Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D02011 (FAD)
 5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In thyroidectomized rats, the activity of FAD-linked glycerophosphate dehydrogenase was severely diminished in liver homogenates but not affected significantly in pancreatic islet homogenates, whilst the activity of 2-ketoglutarate dehydrogenase was decreased modestly in both liver and islet homogenates. Likewise, in intact islets of thyroidectomized rats, the generation of 3HOH from [2-3H]glycerol was not decreased, and the ratio between oxidative and total glycolysis not significantly lower than in islets from sham-operated rats, at least in the presence of a high concentration of D-glucose. Nevertheless impaired oxidation of both D-[3,4-14C]glucose and D-[6-14C]glucose was observed in islets of thyroidectomized rats, the relative magnitude of such a decrease being more pronounced at a low than at a high D-glucose concentration. Such metabolic anomalies coincided with a lower level of plasma insulin and decreased output of insulin by islets incubated at low (2.8 mM), but not higher, concentrations of D-glucose. It is concluded that hypothyroidism does not mimic the deficiency in islet FAD-linked glycerophosphate dehydrogenase activity found in rats with inherited or acquired non-insulin-dependent diabetes.
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PMID:Enzymatic, metabolic and secretory perturbations in pancreatic islets of thyroidectomized rats. 832 84

The mitochondrial enzyme FAD-linked glycerophosphate dehydrogenase (m-GDH) is thought to play a key role in the glucose-sensing mechanism of the insulin-producing B-cell. It catalyses a rate-limiting step of the glycerol phosphate shuttle in pancreatic islets. Its activation by Ca2+ accounts for the preferential stimulation of oxidative glycolysis and, hence, pyruvate oxidation in glucose-stimulated islets. Reduced activity of m-GDH was recently observed in islet, but not liver, homogenates from rats injected with streptozotocin during the neonatal period and in two models of inherited diabetes, i.e. GK rats and db/db mice. In the streptozotocin-injected and GK rats the m-GDH islet defect coincided, in intact islets, with an abnormally low ratio between oxidative and total glycolysis. Decreased activity of m-GDH in T-lymphocytes was also observed in 12 of 32 type 2 (non-insulin-dependent) diabetic patients, but only once among 26 other subjects including 11 healthy volunteers, 9 non-diabetics and 6 patients with either type 1 (insulin-dependent) or symptomatic diabetes. In the T-lymphocytes of type 2 diabetics the m-GDH deficiency occasionally coincided with an abnormally high ratio between glutamate-pyruvate and glutamate-oxaloacetate transaminase activities, as also observed in islets from streptozotocin-injected or GK rats. It is speculated that an islet m-GDH defect could represent a far from uncommon factor contributing to the pathogenesis of type 2 diabetes mellitus.
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PMID:Is type 2 diabetes due to a deficiency of FAD-linked glycerophosphate dehydrogenase in pancreatic islets? 832 24

In vitro, streptozotocin (1.0-2.0 mM) fails to exert any immediate effect on the activity of FAD-glycerophosphate dehydrogenase in either pancreatic islet homogenate or freshly isolated intact islets. However, when injected in vivo, streptozotocin (40 mg/kg body weight) lowers the specific activity of the FAD-linked enzyme in islet homogenates within 24 h, whilst causing little change in 2-ketoglutarate dehydrogenase and increasing glutamate dehydrogenase islet activity. In animals which became frankly hyperglycaemic as the result of the injection of streptozotocin, the activity of islet FAD-glycerophosphate dehydrogenase, measured 2 weeks after administration of the B-cell cytotoxic agent, was decreased to 10-20% of its control value. Neither insulin treatment nor riboflavin supplementation affected this enzymic defect. Even when the animals injected with streptozotocin remained virtually euglycaemic, the activity of islet FAD-glycerophosphate dehydrogenase was markedly decreased. This coincided with a preferential impairment of aerobic glycolysis, as judged from the ratio between D-[3,4-14C]glucose oxidation and D-[5-3H] glucose utilization by the islets. It is proposed, therefore, that the administration of sub-diabetogenic amounts of streptozotocin to adult rats represents an alternative and easier approach to the study of B-cell dysfunction in this model of type 2 (non-insulin-dependent) diabetes than does streptozotocin injection in neonatal rats.
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PMID:Streptozotocin-induced FAD-glycerophosphate dehydrogenase suppression in pancreatic islets. Relationship with the severity and duration of hyperglycaemia and resistance to insulin or riboflavin treatment. 832 33

