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

We studied the possible relationships between the functional status of the beta-cell and activities or mRNA contents of enzymes involved in the catabolism of glucose. Three different in vitro models with attenuated insulin response were used: rat islets cultured at a low glucose concentration, rat islets incubated in vitro with streptozocin, and fetal rat islets. The fetal and streptozocin-administered islets were compared with adult islets cultured in RPMI-1640 containing 11 mM glucose, and the effects of the in vitro glucose concentrations (3.3, 11, and 28 mM) were assessed on adult islets only. Cellular mRNA levels for the mitochondrial DNA-encoded cytochrome b and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were determined by Northern-blot analysis. Enzymatic activities of high-Km (glucokinase) and low-Km (hexokinase) glucose-phosphorylating enzymes and succinate-cytochrome c reductase were also determined. Islets cultured at 3.3 mM glucose displayed a decreased activity of glucokinase compared with islets cultured at 28 mM glucose (23.3 +/- 12%), whereas there was no difference in hexokinase activity or the level of GAPDH mRNA. The activity of succinate-cytochrome c reductase was similar in islets cultured at the different glucose concentrations. The level of cytochrome b mRNA increased at 28 mM glucose compared with islets cultured at 11 mM glucose (140 +/- 14%). Islets incubated with streptozocin and subsequently cultured for 7 days at 11 mM glucose exhibited a decreased level of cytochrome b mRNA (65 +/- 5%) and no differences in the activities of glucokinase, hexokinase, succinate-cytochrome c reductase, or the level of GAPDH mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Jun
PMID:Exhibition of specific alterations in activities and mRNA levels of rat islet glycolytic and mitochondrial enzymes in three different in vitro model systems for attenuated insulin release. 164 83

Tissue culture for one or seven days of pancreatic islets isolated from 21-day old fetal rats was found to be associated with a marked increase in the oxidation of L-(U-14C) glutamine by intact islets and in the activity of both alanine-glutamate and aspartate-glutamate transaminases as well as glutamate dehydrogenase in islet homogenates. This coincided with an increase in the relative amount of mitochondrial DNA. The activities of glucose-phosphorylating enzymes (hexokinase and glucokinase), glyceraldehyde-3-phosphate dehydrogenase and lactate dehydrogenase were less markedly increased during the culture period than those of enzymes involved in amino acid catabolism and located, in part at least, in mitochondria. The combined data suggest that the functional maturation of fetal islets during the culture period is associated with and may be attributable to a preferential maturation of their mitochondria.
Diabetes Res 1990 Apr
PMID:Maturation of fetal rat islet cells in vitro during tissue culture is associated with increased mitochondrial function. 213 6

We assessed our speculation that 2-cyclohexen-1-one (CHX) impairs glucose-induced insulin secretion through inactivation of glucokinase. Treatment of pancreatic islets with CHX at concentrations (0-5 mM) that caused a dose-dependent inactivation of glucokinase activity similarly inhibited glucose-induced insulin secretion. Another glucose-phosphorylating enzyme (hexokinase) in pancreatic islets was little affected by CHX. CHX-induced inactivation of glucokinase was blocked by the presence of its substrates (glucose and mannose) and an inhibitor (N-acetylglucosamine), all of which also protected against the inhibitory effect of the drug on glucose-induced insulin secretion. CHX also impaired insulin secretion induced by D-glyceraldehyde and dimethyl succinate, which are believed to stimulate the release of the hormone by being directly oxidized by glyceraldehyde-3-phosphate dehydrogenase, by entering the midstream of the glycolytic pathway as glyceraldehyde 3-phosphate, or by entering the tricarboxylic acid cycle in mitochondria after intracellular hydrolysis. The inhibitory effect of CHX on glucose-induced insulin secretion, however, was far more marked than that on insulin secretion evoked by D-glyceraldehyde and dimethyl succinate at any CHX concentrations used. Our study revealed that the inhibitory action of CHX on glucose-induced insulin secretion is exerted mainly, but not solely, through inactivation of glucokinase. This conclusion supports the view that glucokinase is a key enzyme in the recognition of glucose as an insulin secretagogue in pancreatic islets.
Diabetes 1990 Oct
PMID:Participation of glucokinase inactivation in inhibition of glucose-induced insulin secretion by 2-cyclohexen-1-one. 221 70

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

D-Glyceraldehyde irreversibly inhibited rat liver glucokinase in a concentration-dependent manner. The inactivation of glucokinase by glyceraldehyde was blocked by the presence of its substrates such as glucose and mannose. Glucokinase was highly sensitive to glyceraldehyde compared with some other glycolytic enzymes (from animal tissues) including hexokinase, glucose-6-phosphate isomerase, 6-phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase. The amino acid analysis of untreated and glyceraldehyde-treated glucokinase suggested that glyceraldehyde-induced inactivation of glucokinase is caused by glycation of Lys residues of the enzyme by the triose. Treatment of pancreatic islets with 6 mM glyceraldehyde for 1 h at 37 degrees C caused both inactivation of glucokinase and inhibition of glucose-induced insulin secretion. Another glucose-phosphorylating enzyme (hexokinase) in pancreatic islets, however, was little affected by glyceraldehyde. In addition, glyceraldehyde did not affect the insulin secretory responses of islets to nonglucose secretagogues such as glyceraldehyde and Leu. When pancreatic islets were cultured with a lower concentration (1 mM) of glyceraldehyde for a longer time (17 h) in the presence of 10 mM glucose to mimic the in vivo conditions, both glucokinase activity and glucose-induced insulin secretion were again decreased. This study demonstrates that glucose-induced insulin secretion is impaired by glyceraldehyde through the inactivation of glucokinase. The implication of this finding in the pathophysiology of type II diabetes is discussed.
Diabetes 1993 Jul
PMID:Inhibition of glucose-induced insulin secretion through inactivation of glucokinase by glyceraldehyde. 851 67

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

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


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