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 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 mRNA abundance of several hepatic glycolytic and gluconeogenic enzymes and blood hormone concentrations were determined in hemorrhagic hypotension-induced rats before and after resuscitation with lactated Ringer's. Northern blot analysis of total liver RNA after 30 min of hemorrhage showed control values for phospho-enolpyruvate carboxykinase and fructose-1,6-bisphosphatase mRNA, but significantly lower values for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF2K/FBPase) as well as 2.5-fold increases in glucose-6-phosphatase (Glu-6-Pase) mRNA. The latter finding is in agreement with the greatly reduced intracellular levels of fructose-6-phosphate and glucose-6-phosphate, and the results are consistent with a rapid activation of hepatic gluconeogenesis by the concomitant decrease in 6PF2K/FBPase and increase in Glu-6-Pase. Blood insulin levels were decreased during hemorrhage and with resuscitation, whereas glucocorticoids were increased 1.5-fold in both cases. Glucagon was unchanged during hemorrhage, but was reduced with resuscitation. Lactated Ringer's resuscitation seemed to affect 6PF2K/FBPase only, which was restored to, and even exceeded, control values. In contrast, Glu-6-Pase mRNA was increased to fourfold control values. The increase in Glu-6-Pase and the decrease in 6PF2K/FBPase mRNA is probably at the level of altered transcriptional rates, because insulin, which plays a dominant role in the regulation of these genes, was decreased during hemorrhage. It remains to be determined what factors are causing further induction of Glu-6-Pase gene after lactated Ringer's resuscitation when hepatic glucose metabolism seems to have reverted to the glycolytic mode.
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PMID:Alterations in hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and glucose-6-phosphatase gene expression after hemorrhagic hypotension and resuscitation. 936 51

Hepatic glucose production is increased as a metabolic consequence of insulin resistance in type 2 diabetes. Because fructose 2,6-bisphosphate is an important regulator of hepatic glucose production, we used adenovirus-mediated enzyme overexpression to increase hepatic fructose 2,6-bisphosphate to determine if the hyperglycemia in KK mice, polygenic models of type 2 diabetes, could be ameliorated by reduction of hepatic glucose production. Seven days after treatment with virus encoding a mutant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase designed to increase fructose 2,6-bisphosphate levels, plasma glucose, lipids, and insulin were significantly reduced in KK/H1J and KK.Cg-A(y)/J mice. Moreover, high fructose 2,6-bisphosphate levels downregulated glucose-6-phosphatase and upregulated glucokinase gene expression, thereby reversing the insulin-resistant pattern of hepatic gene expression of these two key glucose-metabolic enzymes. The increased hepatic fructose 2,6-bisphosphate also reduced adiposity in both KK mice. These results clearly indicate that increasing hepatic fructose 2,6-bisphosphate overcomes the impairment of insulin in suppressing hepatic glucose production, and it provides a potential therapy for type 2 diabetes.
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PMID:Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes. 1173 81

The effects of fructose-2,6-bisphosphate (F-2,6-P(2)) on hepatic glucokinase (GK) and glucose-6-phosphatase (G-6-Pase) gene expression were investigated in streptozotocin-treated mice, which exhibited undetectable levels of insulin. Hepatic F-2,6-P(2) levels were manipulated by adenovirus-mediated overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Streptozotocin treatment alone or with infusion of control adenovirus leads to a dramatic decrease in hepatic F-2,6-P(2) content compared with normal nondiabetic mice. This is accompanied by a 14-fold decrease in GK and a 3-fold increase in G-6-Pase protein levels, consistent with a diabetic phenotype. Streptozotocin-treated mice that were infused with adenovirus-overexpressing an engineered 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase with high kinase activity and little bisphosphatase activity showed high levels of hepatic F-2,6-P(2). Surprisingly, these mice had a 13-fold increase in GK protein and a 2-fold decrease in G-6-Pase protein compared with diabetic controls. The restoration of GK is associated with increases in the phosphorylation of Akt upon increasing hepatic F-2,6-P(2) content. Moreover, the changes in levels of F-2,6-P(2) and Akt phosphorylation revealed a pattern similar to that of streptozotocin mice treated with insulin, indicating that increasing hepatic content of F-2,6-P(2) mimics the action of insulin. Because G-6-Pase gene expression was down-regulated only after the restoration of euglycemia, the effect of F-2,6-P(2) was indirect. Also, the lowering of blood glucose by high F-2,6-P(2) was associated with an increase in hepatic nuclear factor 1-alpha protein, a transcription factor involved in G-6-Pase gene expression. In conclusion, F-2,6-P(2) can stimulate hepatic GK gene expression in an insulin-independent manner and can secondarily affect G-6-Pase gene expression by lowering the level of plasma glucose.
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PMID:A potential role for fructose-2,6-bisphosphate in the stimulation of hepatic glucokinase gene expression. 1461 77