The activity of FAD-linked glycerophosphate dehydrogenase (m-GDH), as well as that of glutamate dehydrogenase and both glutamate-oxalacetate and glutamate-pyruvate transaminases, were measured in islet, liver, and splenocyte homogenates from 6- to 7-week-old female nonobese diabetic mice (NOD) and age- and sex-matched control mice. Despite incipient insulitis and euglycemia, the NOD mice displayed both high islet insulin content and elevated insulinemia. The activity of m-GDH, expressed relative to protein content, was not decreased in islets of NOD mice, despite the fact that such a specific activity is lower in splenic lymphocytes than islet cells. In liver homogenates, the activity of m-GDH was even higher in NOD than control mice. It is proposed, therefore, that in this model of insulin-dependent diabetes no primary decrease in islet m-GDH activity occurs, at variance with the situation recently documented in several animal models of non-insulin-dependent diabetes.
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PMID:FAD-linked glycerophosphate dehydrogenase activity in islets, liver, and splenocytes of NOD mice. 837 36

The activity of FAD-glycerophosphate dehydrogenase, as measured through the generation of either 3HOH from L-[2-3H]glycerol-3-phosphate in the presence of FAD or iodoformazan from iodonitrotetrazolium, displayed comparable values in islet homogenates of lean and obese (ob/ob) mice. In the liver of the obese animals, the results obtained by the colorimetric and radioisotopic assays yielded a paired ratio twice higher than in control mice. Although isoforms of the mitochondrial enzyme could be present in variable proportions depending on the cell type and genetic background, the present results suggest that, in ob/ob mice, the increased secretory responsiveness of the islet B-cell to D-glucose coincides with an unaltered activity of FAD-glycerophosphate dehydrogenase. This contrasts with the situation recently documented in db/db mice, in which an impaired secretory response of the B-cell to D-glucose is associated with a decreased activity of FAD-glycerophosphate dehydrogenase.
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PMID:FAD-glycerophosphate dehydrogenase activity in pancreatic islets and liver of ob/ob mice. 840 Dec 96

In pancreatic islet extracts of rats with hereditary non-insulin-dependent diabetes mellitus (GK rats), the activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase, as measured by either a radioisotopic or colorimetric procedure, only represented 30 to 40% of that found in control rats. This decrease in enzymic activity was not attributable to any sizeable change in either islet DNA content or the relative contribution of insulin-producing beta cells to total islet mass. It contrasted with a normal activity of other mitochondrial dehydrogenases and hexokinase isoenzymes. It coincided, however, with an increased activity of glutamate-pyruvate transaminase, as already observed in adult rats injected with streptozotocin during the neonatal period. The decreased activity of islet FAD-linked glycerophosphate dehydrogenase also contrasted with an increased activity of the same enzyme in the liver of GK, as compared to control rats. In the light of these findings and recent metabolic data collected in intact islets of GK rats, it is proposed that a deficiency of beta-cell FAD-linked glycerophosphate dehydrogenase, the key enzyme of the glycerol phosphate shuttle, may represent a cause of inherited non-insulin-dependent diabetes.
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PMID:Deficient activity of FAD-linked glycerophosphate dehydrogenase in islets of GK rats. 840 39

The mitochondrial enzyme FAD-linked glycerophosphate dehydrogenase plays a key role in the glucose-sensing device of the insulin-producing pancreatic B-cell. Its activity was found to be decreased in islet, but not liver, homogenates of BL/Ks-db/db mice, in which diabetes mellitus represents an inherited disease. The decreased activity of FAD-linked glycerophosphate dehydrogenase contrasted with a normal activity of glutamate dehydrogenase and 2-ketoglutarate dehydrogenase in the islets of db/db mice. It is proposed that a site-specific defect of FAD-linked glycerophosphate dehydrogenase in the pancreatic B-cell might represent a far-from-uncommon causal or contributing factor in the pathogenesis of non-insulin-dependent diabetes mellitus.
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PMID:FAD-linked glycerophosphate dehydrogenase deficiency in pancreatic islets of mice with hereditary diabetes. 842 47

