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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mammalian heart is normally well oxygenated and anaerobic glycolysis is extremely rare except for the production of extra ATP during extreme exercise like a marathon race. Anaerobic glycolysis plays a role when there is a serious impairment in coronary blood flow such as during heart attack and open heart surgery. The control of glycolysis in ischemic myocardial tissue appears to be extremely complex. During aerobic glycolysis, phosphofructokinase is the most important regulatory enzyme that controls the energy requirements of the cell. Under anaerobic conditions, however, glyceraldehyde-3-phosphate dehydrogenase becomes the key enzyme because it responds promptly to any changes in the essential supply of co-factors for oxidation. The conversion of pyruvate to acetyl CoA (aerobic metabolism) involves a series of chain reactions primarily catalyzed by pyruvate dehydrogenase complex which is situated at the cross roads between both aerobic and anaerobic glycolysis. It is important to remember that substrate utilization is carefully controlled by substrate availability. During aerobic metabolism, control mechanisms using fatty acids, lactate and glucose as energy substrates regulate the rate of ATP production according to energy demand. This precise mechanism is upset during ischemia and post-ischemic reperfusion for reasons discussed in this review. The demand for ATP can no longer be met by its supply because of severely reduced anaerobic glycolysis and significantly inhibited beta-oxidation of fatty acids. The impairment of bioenergetics is discussed in the context of several diseases such as cardiomyopathy, heart failure, diabetes, arrhythmias, cardiac surgery, heart-lung transplantation, and also in aging and oxidative stress. The regulation of energy metabolism in preconditioned heart is also discussed. Finally, methods used to preserve energy in ischemic myocardium are summarized and quantitation of the high-energy phosphates is discussed. This review challenges scientists to discover drugs which will stimulate energy supply during myocardial ischemia.
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PMID:Bioenergetics, ischemic contracture and reperfusion injury. 880 94

The effects of troglitazone and pioglitazone on glucose and fatty acid metabolism were studied in hepatocytes isolated from 24-h-starved rats. These thiazolidinediones inhibited long-chain fatty acid (oleate) oxidation and produced a very oxidized mitochondrial redox state. By contrast, thiazolidinediones did not affect the rate of medium-chain fatty acid (octanoate) oxidation or the activity of mitochondrial carnitine palmitoyltransferase (CPT) I. Thiazolidinediones inhibited selectively triglyceride synthesis but not phospholipid synthesis. The combined inhibition of oleate oxidation and esterification by troglitazone was due to a noncompetitive inhibition of mitochondrial and microsomal long-chain acyl-CoA synthetase (ACS) activities. It was suggested that troglitazone must be metabolized into its sulfo-conjugate derivative in liver cells to inhibit mitochondrial and microsomal ACS activities. Thiazolidinediones inhibited glucose production from lactate/pyruvate or from alanine. Analysis of gluconeogenic metabolite concentrations suggested that troglitazone would inhibit gluconeogenesis at the level of pyruvate carboxylase and glyceraldehyde-3-phosphate dehydrogenase reactions. It was concluded that 1) at a similar concentration, troglitazone was more efficient than pioglitazone to inhibit fatty acid metabolism and gluconeogenesis and 2) the inhibition of gluconeogenesis by troglitazone could be the result of the inhibition of long-chain fatty acid oxidation (decrease in acetyl-CoA, NADH-to-NAD+, and ATP-to-ADP ratios).
Diabetes 1996 Nov
PMID:Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats. 886 61

In type I (insulin-dependent) diabetes, destruction of pancreatic beta cells has been associated with the presence of circulating antibodies against glutamate decarboxylase (GAD), a GABA (gamma-aminobutyric acid) synthesizing enzyme which is located in the beta cells. We examined whether destruction of islet beta cells can lead to discharge of GAD in the extracellular medium, making it a potential autoantigen. Rat islet beta cells were first exposed for 1 hour to streptozotocin and then cultured for 4 to 24 hours before cellular and medium GAD activities were measured. After 24 hours culture, 70 percent of streptozotocin-treated beta cells were disintegrated whereas the number of control cells remained unchanged. Control cells exhibited a stable cellular GAD activity over the 24 hour period with no enzyme activity detectable in their culture medium. The cells recovered 24 hours after streptozotocin treatment exhibited 10-fold lower levels of GAD-activity and of GABA; their culture medium contained GAD, its enzymatic activity reaching peak values after 10 hours. The beta-cell enzymes glutamate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase were not detectable in the medium of control or streptozotocin-treated cells. Similar observations were made when beta cells had been exposed to cytotoxic concentrations of alloxan. It is concluded that damage to rat islet beta cells results in transient discharge of GAD in the extracellular medium making this enzyme a candidate extracellular marker for beta cell toxic processes and a potential autoantigen for immune reactivity.
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PMID:Damaged rat beta cells discharge glutamate decarboxylase in the extracellular medium. 892 Sep 8

