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Query: KEGG:D02011 (FAD)
 5,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review reevaluates the possible roles of glut-2 underexpression, glucokinase gene mutation, glucose-6-phosphate hyperactivity, glycerophosphate dehydrogenase (FAD-linked) deficiency and glycogen accumulation in the pancreatic B-cell as contributive factors in the pathogenesis of Type 2 diabetes.
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PMID:Physiology and pathology of islet metabolism. 780 57

Impairment of glucose-induced insulin secretion in non-insulin-dependent diabetes mellitus (NIDDM) may be caused by GLUT 2 underexpression in the pancreatic beta cell, a mutation of the glucokinase gene, glucose 6-phosphatase overactivity, FAD-linked glycerophosphate dehydrogenase deficiency, a mitochondrial DNA defect and/or a secondary phenomenon of so-called glucotoxicity possibly involving glycogen accumulation in the beta-cell. It is proposed tht the methyl esters of succinic acid and related molecules may represent new tools with which to bypass these defects in glucose transport, phosphorylation and further catabolism and, hence, to stimulate both proinsulin biosynthesis and insulin release in NIDDM.
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PMID:The beta cell in NIDDM: giving light to the blind. 782 38

Islets were isolated by automatic digestion from non-diabetic cadaveric organ donors and from Type 2 (non-insulin-dependent) diabetic subjects. The activity of FAD-glycerophosphate dehydrogenase, but not that of either glutamate dehydrogenase, glutamate-oxalacetate transaminase or glutamate-pyruvate transaminase, was lower in Type 2 diabetic patients than control subjects. Hexokinase, glucokinase and glutamate decarboxylase activities were also measured in islets from control subjects. The utilization of D-[5-3H]glucose, oxidation of D-[6-14C]glucose and release of insulin evoked by D-glucose were all lower in Type 2 diabetic patients than control subjects. The secretory response to the combination of L-leucine and L-glutamine appeared less severely affected. Islets from Type 2 diabetic patients may thus display enzymatic, metabolic and secretory anomalies similar to those often observed in animal models of Type 2 diabetes, including a deficiency of beta-cell FAD-linked glycerophosphate dehydrogenase, the key enzyme of the glycerol phosphate shuttle.
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PMID:Enzymatic, metabolic and secretory patterns in human islets of type 2 (non-insulin-dependent) diabetic patients. 816 52

The activities of hexokinase isoenzymes, lactate dehydrogenase, cytosolic NAD-linked glycerophosphate dehydrogenase, mitochondrial FAD-linked glycerophosphate dehydrogenase, and glutamate dehydrogenase were measured in homogenates of rat purified pancreatic B and non-B islet cells. In B cell homogenates, the maximal activity of hexokinase and glucokinase was one to two orders of magnitude lower than that of lactate dehydrogenase. The activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase was also much lower than that of the cytosolic NAD-linked glycerophosphate dehydrogenase . A comparable hierarchy in the activity of these enzymes was observed in non-B islet cells. These findings reinforce the view that the preferential stimulation of oxidative glycolysis observed in insulin-producing cells, when exposed to high concentrations of D-glucose, is attributable to a Ca2+-induced activation of the mitochondrial FAD-linked glycerophosphate dehydrogenase, rather than to saturation of the catalytic activity of lactate dehydrogenase.
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PMID:Relevance of lactate dehydrogenase activity to the control of oxidative glycolysis in pancreatic islet B-cells. 861 12

Hyperinsulinemia accompanies obesity in human patients and experimental rodent models and exacerbates insulin resistance, but the causes of increased insulin secretion remain obscure. This review examines progress in defining biochemical and molecular beta-cell defects that have elucidated in the past 5 years. Some defects, such as decreased glucose transport, decreased mitochondrial FAD-linked glycerophosphate dehydrogenase activity, and altered anomeric specificity for glucose, become evident only after onset of non-insulin-dependent diabetes mellitus. Thus, these defects are unlikely to play a role in the pathogenesis of hyperinsulinemia in obesity. Other biochemical changes, including increased glucokinase and (or) hexokinase function, increased glucose cycling, and altered regulation of intracellular Ca2+ are present in obese nondiabetic animals and may therefore contribute to development of hyperinsulinemia. Few developmental studies have been performed to correlate onset of defects with environmentally and genetically mediated control mechanisms of beta-cell function. However, the availability of new molecular biology techniques should facilitate identification of factors causing hyperinsulinemia in obesity.
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PMID:beta-cell stimulus - secretion coupling defects in rodent models of obesity. 874 32

The physiological regulation of nutrient catabolism in islet cells, its perturbation in non-insulin-dependent diabetes mellitus, and the tools available to compensate for such a perturbation are reviewed. In terms of physiology, emphasis is placed on the relevance of glucokinase to hexose-induced insulin release, protein-to-protein interaction and enzyme-to-enzyme channelling, and the preferential stimulation of mitochondrial oxidative events in glucose-stimulated B-cells. In terms of pathology, attention is drawn to the deficiency of FAD-linked mitochondrial glycerophosphate dehydrogenase. Last, as far as therapeutic aspects are concerned, the potential usefulness of hypoglycemic sulfonylureas and meglitinide analogs, adenosine analogs, non-glucidic nutrients, and GLP-1 is underlined.
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PMID:Regulation, perturbation, and correction of metabolic events in pancreatic islets. 890 21

