Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In mice with streptozotocin-induced diabetes of 3 days' duration, the hexokinase/glucose-6-phosphatase (HK/G6Pase) ratio in the kidney was enhanced by 52% (mean +/- SEM: 0.40 +/- 0.04 vs. 0.26 +/- 0.03; p less than 0.02) compared to control mice as a result of a 25% increase of HK (16.68 +/- 0.93 vs. 13.31 +/- 1.04 nmol/min/mg protein; p = 0.05) and a 17% decrease of G6Pase (42.51 +/- 2.75 vs. 51.25 +/- 1.89; p less than 0.05). In contrast, as expected, the corresponding ratio (HK + glucokinase/G6Pase) was strikingly reduced in the liver. In 9-day diabetic mice, the kidney enzyme changes were much smaller; however, in a chronic disease such as diabetes, even minimal deviations from the normal may lead to significant metabolic changes with time. The enhanced HK/G6Pase ratio in the diabetic kidney suggests an increase in glucose utilization. This may contribute to the increased synthesis of glycogen, glycoproteins (including basement membrane) and RNA (via provision of ribose-phosphate) occurring in the diabetic kidney and supports the view that the kidney (as opposed to other tissues) shows an 'anabolic response' to diabetes.
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PMID:Increased hexokinase/glucose-6-phosphatase ratio in the diabetic kidney as index of glucose overutilization. 255 19

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

Summary. Insulin is known to inhibit glucose-6-phosphatase gene expression through PI 3-kinase/PKB mediated phosphorylation and inactivation of the forkhead transcription factor FKHR, which is a potent transactivator of the glucose-6-phosphatase gene. To study the function and regulation of the transcription factor FKHR in hepatic cells, we constructed a hydroxytamoxifen-inducible version of FKHR by fusing a part of the hormone binding domain of the estrogen receptor (ER) to the C-terminus of FKHR (FKHR-ER). In HepG2-cells transiently transfected with plasmids encoding the FKHR-ER fusion protein and a glucose-6-phosphatase reporter construct, hydroxytamoxifen induced a marked induction of glucose-6-phosphatase promoter activity, whereas no effect was observed in control cells. We next generated a H4IIEC3 rat hepatoma cell line stably expressing both FKHR-ER and a glucose-6-phosphatase promoter-based reporter construct. After 2h stimulation with hydroxytamoxifen, the promoter activity was stimulated 3-5 fold, and continued to increase up to 100-fold after 15 h. The response was half maximal at 0.5 microM hydroxytamoxifen. Insulin (1 nM) decreased the hydroxytamoxifen induced promoter activity by about 70% of the maximal response. This cell system can be used for (1) the identification of FKHR dependent genes and for (2) high throughput screening (HTS) of agents affecting the activity of FKHR and its regulation by insulin. Abbreviations used: FKHR, forkhead in rhabdomyosarcoma; G6Pase, glucose-6-phosphatase; PKB, protein kinase B; PI 3-kinase, phosphatidyl-inositol 3-kinase; IRU, insulin-responsive unit; Tx, 4-hydroxytamoxifen, ER, estrogen receptor; HBD, hormone binding domain
Exp Clin Endocrinol Diabetes 2002 Sep
PMID:Construction and characterization of a conditionally active construct of the insulin-regulated forkhead transcription factor FKHR. 1237 35

A fine control of the blood glucose level is essential to avoid hyper- or hypo-glycemic shocks associated with many metabolic disorders, including diabetes mellitus and type I glycogen storage disease. Between meals, the primary source of blood glucose is gluconeogenesis and glycogenolysis. In the final step of both pathways, glucose-6-phosphate (G6P) is hydrolyzed to glucose by the glucose-6-phosphatase (G6Pase) complex. Because G6Pase (renamed G6Pase-alpha) is primarily expressed only in the liver, kidney, and intestine, it has implied that most other tissues cannot contribute to interprandial blood glucose homeostasis. We demonstrate that a novel, widely expressed G6Pase-related protein, PAP2.8/UGRP, renamed here G6Pase-beta, is an acid-labile, vanadate-sensitive, endoplasmic reticulum-associated phosphohydrolase, like G6Pase-alpha. Both enzymes have the same active site structure, exhibit a similar Km toward G6P, but the Vmax of G6Pase-alpha is approximately 6-fold greater than that of G6Pase-beta. Most importantly, G6Pase-beta couples with the G6P transporter to form an active G6Pase complex that can hydrolyze G6P to glucose. Our findings challenge the current dogma that only liver, kidney, and intestine can contribute to blood glucose homeostasis and explain why type Ia glycogen storage disease patients, lacking a functional liver/kidney/intestine G6Pase complex, are still capable of endogenous glucose production.
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PMID:A glucose-6-phosphate hydrolase, widely expressed outside the liver, can explain age-dependent resolution of hypoglycemia in glycogen storage disease type Ia. 1312 15