Fructose-2,6-bisphosphate (F26P2) was identified as a regulator of glucose metabolism over 25 years ago. A truly bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PFK2/FBP2), with two active sites synthesizes F26P2 from fructose-6-phosphate (F6P) and ATP or degrades F26P2 to F6P and Pi. In the classic view, F26P2 regulates glucose metabolism by allosteric effects on 6-phosphofructo-1-kinase (6PFK1, activation) and fructose-1,6-bisphosphatase (FBPase, inhibition). When levels of F26P2 are high, glycolysis is enhanced and gluconeogenesis is inhibited. In this regard, altering levels of F26P2 via 6PFK2/FBP2 overexpression has been used for metabolic modulation, and has been shown capable of restoring euglycemia in rodent models of diabetes. Recently, a number of novel observations have suggested that F26P2 has much broader effects on the enzymes of glucose metabolism. This is evidenced by the effects of F26P2 on the gene expression of two key glucose metabolic enzymes, glucokinase (GK) and glucose-6-phosphatase (G6Pase). When levels of F26P2 are elevated in the liver, the gene expression and protein amount of GK is increased whereas G6Pase is decreased. These coordinated changes in GK and G6Pase protein illustrate how F26P2 regulates glucose metabolism. F26P2 also affects the gene expression of enzymes related to lipid metabolism. When F26P2 levels are elevated in liver, the expression of two key lipogenic enzymes, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) is reduced, contributing to a unique coordinated decrease in lipogenesis. When combined, F26P2 effects on glucose and lipid metabolism provide cooperative regulation of fuel metabolism. The regulatory roles for F26P2 have also expanded to transcription factors, as well as certain key proteins (enzymes) of signaling and/or energy sensoring. Although some effects may be secondary to changes in metabolite levels, high levels of F26P2 have been shown to regulate protein amount and/or phosphorylation state of hepatic nuclear factor 1-alpha (HNF1alpha), carbohydrate response element binding protein (ChREBP), peroxisome proliferators-activated receptor alpha (PPARalpha), and peroxisome proliferators-activated receptor gamma co-activator 1beta (PGC1beta), as well as Akt and AMP-activated protein kinase (AMPK). Importantly, changes in these transcription factors, signaling proteins, and sensor proteins are produced in a way that appropriately coordinates whole body fuel metabolism.
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PMID:Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: beyond its allosteric effects on glycolytic and gluconeogenic enzymes. 1686 Mar 76

Glucose plays a key role as energy source in the majority of mammals, but its importance in fish appears limited. Until now, the physiological basis for such apparent glucose intolerance in fish has not been fully understood. A distinct regulation of hepatic glucose utilization (glycolysis) and production (gluconeogenesis) may be advanced to explain the relative inability of fish to efficiently utilize dietary glucose. We summarize here information regarding the nutritional regulation of key enzymes involved in glycolysis (hexokinases, 6-phosphofructo-1-kinase and pyruvate kinase) and gluconeogenesis (phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase and glucose-6-phosphatase) pathways as well as that of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. The effect of dietary carbohydrate level and source on the activities and gene expression of the mentioned key enzymes is also discussed. Overall, data strongly suggest that the liver of most fish species is apparently capable of regulating glucose storage. The persistent high level of endogenous glucose production independent of carbohydrate intake level may lead to a putative competition between exogenous (dietary) glucose and endogenous glucose as the source of energy, which may explain the poor dietary carbohydrate utilization in fish.
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PMID:Nutritional regulation of hepatic glucose metabolism in fish. 1879 53