-15 medium decreased to less than 10-30% of the activity in freshly isolated cells by 96 h. However, when L-15 plus newborn or fetal calf serum was supplemented with glucagon (10(-6)M), epinephrine (10(-6)M), triiodothyronine (10(-6)M), and dexamethasone (10(-5)M) (L-15-GETD), the activity of glucose-6-phosphatase was maintained so that, after 144 h, the activity was at least 80% of that detected in freshly isolated cells. In cells cultured in L-15 plus serum for 72 or 96 h and then in L-15-GETD, glucose-6-phosphatase increased 30-50% over that in control cultures after 24 h. Insulin, which decreases glucose-6-phosphatase activity when administered to intact animals, also decreased the glucose-6-phosphatase activity in cultured hepatocytes to 20-50% of that in controls.
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PMID:Effects of hormones on the activity of glucose-6-phosphatase in primary cultures of rat hepatocytes. 631 98

The regenerating liver after partial hepatectomy is one of the few physiologic models of cellular proliferation in the adult animal. During hepatic regeneration, the animal is able to maintain metabolic homeostasis despite the acute loss of two thirds of hepatic tissue. In examining the molecular mechanisms regulating hepatic regeneration, we isolated novel immediate-early genes that are rapidly induced as the remnant liver undergoes the transition from its normal quiescent state into the G1 phase of the cell cycle. One of the most rapidly and highly induced genes which we initially termed RL-1, encodes rat glucose-6-phosphatase (rG6Pase). G6Pase mRNA peaks at 30 min and 36-48 h after hepatectomy correlating with the first and second rounds of cell division. This finding is compatible with studies that showed that G6Pase enzyme activity increases during liver regeneration. However, the increase in G6Pase mRNA is much more dramatic, indicating that it is a more sensitive indicator of this regulation. G6Pase gene expression peaks in the perinatal time period in the liver and remains elevated during the first month of life. The expression of the G6Pase gene is also dramatically elevated in BB diabetic rats, again higher than the enzyme elevation, and its relative induction after partial hepatectomy is blunted in these animals. Insulin treatment of partially hepatectomized diabetic animals downregulates the expression of G6Pase mRNA. Using specific antibodies against G6Pase, we detect a 36-kD G6Pase protein, and its level is elevated in regenerating and diabetic livers. The pattern of G6Pase mRNA expression appears to reflect similar changes in insulin and glucagon levels which accompany diabetes and hepatic proliferation. The elevation of G6Pase expression in these conditions is indicative of its importance as a regulator of glucose homeostasis in normal and abnormal physiologic states.
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PMID:High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes. 786 Jul 67

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

We have cloned and sequenced the first 1.2 kb of the 5' region of the human glucose-6-phosphatase gene. Transfection of H4IIE hepatoma cells with the 1.2 kb fragment fused to a luciferase reporter gene demonstrated both basal and hormone responsive luciferase activity. Dexamethasone increased and insulin decreased luciferase activity. Insulin and dibutyryl cyclic AMP both significantly decreased activity in the presence of dexamethasone.
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PMID:Cloning and sequencing of the 5' region of the human glucose-6-phosphatase gene: transcriptional regulation by cAMP, insulin and glucocorticoids in H4IIE hepatoma cells. 861 93


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