Obesity, a state of increased adipose tissue mass, is a major cause for type 2 diabetes, hyperlipidemia, and hypertension, resulting in clustering of risk factors for atherosclerosis. Heterozygous PPARgamma knockout mice and KKA(y) mice administered with a PPARgamma antagonist were protected from high-fat diet-induced adipocyte hypertrophy and insulin resistance. Moderate reduction of PPARgamma activity prevented adipocyte hypertrophy, thereby diminution of TNFalpha, resistin, and FFA and upregulation of adiponectin and leptin. These alterations led to reduction of tissue TG content in muscle/liver, thereby ameliorating insulin resistance. Insulin resistance in the lipoatrophic mice and KKA(y) mice were ameliorated by replenishment of adiponectin. Moreover, adiponectin transgenic mice ameliorated insulin resistance and diabetes, but not the obesity of ob/ob mice. Furthermore, targeted disruption of the adiponectin gene caused moderate insulin resistance and glucose intolerance. In muscle, adiponectin activated AMP kinase and PPARgamma pathways, thereby increasing beta-oxidation of lipids, leading to decreased TG content, which ameliorated muscle insulin resistance. In the liver, adiponectin also activated AMPK, thereby downregulating PEPCK and G6Pase, leading to decreased glucose output from the liver. In conclusion, PPARgamma plays a central role in the regulation of adipocyte hypertrophy and insulin sensitivity. The upregulation of the adiponectin pathway by PPARgamma may play a role in the increased insulin sensitivity of heterozygous PPARgamma knockout mice, and activation of adiponectin pathway may provide novel therapeutic strategies for obesity-linked disorders such as type 2 diabetes and metabolic syndrome.
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PMID:[The mechanisms by which PPARgamma and adiponectin regulate glucose and lipid metabolism]. 1450 Nov 64

The liver plays an important role in insulin-regulated glucose homoeostasis. To study the function of the PDK1 (3-phosphoinositide-dependent protein kinase-1) signalling pathway in mediating insulin's actions in the liver, we employed CRE recombinase/loxP technology to generate L(liver)-PDK1-/- mice, which lack expression of PDK1 in hepatocytes and in which insulin failed to induce activation of PKB in liver. The L-PDK1-/- mice were not insulin-intolerant, possessed normal levels of blood glucose and insulin under normal feeding conditions, but were markedly glucose-intolerant when injected with glucose. The L-PDK1-/- mice also possessed 10-fold lower levels of hepatic glycogen compared with control littermates, and were unable to normalize their blood glucose levels within 2 h after injection of insulin. The glucose intolerance of the L-PDK1-/- mice may be due to an inability of glucose to suppress hepatic glucose output through the gluconeogenic pathway, since the mRNA encoding hepatic PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase) and SREBP1 (sterol-regulatory-element-binding protein 1), which regulate gluconeogenesis, are no longer controlled by feeding. Furthermore, three other insulin-controlled genes, namely IGFBP1 (insulin-like-growth-factor-binding protein-1), IRS2 (insulin receptor substrate 2) and glucokinase, were regulated abnormally by feeding in the liver of PDK1-deficient mice. Finally, the L-PDK1-/- mice died between 4-16 weeks of age due to liver failure. These results establish that the PDK1 signalling pathway plays an important role in regulating glucose homoeostasis and controlling expression of insulin-regulated genes. They suggest that a deficiency of the PDK1 pathway in the liver could contribute to development of diabetes, as well as to liver failure.
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PMID:Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure. 1555 2

Increase in glucose-6-phosphatase catalytic subunit (G6Pase, G6pc) transcription enhances hepatic glucose production in non-insulin-dependent diabetes mellitus (NIDDM). The fact that carnivorous fish is an alternative model to study NIDDM led us to clone and characterise the first G6pc promoter region reported for fish and non-mammalian animals. The 5'-flanking region of G6pc from gilthead sea bream (Sparus aurata) was isolated by chromosome walking. With SMART RACE-PCR, the transcription start site was located 106 base pairs (bp) upstream of the translational start. Transfection analysis in HepG2 cells located a functional promoter in the 850 bp 5'-flanking isolated fragment (positions -770 to +80 relative to the transcription start). Sequential 5'-deletion analysis of the promoter fragment revealed that a core functional promoter for basal transcription is comprised within the 190 bp upstream of the transcription start site. In vivo, glucose and insulin reduced G6Pase mRNA levels in the fish liver. Transfection experiments in HepG2 cells showed that insulin repressed S. aurata G6pc under high-glucose conditions. Synergistic activation of piscine G6pc promoter was induced by cotransfection with expression plasmids for hepatocyte nuclear factor-4alpha (HNF-4alpha) and peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1alpha). No direct relationship was found between PGC-1alpha coactivation of HNF-4alpha transactivation and the repressive effect of insulin. Interestingly, insulin hardly affected G6pc promoter activity in the absence of glucose, suggesting that a reduced capacity of insulin-dependent repression of piscine G6pc may lead to insulin resistance in carnivorous fish.
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PMID:Transcriptional regulation of glucose-6-phosphatase catalytic subunit promoter by insulin and glucose in the carnivorous fish, Sparus aurata. 1559 Oct 35

