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)

Control rats and diabetic animals injected with streptozotocin during the neonatal period were either maintained on a standard diet or given access to food supplemented with dehydroepiandrosterone (DHEA, 0.2%) for 11 days before sacrifice. In both control and diabetic rats, DHEA feeding augmented the activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase and cytosolic NADP-linked malate dehydrogenase in liver, but not so in either the parotid gland or pancreatic islets. DHEA lowered, in both control and diabetic rats, the ratio between D-glucose oxidation and utilization and the rate of insulin release in pancreatic islets exposed to a high concentration of D-glucose, as well as the insulin concentration and insulin/glucose ratio in plasma. These findings support the view that, in diabetes, DHEA, by increasing sensitivity to insulin, may allow islet B-cells to avoid the otherwise unfavorable consequences of chronic hyperactivity.
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PMID:Effects of dehydroepiandrosterone in rats injected with streptozotocin during the neonatal period. 923

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.
Diabetes Metab 1997 Sep
PMID:Physiology, pathology and pharmacology of insulin secretion: recent acquisitions. 934 37

The mitochondrial enzyme FAD-linked glycerophosphate dehydrogenase (mGDH) plays a key role in the recognition of D-glucose as a stimulus for insulin release from the pancreatic islet B-cell. This study reveals that autoantibodies against this enzyme are not uncommonly found in patients with insulin-dependent diabetes mellitus (IDDM) examined at the onset of the disease. Antibodies reacting with a recombinant mGDH fragment product were observed in the serum of four out of 15 type-1 diabetics, but in none of 15 control subjects. The serum of patients positive for the recombinant mGDH fragment also recognized native mGDH in a rat testis extract, provided that the enzymatic protein was first exposed to an anti-mGDH rabbit serum. Antibodies against mGDH were also found in four out 12 patients with autoimmune thyroiditis. These findings reveal that a mitochondrial enzyme, that represents an essential component of the islet B-cell glucose-sensing device, may act as an antigenic determinant in patients with IDDM or other autoimmune diseases.
Diabetes Res Clin Pract 1997 Nov
PMID:Autoantibodies against mitochondrial glycerophosphate dehydrogenase in patients with IDDM. 948 75

To evaluate if potential defects in the FAD-binding domain of the mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) gene could contribute to susceptibility to type 2 diabetes mellitus, we have screened 151 type 2 DM patients for mutations using PCR single-strand conformational polymorphism. Both a single substitution (T to A) at position 18 and a 6-base-pair deletion (TTTTAA) at position 26 of intron 3 have been detected in five type 2 DM patients and in one control subject. The evolution time of diabetes was longer in patients with these mutations than in patients without (24.2 +/- 11.1 vs 12.6 +/- 8.7 years, p < 0.02). These mutations generate a cryptic site that may have functional significance in the correct mechanism of the FAD-binding domain. In the process of PCR amplification of the mGPDH gene we also unexpectedly amplified the mGPDH retropseudogene. Subsequently, we decided to further characterize and completely sequence 2213 bp of this mGPDH retropseudogene. Our results suggest that two previously reported mGPDH pseudogene partial sequences may be identical copies of the mGPDH gene inserted in two different genomic locations and provide information about the alternative 5'- and 3'-untranslated regions. The data obtained are also important in order to avoid artifactual amplification of the mGPDH pseudogene in the process of screening for mGPDH mutations in diabetic patients.
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PMID:Detection of a new variant of the mitochondrial glycerol-3-phosphate dehydrogenase gene in Spanish type 2 DM patients. 1049 12

Type 2 diabetes mellitus is one of the most common chronic metabolic diseases in man. Due to long-term complications of the disease, severely decreasing the quality of life of diabetic patients, early interventions to obviate the risk of complications are of major importance. Therefore, diabetic animal models are of major importance in research for interventional treatment of type 2 diabetes. In this work we investigated the possible alterations in mitochondrial energetic metabolism of Goto-Kakizaki (GK) rats during the progression of the disease, since glucose metabolism is closely related to intracellular ATP content. For that reason, respiratory indexes (state 4, state 3, RCR and ADP/O) were evaluated either in the presence of NAD- or FAD-linked substrates (glutamate + malate and succinate, respectively) in mitochondrial preparations of GK and control rats with 8, 12, 26 and 52 weeks of age. Until the age of 1 year (52 weeks) we found no impairment of mitochondrial respiratory indexes both in the presence of glutamate + malate and succinate. In conclusion, this study indicates that GK rat is a good model for studying the initial events of diabetes, since it presents no impairment of liver mitochondrial functions during the first year of life, contrasting clearly with pharmacological induced diabetes.
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PMID:Age-related alterations in liver mitochondrial bioenergetics of diabetic Goto-Kakizaki rats. 1066 24

