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)

Streptozotocin-induced maternal diabetes has been shown to alter developmental patterns of carbohydrate-metabolizing enzyme activities, glycogen deposition and surfactant levels in late fetal rat lung in a tissue-specific manner, as follows: (a) marked reduction in glycogen synthase a activity, due to aberrant interconversion between active and inactive forms of the enzyme; less glycogen was thus accumulated; (b) lowered activities of hexokinase, phosphofructokinase and pyruvate kinase at term; (c) reduced disaturated phosphatidylcholine (surfactant) concentrations. The diminished synthesis and accumulation of glycogen and glycolytic capacity in the lungs of fetuses of diabetic mothers has been related to reduction in surfactant level, which underlies respiratory distress syndrome frequently encountered in neonates of diabetic pregnancies.
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PMID:Effects of maternal diabetes on the development of carbohydrate-metabolizing enzymes, glycogen deposition and surface active phospholipid levels in fetal rat lung. 630 58

The flux of glucose through the pentose phosphate pathway, important in relation to the provision of ribose 5-phosphate for nucleotide and RNA synthesis, was decreased by 70% in the diabetic rat heart in parallel with a similar decreased flux through the glycolytic route. A common factor linking the decreased flux through these alternative routes is the known fall in cardiac hexokinase; in these experiments there is a 50% decrease in Type II hexokinase (EC 2.7.1.1.) in both soluble and particulate fractions. The level of fructose 2,6-bisphosphate, a regulator of phosphofructokinase activity, is decreased by 20% in the alloxan diabetic rat heart, this may be a significant additional factor in the marked decrease in the flux of glucose through the glycolytic route in the myocardium in diabetes.
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PMID:Regulation of alternative pathways of glucose metabolism in rat heart in alloxan diabetes: changes in the pentose phosphate pathway. 636 95

Phosphofructokinase (ATP:D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) was partially purified from the livers of genetically diabetic mice (C57BL/KsJ-db) and their lean littermates (C57BL/KsJ). These genetically diabetic mice have been shown to be hyperglucagonemic and to exhibit symptoms resembling those of maturity-onset diabetes in humans. Two isoenzymes of phosphofructokinase were obtained after DEAE-Sephadex chromatography of extracts of livers from either normal or diabetic animals. One of these isozymes, peak II, from the genetically diabetic mice was shown to be more sensitive to ATP inhibition at physiological pH than the peak II isozyme from the normal animals. In addition, the peak II isozyme from the diabetic mice exhibited decreased affinity for fructose 6-phosphate. The altered kinetic properties of phosphofructokinase from diabetic animals are markedly similar to those recently reported for liver phosphofructokinase isolated from normal animals after glucagon treatment. Our results suggest that increased glucagon levels in diabetes may lead to altered regulation of phosphofructokinase in this disease.
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PMID:Increased ATP inhibition of liver phosphofructokinase from genetically diabetic mice. 644 14

The concentrations of glycolytic intermediates and adenine nucleotides were determined in erythrocytes from patients with diabetic ketoacidosis before and during insulin treatment. Ketoacidosis resulted in an increase in the levels of intermediates above the phosphofructokinase (PFK) step and a marked decrease in the levels of those below this step. Thus, a "crossover" point was seen at the PFK step in a crossover plot. This indicated that the rate of glycolytic flow during ketoacidosis was controlled by PFK and that the reduced level of 2,3-bisphosphoglycerate (2, 3-BPG) was attributed to the inhibition of this enzyme. In vitro studies revealed that acidemia is mainly responsible for the inhibition of PFK, whereas elevated levels of ketone bodies and free fatty acids have no direct bearing on it. Insulin administration produced hypophosphatemia within 8-12 h and it persisted for 24 h or longer. The levels of fructose-6-phosphate and glucose-6-phosphate were decreased transiently during this hypophosphatemic phase, while those of fructose bisphosphate and triose phosphates were increased. This indicated that PFK was activated. Thus, it is no longer reasonable to think that the inhibition of PFK is a factor responsible for a delay in normalization of the 2, 3-BPG level during the recovery phase. The levels of these glycolytic intermediates, including 2, 3-BPG, were normalized within 4 days by appropriate therapy.
Diabetes 1981 Apr
PMID:Alteration of glycolytic intermediary metabolism in erythrocytes during diabetic ketoacidosis and its recovery phase. 645 63