Recent acquisitions concerning the physiology, pathology and pharmacology of insulin secretion are reviewed. In terms of physiology, emphasis is placed on new information concerning the role of glucokinase and the identity of coupling factors in the process of glucose-stimulated insulin release. Pathological considerations concern mainly the possible participation of an inherited or acquired defect of FAD-linked mitochondrial glycerophosphate dehydrogenase in the impairment of insulin release in non-insulin-dependent diabetes. Although experimental approaches to correct such a site-specific defect have so far been unsuccessful, new therapeutic tools, especially the esters of certain nutrients, may soon be available for stimulation of proinsulin biosynthesis as well as insulin release in the diseased B cell.
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PMID:Physiology, pathology and pharmacology of insulin secretion: recent acquisitions. 934 37

Protein kinase activation is known to stimulate glucose-induced insulin secretion in the presence of diazoxide. Diazoxide opens the ATP-sensitive K(+) channel and inhibits FAD-linked glycerophosphate dehydrogenase activity in a concentration-dependent manner. In the present study, we examined the effect of lower (100 microM) and higher (250 microM) concentrations of diazoxide on insulin release by protein kinase A (PKA) and protein kinase C (PKC) activation. Forced depolarization by a high potassium concentration, augmented the intracellular Ca(2+) concentration ([Ca(2+)](i)) similarly in the presence of both concentrations of diazoxide. Under this condition, 250 microM diazoxide inhibited insulin release enhanced by PKA activation but not that by PKC. Under a basal concentration of [Ca(2+)](i), PKC activation elicited glucose-induced insulin secretion at 100 and 250 microM diazoxide, while PKA activation did so only at 100 microM. These augmentations were completely inhibited by mannoheptulose, a glucokinase inhibitor. Glyceraldehyde, in place of glucose, enhanced insulin secretion by PKC activation under both concentrations of diazoxide. On the other hand, it did not affect PKA-stimulated insulin release under either conditions, but in the case of 100 microM, glucose augmented the insulin secretion in the presence of glyceraldehyde and db-cAMP concentration-dependently. These data suggest that insulin release stimulated by PKA and PKC activation under diazoxide is dependent on glucose metabolism, and that a signal derived from proximal steps in glycolysis may be necessary for the secretion by PKA activation.
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PMID:Distinct effect of diazoxide on insulin secretion stimulated by protein kinase A and protein kinase C in rat pancreatic islets. 1137 8

In terms of glucose sensing by pancreatic islet beta-cells, emphasis is currently placed on both the role of glucokinase, with negligible activity of low-Km hexokinase(s), and the prevalence of the oxidative over non-oxidative modality of glycolysis, a situation tentatively attributed, in part at least, to a low activity of lactate dehydrogenase. Conflicting information is available, however, on the activity of both low-Km hexokinase(s) and lactate dehydrogenase in purified beta-cell homogenates. This issue was reinvestigated, therefore, in two populations of purified rat islet beta-cells selected on the basis of their low (betaL) or high (betaH) content in reduced pyridine nucleotides. The size and protein content of betaH cells represented about twice that of betaL cells. Such was also the case for low-Km hexokinase(s), lactate dehydrogenase, mitochondrial FAD-linked glycerophosphate dehydrogenase, glutamate dehydrogenase and glutamate-alanine and glutamate-aspartate transaminases. Whether in betaH or betaL cells, the activity of low-Km hexokinase(s) was at least as high as or higher than that of glucokinase. In both betaH and betaL, the activity of lactate dehydrogenase exceeded that required to catalyze the full reduction of glucose-derived pyruvate to L-lactate, as estimated from the rate of D-glucose phosphorylation under physiological conditions. These findings thus argue against a low expression of either low-Km hexokinase(s) or lactate dehydrogenase as major determinants of the glucose-sensing device in beta-cells.
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PMID:Enzymic activities in two populations of purified rat islet beta-cells. 1149 57

In this article we show the recent progress in the field of glucose sensing based on the utilization of enzymes and proteins as probes for stable and non-consuming fluorescence biosensors. We developed a new methodology for glucose sensing using inactive forms of enzymes such as the glucose oxidase from Aspergillus niger, the glucose dehydrogenase from the thermophilic microorganism Thermoplasma acidophilum, and the glucokinase from the thermophilic eubacterium Bacillus stearothermophilus. Glucose oxidase was rendered inactive by removal of the FAD cofactor. The resulting apo-glucose oxidase still binds glucose as observed from a decrease in its intrinsic tryptophan fluorescence. 8-Anilino-1-naphthalene sulfonic acid was found to bind spontaneously to apo-glucose oxidase as seen from an enhancement of the ANS fluorescence. The steady state intensity of the bound ANS decreased 25% upon binding of glucose, and the mean lifetime of the bound ANS decreased about 40%. These spectral changes occurred with a midpoint from 10 to 20 mM glucose, which is comparable to the KD of holo-glucose oxidase. The ANS-labeled apo-glucose dehydrogenase from Thermoplasma acidophilum also displayed an approximate 25% decrease in emission intensity upon binding glucose. This decrease can be also used to measure the glucose concentration. The thermophilic apo-glucose dehydrogenase was also stable in the presence of organic solvents, allowing determination of glucose in the presence of acetone. The third enzyme used for glucose sensing was the glucokinase from Bacillus stearothermophilus. A fluorescence competitive assay for the determination of glucose was developed based on the utilization of this thermostable enzyme. Taken together, our results show that enzymes which use glucose as their substrate can be used as reversible and non-consuming glucose biosensors in the absence of required co-factors. Moreover, the possibility of using inactive apo-enzymes for a reversible sensor greatly expands the range of proteins which can be used as sensors, not only for glucose, but for a wide variety of biochemically relevant analytes.
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PMID:Protein-based biosensors for diabetic patients. 1561 57


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