Human pancreatic islets were cultured for 63 hr at 2.8 or 16.7 mM D-glucose in the absence or presence of dexamethasone. In the 1.0 to 10 microM range, dexamethasone caused a concentration-related decrease in the FAD (flavin adenine dinucleotide)-linked mitochondrial glycerophosphate dehydrogenase (mGDH) mRNA content of the islets, and decreased both the mGDH content of the islets and the catalytic activity of the enzyme in islet homogenates, these effects being often more marked in islets cultured at 16.7 mM, rather than 2.8 mM, D-glucose. Even after culture in the presence of no more than 10 nM dexamethasone, namely under conditions in which the mGDH mRNA content and activity were both virtually unaffected, the corticosteroid restored the capacity of the beta-cells to display an increase in insulin output in response to a rise in D-glucose concentration in islets first cultured at 2.8 mM D-glucose but suppressed the insulinotropic action of the hexose in islets first cultured at 16.7 mM D-glucose. Whilst revealing an untoward effect of high concentrations of dexamethasone upon mGDH mRNA, content and activity in human islets, these findings also document a dual effect of a low concentration of the corticosteroid (10 nM) upon the secretory responsiveness of human islets to D-glucose, independently of any significant change in mGDH gene expression. It is proposed that such a dual action may account, in part at least, for both the well known increase in insulin output found in hypercorticism and the more recently discovered unfavourable direct effect of corticosteroid hormones on the secretory activity of islet beta-cells.
Diabetes Nutr Metab 1999 Dec
PMID:Dexamethasone-induced changes in FAD-glycerophosphate dehydrogenase mRNA, content and activity, and insulin release in human pancreatic islets. 1078 59

In a new experimental type 2 diabetic syndrome, a 40% reduction of pancreatic beta cells was observed by morphometric analysis. In diabetic islets, as compared to control islets, insulin release was decreased in response to high glucose but not to other stimuli, and total glucose oxidation and utilization were unchanged or slightly reduced. The extent of metabolic and functional impairment appeared proportional to the beta-cell loss. However, a substantial decrease was found in protein level and activity (by 77 and 60%, respectively, versus controls) of mitochondrial FAD-glycerophosphate dehydrogenase (mGDH), the key enzyme of the glycerophosphate shuttle. Interestingly, in diabetic islets, as recently reported for mGDH-deficient transgenic mice, definite functional alterations (mainly in response to D-glyceraldehyde) were only obtained upon pharmacological blockade of the second shuttle (i.e. malate-aspartate) responsible for mitochondrial transfer of reducing equivalents. In conclusion, in this diabetes model with reduction of beta-cell mass, the islets, despite decreased mGDH amount and activity, appear metabolically and functionally active in vitro, likely through the intervention of adaptive mechanisms, yet prone to failure in challenging situations.
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PMID:Metabolic and functional studies on isolated islets in a new rat model of type 2 diabetes. 1132 16

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.
Diabetes Res Clin Pract 2001 Jul
PMID:Distinct effect of diazoxide on insulin secretion stimulated by protein kinase A and protein kinase C in rat pancreatic islets. 1137 8

14-3-3-interacting proteins were isolated from extracts of proliferating HeLa cells using 14-3-3 affinity chromatography, eluting with a phosphopeptide that competes with targets for 14-3-3 binding. The isolated proteins did not bind to 14-3-3 proteins (14-3-3s) after dephosphorylation with protein phosphatase 2A (PP2A), indicating that binding to 14-3-3s requires their phosphorylation. The binding proteins identified by tryptic mass fingerprinting and Western blotting include many enzymes involved in generating precursors such as purines (AMP, GMP and ATP), FAD, NADPH, cysteine and S-adenosylmethionine, which are needed for cell growth, regulators of cell proliferation, including enzymes of DNA replication, proteins of anti-oxidative metabolism, regulators of actin dynamics and cellular trafficking, and proteins whose deregulation has been implicated in cancers, diabetes, Parkinsonism and other neurological diseases. Several proteins bound to 14-3-3-Sepharose in extracts of proliferating cells, but not in non-proliferating, serum-starved cells, including a novel microtubule-interacting protein ELP95 (EMAP-like protein of 95 kDa) and a small HVA22/Yop1p-related protein. In contrast, the interactions of 14-3-3s with the N-methyl-D-aspartate receptor 2A subunit and NuMA (nuclear mitotic apparatus protein) were not regulated by serum. Overall, our findings suggest that 14-3-3s may be central to integrating the regulation of biosynthetic metabolism, cell proliferation, survival, and other processes in human cells.
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PMID:14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking. 1506 4

Mitochondrial medium-chain acyl-CoA dehydrogenase is a key enzyme for the beta-oxidation of fatty acids, which catalyzes the FAD-dependent oxidation of a variety of acyl-CoA substrates to the corresponding trans-2-enoyl-CoA thioesters. Oct-4-en-2-ynoyl-CoA was identified as a new irreversible inhibitor of acyl-CoA dehydrogenase, and kinetic parameters K(I) and k(inact) were determined to be 11 microM and 0.025 min(-1), respectively. Triple bond between C2 and C3 of the inhibitor was identified as the functional group responsible for enzyme inactivation, and Michael addition is proposed as the mechanism for this inactivation, which is a new pathway for inactivation of MCAD by inhibitors. The inhibitor may become a lead for further development for treating non-insulin-dependent diabetes mellitus.
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PMID:Inactivation of medium-chain acyl-CoA dehydrogenase by oct-4-en-2-ynoyl-CoA. 1629 16


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