Purified rat pancreatic insulin-producing B-cells, which display a 12-fold higher activity of FAD-linked glycerophosphate dehydrogenase than other islet endocrine cells, were exposed for 30 min to 2 mM streptozotocin and subsequently cultured for 2 days in the absence or presence of 2 mM nicotinamide. Streptozotocin decreased by 54% the number of B-cells and, in surviving cells, lowered by 75% the activity of FAD-linked glycerophosphate dehydrogenase, whilst failing to affect that of glutamate dehydrogenase. This coincided with a 42-51% reduction of insulin secretion, when expressed relative to either the DNA or hormonal content of surviving cells. After exposure to streptozotocin, the presence of nicotinamide in the culture medium reduced cell death by 44% and also reduced the deleterious effects of streptozotocin upon both the enzymic and secretory activities of surviving cells. These findings indicate that the decreased activity of FAD-linked glycerophosphate dehydrogenase previously documented in pancreatic islets from streptozotocin-injected rats, as well as the protective effect of nicotinamide thereupon, are not attributable solely to changes in the number of B-cells but also to an altered enzymic activity in surviving B-cells. The latter anomaly may account, in part at least, for an impaired B-cell secretory response to D-glucose.
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PMID:Effect of streptozotocin and nicotinamide upon FAD-glycerophosphate dehydrogenase activity and insulin release in purified pancreatic B-cells. 848 53

In several animal models of non-insulin-dependent diabetes, a decreased activity of FAD-linked glycerophosphate dehydrogenase was recently documented in pancreatic islet, but not liver, homogenates. The present study reveals that, on the contrary, the activity of the same mitochondrial enzyme is increased in islet, but not liver or spleen, homogenates of BB, as compared to BW, rats examined before the onset of severe hyperglycemia in this animal model of autoimmune insulin-dependent diabetes.
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PMID:Increased activity of FAD-linked glycerophosphate dehydrogenase in pancreatic islets of BB rats. 849 19

cDNAs which encode the rat testis and pancreatic islet mitochondrial glycerol phosphate dehydrogenase (mGPD) (EC 1.1.99.5), the key enzyme of the glycerol phosphate shuttle, were recently cloned and sequenced and found to contain calmodulin-like calcium-binding sequences, thus explaining the widely observed calcium activation of the enzyme from many tissues of higher eukaryotes. mGPD activity and protein, as judged from Western analysis, appear to be most abundant in testis and pancreatic islets in the rat. mGPD is known to be located within the inner mitochondrial membrane. At a physiologic concentration of glycerol phosphate (75 microM), half maximal activity of Triton X-100-solubilized testis mGPD was seen in the presence of 0.1-0.25 microM free calcium. Calcium (10(-6)-10(-5) M) lowered the Km of mGPD from 2.5 mM glycerol phosphate (islet mGPD) and 3.2 mM glycerol phosphate (testis mGPD) to 0.4 mM glycerol phosphate. Calcium activation of mGPD from both testis and islets was not prevented by calmodulin inhibitors, which is consistent with mGPD possessing regions that can mediate its own activation by calcium. 45Calcium overlay experiments, in which proteins were separated by SDS-polyacrylamide gel electrophoresis, blotted onto nitrocellulose membranes, and probed with 45Ca, showed that mGPD is a major calcium-binding protein in testis mitochondrial membranes. A hydropathy plot suggested that the mature mGPD protein has three transmembrane helices. The first membrane-spanning region coincides with the FAD site and thus this site is placed within the membrane. The hydropathy analysis indicated that the calcium-binding region and the putative glycerol phosphate-binding site lie outside the membrane exposed to the cytosolic environment. This is consistent with earlier biochemical evidence which indicated that these sites are situated outside the membrane (M. Klingenberg, Eur. J. Biochem. 13, 247-252, 1970). This suggests that cytosolic calcium can regulate mGPD activity. Since simultaneous oscillations in electrical activity, cytosolic calcium, glycolysis, and insulin release occur in the pancreatic beta cell, mGPD activity might also fluctuate and allow the glycerol phosphate shuttle to participate in glycolytic oscillations.
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PMID:Calcium activation of mitochondrial glycerol phosphate dehydrogenase restudied. 857 75


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