The insulin resistance of skeletal muscle in glucose-tolerant obese individuals is associated with reduced activity of oxidative enzymes and a disproportionate increase in activity of glycolytic enzymes. Because non-insulin-dependent diabetes mellitus (NIDDM) is a disorder characterized by even more severe insulin resistance of skeletal muscle and because many individuals with NIDDM are obese, the present study was undertaken to examine whether decreased oxidative and increased glycolytic enzyme activities are also present in NIDDM. Percutaneous biopsy of vatus lateralis muscle was obtained in eight lean (L) and eight obese (O) nondiabetic subjects and in eight obese NIDDM subjects and was assayed for marker enzymes of the glycolytic [phosphofructokinase, glyceraldehyde phosphate dehydrogenase, hexokinase (HK)] and oxidative pathways [citrate synthase (CS), cytochrome-c oxidase], as well as for a glycogenolytic enzyme (glycogen phosphorylase) and a marker of anaerobic ATP resynthesis (creatine kinase). Insulin sensitivity was measured by using the euglycemic clamp technique. Activity for glycolytic enzymes (phosphofructokinase, glyceraldehye phosphate dehydrogenase, HK) was highest in subjects with subjects with NIDDM, following the order of NIDDM > O > L, whereas maximum velocity for oxidative enzymes (CS, cytochrome-c oxidase) was lowest in subjects with NIDDM. The ratio between glycolytic and oxidative enzyme activities within skeletal muscle correlated negatively with insulin sensitivity. The HK/CS ratio had the strongest correlation (r = -0.60, P < 0.01) with insulin sensitivity. In summary, an imbalance between glycolytic and oxidative enzyme capacities is present in NIDDM subjects and is more severe than in obese or lean glucose-tolerant subjects. The altered ratio between glycolytic and oxidative enzyme activities found in skeletal muscle of individuals with NIDDM suggests that a dysregulation between mitochondrial oxidative capacity and capacity for glycolysis is an important component of the expression of insulin resistance.
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PMID:Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM. 921 60

Hepatocyte nuclear factor 4alpha (HNF4alpha) plays a critical role in regulating the expression of many genes essential for normal functioning of liver, gut, kidney, and pancreatic islets. A nonsense mutation (Q268X) in exon 7 of the HNF4alpha gene is responsible for an autosomal dominant, early-onset form of non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young; gene named MODY1). Although this mutation is predicted to delete 187 C-terminal amino acids of the HNF4alpha protein the molecular mechanism by which it causes diabetes is unknown. To address this, we first studied the functional properties of the MODY1 mutant protein. We show that it has lost its transcriptional transactivation activity, fails to dimerize and bind DNA, implying that the MODY1 phenotype is because of a loss of HNF4alpha function. The effect of loss of function on HNF4alpha target gene expression was investigated further in embryonic stem cells, which are amenable to genetic manipulation and can be induced to form visceral endoderm. Because the visceral endoderm shares many properties with the liver and pancreatic beta-cells, including expression of genes for glucose transport and metabolism, it offers an ideal system to investigate HNF4-dependent gene regulation in glucose homeostasis. By exploiting this system we have identified several genes encoding components of the glucose-dependent insulin secretion pathway whose expression is dependent upon HNF4alpha. These include glucose transporter 2, and the glycolytic enzymes aldolase B and glyceraldehyde-3-phosphate dehydrogenase, and liver pyruvate kinase. In addition we have found that expression of the fatty acid binding proteins and cellular retinol binding protein also are down-regulated in the absence of HNF4alpha. These data provide direct evidence that HNF4alpha is critical for regulating glucose transport and glycolysis and in doing so is crucial for maintaining glucose homeostasis.
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PMID:The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. 937 25