As part of an ongoing search for diabetes susceptibility loci, we tested linkage with non-insulin-dependent diabetes mellitus (NIDDM) for 19 candidate loci or regions chosen for their potential to affect directly or indirectly the action of insulin. Loci were associated with insulin resistance, known effects on lipid metabolism, or effects on glucose metabolism or insulin action. Loci included the insulin-responsive (GLUT4) glucose transporter, hexokinase 2, glucagon, growth hormone, insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase, hepatic and muscle forms of pyruvate kinase, hepatic phosphofructokinase, the apolipoprotein B and the apolipoprotein A2 cluster, lipoprotein lipase, hepatic triglyceride lipase, the very-low-density-lipoprotein receptor, and the Pima insulin resistance locus on chromosome 4. For several candidates, no specific informative marker was available; consequently, we tested the surrounding region with highly informative markers. These regions included the diabetes-associated ras-like gene, rad, and the cholesterol ester-transfer gene, both mapped to chromosome 16. Additionally, we tested for linkage with markers at the tumor necrosis factor-alpha gene and the Friedreich's ataxia region. All regions were tested for linkage with microsatellite polymorphisms in > 450 individuals from a minimum of 16 Caucasian families under parametric (LINKAGE 5.1) and nonparametric (affected pedigree member) models.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Nov
PMID:Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM. 758 21

Normal insulin secretion is oscillatory in vivo, and the oscillations are impaired in type II diabetes. We and others have shown oscillations in insulin secretion from isolated perifused islets stimulated with glucose, and in this study we show oscillations in insulin secretion from the glucose-sensitive clonal beta-cell line INS-1. We have proposed that the oscillatory insulin secretion may be caused by spontaneous oscillations of glycolysis and the ATP:ADP ratio in the beta-cell, analogous to those seen in glycolyzing muscle extracts. The mechanism of the latter involves autocatalytic activation of the key regulatory enzyme, phosphofructokinase (PFK), by its product fructose 1,6-bisphosphate (F16BP). However, of the three PFK subunit isoforms (M-[muscle], L-[liver], and C-type, predominant in fibroblasts), only M-type is activated by micromolar F16BP at near-physiological conditions. We therefore studied PFK isoforms in the beta-cell. Western analysis of PFK subunits in isolated rat islets and INS-1 cells showed the presence of M-type, as well as C-type and perhaps lesser amounts of L-type. Kinetic studies of PFK activity in INS-1 cell extracts showed strong activation by micromolar concentrations of F16BP at near-physiological concentrations of ATP (several millimolar) and AMP and fructose 6-phosphate (micromolar), indicative of the M-type isoform. Activation by submicromolar concentrations of fructose 2,6-bisphosphate (F26BP) and potent inhibition by citrate were also observed. The F16BP-stimulatable activity was about one-half of the F26BP-stimulatable activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Nov
PMID:Phosphofructokinase isozymes in pancreatic islets and clonal beta-cells (INS-1). 758 25

We show here that long-term streptozotocin diabetes affects differently the intracellular distribution of phosphofructokinase (PFK), the rate-limiting enzyme of glycolysis, in tibialis anterior and gastrocnemius muscles. Diabetes, which causes ultrastructural damage in both muscle fibers, induced a decrease in PFK binding to cytoskeleton in gastrocnemius muscle but not in the tibialis anterior muscle. However, the allosteric activity of cytoskeleton-bound and soluble PFK was reduced in both kinds of muscles, most probably due to the decrease in the level of glucose 1,6-bisphosphate, the potent allosteric activator of the enzyme. Levels of fructose 2,6-bisphosphate remained unchanged. A change in the allosteric properties of the cytoskeleton-bound PFK was found only in the diabetic tibialis anterior muscle; in contrast to normal muscle, where only the soluble but not the bound enzyme responded to allosteric effectors, in the diabetic tibialis anterior muscle, the bound enzyme exhibited allosteric properties similar to the soluble enzyme. The reduction in both cytosolic and cytoskeletal PFK, and, thereby, glycolysis in these two kinds of muscles, which results most probably from the reported high pathological intracellular Ca2+ concentration, may contribute to muscle damage in diabetes.
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PMID:Effects of long-term streptozotocin diabetes on cytoskeletal and cytosolic phosphofructokinase and the levels of glucose 1,6-bisphosphate and fructose 2,6-bisphosphate in different rat muscles. 771 Jul 70