The liver plays a unique role in controlling carbohydrate metabolism by maintaining glucose concentrations in a normal range over both short and long periods of times. In type 2 diabetes, alterations in hepatic glucose metabolism are observed, i.e. increased post-absorptive glucose production and impaired suppression of glucose production together with diminished glucose uptake following carbohydrate ingestion. The simultaneous overproduction of glucose and fatty acids in liver further stimulates the secretion of insulin by the pancreatic B cells, and elicits further peripheral insulin resistance thereby establishing a vicious circle. The present review will focus on some of the genetically-altered mouse models that have helped identify enzymes or transcription factors that are essential for maintaining either glucose or lipid homeostasis in liver. Among these mouse models, we will discuss transgenic mice overexpressing key gluconeogenic enzymes (PEPCK, G6Pase) or transcription factors (Foxo1, Pgc1-alpha) that control de novo glucose synthesis. In addition, since the possibility of controlling hepatic glucose utilization as a treatment of type 2 diabetes has been explored we will review some of the strategies proved to be valuable for improving the hyperglycemic phenotype.
Diabetes Metab 2004 Nov
PMID:Role of the liver in the control of carbohydrate and lipid homeostasis. 1567 6

Sudden and unexpected infant deaths can be unexplained [sudden infant death syndrome (SIDS)] or explained (non-SIDS) but risk factors including lower birthweight are similar in both groups. Mutations in the glucokinase (GK) gene result in Maturity Onset Diabetes of the Young type 2 (MODY 2) and are associated with lower birthweight. Low hepatic glucose-6-phosphatase (G6PC1) expression occurs in both low birthweight and SIDS infants. We investigated whether polymorphisms are prevalent in the GK and G6PC1 genes in infants who died suddenly and unexpectedly. Mutation analysis was performed by polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) in samples from 126 infants who died suddenly and unexpectedly (78 SIDS, 48 non-SIDS) and from 70 healthy, living infants. G6PC1 promoter polymorphism significance was investigated by transfection of reporter gene constructs into a H4IIE cell line. Heterozygous GK polymorphisms were identified in 17.9% of SIDS and 20.8% of non-SIDS infants: two rare silent polymorphisms, Y215Y and S263S, in the coding region; a third rare polymorphism, -45G>A, in the hepatic promoter and the most prevalent polymorphism, c.484-29G>C, in a non-coding region upstream from the intron 4-exon 5 junction. A novel heterozygous polymorphism -77G>A in the G6PC1 promoter in 6.3% of non-SIDS and 2.9% of control infants decreased basal G6PC1 promoter activity (p<0.001). We describe three novel polymorphisms in the GK gene, S263S, -45G>A, and a common (14.3%) intronic substitution, c.484-29G>C, in infants who died suddenly and unexpectedly. We identified the first G6PC1 promoter polymorphism, which lowers expression, potentially increasing risk of hypoglycaemia and hence risk of sudden and unexpected death.
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PMID:Identification of novel polymorphisms in the glucokinase and glucose-6-phosphatase genes in infants who died suddenly and unexpectedly. 1591 42

GSK3 (glycogen synthase kinase-3) regulation is proposed to play a key role in the hormonal control of many cellular processes. Inhibition of GSK3 in animal models of diabetes leads to normalization of blood glucose levels, while high GSK3 activity has been reported in Type II diabetes. Insulin inhibits GSK3 by promoting phosphorylation of a serine residue (Ser-21 in GSK3alpha, Ser-9 in GSK3beta), thereby relieving GSK3 inhibition of glycogen synthesis in muscle. GSK3 inhibition in liver reduces expression of the gluconeogenic genes PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase), as well as IGFBP1 (insulin-like growth factor binding protein-1). Overexpression of GSK3 in cells antagonizes insulin regulation of these genes. In the present study we demonstrate that regulation of these three genes by feeding is normal in mice that express insulin-insensitive GSK3. Therefore inactivation of GSK3 is not a prerequisite for insulin repression of these genes, despite the previous finding that GSK3 activity is absolutely required for maintaining their expression. Interestingly, insulin injection of wild-type mice, which activates PKB (protein kinase B) and inhibits GSK3 to a greater degree than feeding (50% versus 25%), does not repress these genes. We suggest for the first time that although pharmacological inhibition of GSK3 reduces hepatic glucose production even in insulin-resistant states, feeding can repress the gluconeogenic genes without inhibiting GSK3.
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PMID:Analysis of hepatic gene transcription in mice expressing insulin-insensitive GSK3. 1617 84


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