Alterations in glucose metabolism have been implicated in the cardiovascular complications of diabetes. Previous work in this laboratory demonstrated that hearts from diabetic animals have an elevated cytosolic redox ratio (NADH/NAD+) and that this redox imbalance is probably due to elevated polyol pathway flux. We therefore hypothesized that 1) the elevated cytosolic redox ratio of diabetic hearts could result in inhibition of glycolytic enzymes sensitive to the redox state, 2) polyol pathway inhibition could restore the abnormal glucose metabolism of diabetic hearts, and 3) the relative incorporation of mixed substrates into hearts from diabetic animals would demonstrate less glycolytic and more fatty acid oxidation. Hearts from diabetic (BB/W) and nondiabetic control rats were perfused with buffers containing 13C-labeled substrates, and the metabolism of these hearts was analyzed using 13C NMR spectroscopy. Tissue samples were analyzed for metabolite levels using biochemical assay. Compared with controls, diabetic hearts had glyceraldeyde 3-phosphate levels that were four times greater than nondiabetic hearts and exhibited 91% less 13C labeling of lactate and 92% less 13C labeling of glutamate (P < 0.03). Aldose reductase inhibition with zopolrestat restored the metabolite labeling of diabetic hearts. Diabetic hearts perfused with a mixture of substrates used 53% more acetate than nondiabetic control hearts (P < 0.05), and aldose reductase inhibition lowered the acetate utilization of diabetic hearts by 9% (P < 0.05). These data suggest that glycolytic flux in diabetic hearts is inhibited at glyceraldehyde-3-phosphate dehydrogenase and that inhibition of the polyol pathway with zopolrestat increases glycolytic flux in these hearts. Furthermore, hearts from diabetic animals showed a marked dependence on fatty acids for substrate utilization compared with nondiabetic controls, consistent with inhibition of the pyruvate dehydrogenase complex in diabetic hearts.
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PMID:Aldose reductase inhibition improves altered glucose metabolism of isolated diabetic rat hearts. 968 98

The metabolism of [1,3-(13)C]glycerol-1,2,3-tris(methylsuccinate) and glycerol-1,2,3-tris(methyl[2,3-(13)C] succinate) was examined in hepatocytes prepared from hereditarily diabetic Goto-Kakizaki rats. Over 120 min incubation in the presence of one of the two (13)C-labelled esters (2.5 mM), the output of (13)C-enriched glucose averaged 57.1 +/- 18.5 and 54.1 +/- 22.7 nmol per 10(6) cells, when expressed as [1,3-(13)C]glycerol and [2,3-(13)C] succinate equivalent, respectively. In the case of [1,3-(13)C]glycerol-1,2,3-tris(methyl-succinate), the molecules of glucose were symmetrically labelled. In the case of glycerol-1,2,3-tris(methyl[2,3-(13)C] succinate), however, both the single-labelled and double-labelled isotopomers of glucose contained more (13)C atoms in their C(6)-C(5)-C(4) than C(1)-C(2)-C(3) moiety. These findings indicate that glycerol-1,2,3-tris(methylsuccinate), recently proposed as a novel insulinotropic tool for the treatment of non-insulin-dependent diabetes mellitus, is efficiently metabolized in hepatocytes from diabetic rats, the high rate of gluconeogenesis coinciding with channelling of D-glyceraldehyde-3-phosphate between glyceraldehyde-3-phosphate dehydrogenase and phosphofructoaldolase.
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PMID:Metabolism of [1,3-(13)C]glycerol-1,2,3-tris(methylsuccinate) and glycerol-1,2,3-tris(methyl[2,3-(13)C]succinate) in hepatocytes from Goto-Kakizaki rats. 1002 53