The effects of glucose concentration on D-glucose oxidation and reduced nicotinamide adenine dinucleotide phosphate (NADPH) supply were studied during exposure of cultured human umbilical vein endothelial cells to hydrogen peroxide (H2O2). The activation of glucose oxidation via the pentose phosphate pathway (PPP), induced by exposure of cells to 200 mumol/l H2O2 for 1 h, was reduced by 50% (P < 0.01) in cells cultured for 5-7 days in 33 mmol/l D-glucose (HG) versus those cultured in 5.5 mmol/l D-glucose without (NG) or with (HR) 27.5 mmol/l D-raffinose. The intracellular NADPH content in HG cells, but not in NG or HR cells, was decreased by 42% (P < 0.01) by exposing cells to 200 mumol/l H2O2. The decrease in NADPH was dependent on D-glucose concentration in the medium and was prevented in glutathione (GSH)-depleted cells. The latter observation suggests that the decrease in NADPH is associated with activation of the GSH redox cycle. In the presence of 200 mumol/l H2O2, lactate release into the medium, NADH/NAD ratio, and phosphofructokinase activity in HG cells were 56, 53, and 68% greater, respectively, than in the NG group, which indicates that inhibition of glycolysis by H2O2 is less marked in the HG group compared with NG group. These results indicate that activation of the PPP was impaired in endothelial cells cultured under conditions of high-glucose and oxidative stress, resulting in a decreased supply of NADPH to various NADPH-dependent pathways, including the GSH redox cycle.
Diabetes 1995 May
PMID:Impaired activation of glucose oxidation and NADPH supply in human endothelial cells exposed to H2O2 in high-glucose medium. 772 9

The acute effects of streptozotocin-induced diabetes on several parameters of glucose metabolism were investigated in rat peritoneal macrophages. These cells accumulated in vitro about twofold more fructose 2,6-bisphosphate in the presence of increasing glucose concentration than cells from normal rats, and an increased production of lactate was observed. Phosphofructokinase-1, phosphofructokinase-2, hexokinase, and pyruvate kinase activities were increased in cells from diabetic rats compared with those from normal rats. Transport of 2-deoxy-D-glucose was increased in cells from diabetic rats. [U-14C]Glucose incorporation into glycogen was also increased in cells from diabetics and the 14CO2 liberation was less than in cells from normal animals. Moreover, macrophages from diabetics did not possess a more active pentose phosphate pathway (measure with [1-14C]glucose oxidation) nor a greater production of superoxide anion (index of activation of macrophages) than in cells from normal animals.
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PMID:Streptozotocin-induced diabetes increases fructose 2,6-bisphosphate levels and glucose metabolism in rat macrophages. 812 90

In sporadic Alzheimer's disease (AD), a number of metabolic alterations to the brain have been observed soon after the onset of the initial clinical symptoms. In particular, impairments of glucose utilization and related metabolic pathways are prominent and well-established findings in incipient AD, resembling metabolic abnormalities such as have been found in noninsulin-dependent diabetes mellitus. To mimic these abnormalities, we administered an intracerebroventricular (icv) injection of streptozotocin (STZ) to rats and studied the effects of glucose and glycogen metabolism in the cerebral cortex and hippocampus compared with controls. The enzymatic activities studied dropped significantly by 10-30% in brain cortex (cort.) and hippocampus (hc) 3 and 6 weeks after icv STZ injection: hexokinase (15% 3 weeks cort.; 14% 6 weeks cort.; 12% 3 weeks hc; 28% 6 weeks hc), phosphofructokinase (15%; 15%; 24%; 15%), glyceraldehyde-3-phosphate dehydrogenase (10%; 12%; 30%; 19%), pyruvate kinase (22%; 13%; 22%; 28%), glucose-6-phosphatase (10%; 23%; 14%; 19%) and phosphorylase a (22%; 11%; 30%; 15%). The content of glycogen was significantly higher in STZ-treated rats than in control animals (7% 3 weeks and 15% 6 weeks in cortex). In contrast to the reduced enzymatic activities, we observed no changes in the concentrations of the glycolytic intermediates glucose, glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-diphosphate, pyruvate, lactate and glucose-1-phosphate. These data clearly indicate reduced glycolytic enzyme activity after icv administration of STZ and suggest gluconeogenesis consequent on abnormalities in glucose breakdown. This model may thus be assumed to be a useful tool to investigate pathogenetic factors involved in sporadic dementia of Alzheimer type.
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PMID:Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus. 823 64


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