Glycation initiated changes in tissue proteins, which are triggered by the Schiff base formation between the sugar carbonyl and the protein -NH2, have been suggested to play an important role in the development of diabetes-related pathological changes such as the formation of cataracts. While the initial reaction takes place by the interaction of >C=O of the parent sugars with the -NH2 of proteins, reactive oxygen species (ROS) dependent generation of more reactive dicarbonyl derivatives from the oxidation of sugars also plays a significant role in these changes, altering the structural as well as functional properties of proteins. The purpose of this study was to examine whether the activities of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), catalase and superoxide dismutase (SOD) could be affected by the high levels of fructose prevalent in diabetic lenses. Incubation of the enzymes with this sugar led to a significant loss of their activities. GAPDH was inactivated within a day. This was followed by the inactivation of catalase (3-4 days) and SOD (6 days). The loss of the activities was prevented significantly by incorporation of pyruvate in the incubation mixture. The protective effect is ascribable to its ability to competitively inhibit glycation as well as to its ROS scavenging activity. Hence, it could play a significant role in the maintenance of lens physiology and cataract prevention.
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PMID:Fructose induced deactivation of antioxidant enzymes: preventive effect of pyruvate. 1082 18

Oxidant stress, in vivo or in vitro, is known to induce oxidative changes in human red blood cells (RBCs). Our objective was to examine the effect of augmenting RBC glutathione (GSH) synthesis on 1) degenerative protein loss and 2) RBC chemokine- and free radical-scavenging functions in the oxidatively stressed human RBCs by using banked RBCs as a model. Packed RBCs were stored up to 84 days at 1-6 degrees C in Adsol or in the experimental additive solution (Adsol fortified with glutamine, glycine, and N-acetyl-L-cysteine). Supplementing the conventional additive with GSH precursor amino acids improved RBC GSH synthesis and maintenance. The rise in RBC gamma-glutamylcysteine ligase activity was directly proportional to the GSH content and inversely proportional to extracellular homocysteine concentration, methemoglobin formation, and losses of the RBC proteins band 3, band 4.1, band 4.2, glyceraldehyde-3-phosphate dehydrogenase, and Duffy antigen (P < 0.01). Reduced loss of Duffy antigen correlated well with a decrease in chemokine RANTES (regulated upon activation, normal T-cell expressed, and secreted) concentration. We conclude that the concomitant loss of GSH and proteins in oxidatively stressed RBCs can compromise RBC scavenging function. Upregulating GSH synthesis can protect RBC scavenging (free radical and chemokine) function. These results have implications not only in a transfusion setting but also in conditions like diabetes and sickle cell anemia, in which RBCs are subjected to chronic/acute oxidant stresses.
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PMID:Glutathione protects chemokine-scavenging and antioxidative defense functions in human RBCs. 1124 4

The effects of benfluorex and two of its metabolites (S 422-1 and S 1475-1) on fatty acid and glucose metabolic fluxes and specific gene expression were studied in hepatocytes isolated from 24-h fasted rats. Both benfluorex and S 422-1 (0.1 or 1 mmol/l) reduced beta-oxidation rates and ketogenesis, whereas S 1475-1 had no effect. At the same concentration, benfluorex and S 422-1 were more efficient in reducing gluconeogenesis from lactate/pyruvate than S 1475-1. Benfluorex inhibited gluconeogenesis at the level of pyruvate carboxylase (45% fall in acetyl-CoA concentration) and of glyceraldehyde-3-phosphate dehydrogenase (decrease in ATP/ADP and NAD(+)/NADH ratios). Accordingly, neither benfluorex nor S 422-1 inhibited gluconeogenesis from dihydroxyacetone, but both stimulated gluconeogenesis from glycerol. In hepatocytes cultured in the presence of benfluorex or S 422-1 (10 or 100 micromol/l), the expression of genes encoding enzymes of fatty acid oxidation (carnitine palmitoyltransferase [CPT] I), ketogenesis (hydroxymethylglutaryl-CoA synthase), and gluconeogenesis (glucose-6-phosphatase, PEPCK) was decreased, whereas mRNAs encoding glucokinase and pyruvate kinase were increased. By contrast, Glut-2, acyl-CoA synthetase, and CPT II gene expression was not affected by benfluorex or S 422-1. In conclusion, this work suggests that benfluorex mainly via S 422-1 reduces gluconeogenesis by affecting gene expression and metabolic status of hepatocytes.
Diabetes 2002 Aug
PMID:Effects of benfluorex on fatty acid and glucose metabolism in isolated rat hepatocytes: from metabolic fluxes to gene expression. 1214 46


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