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

In the model of non-insulin-dependent diabetes found in adult rats injected with streptozotocin during the neonatal period, the activity of the mitochondrial glycerophosphate dehydrogenase is severely reduced in pancreatic islets. This coincides with a decreased contribution of aerobic to total glycolysis in intact islets and could account for the preferential impairment of the insulin secretory response to glucose.
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PMID:[Insular modifications in glycerophosphate dehydrogenase in diabetes]. 193 65

The molecular basis for the beta-cell dysfunction that characterizes non-insulin-dependent diabetes mellitus (NIDDM) is unknown. The Zucker diabetic fatty (ZDF) male rat is a rodent model of NIDDM with a predictable progression from the prediabetic to the diabetic state. We are using this model to study beta-cell function during the development of diabetes with the goal of identifying genes that play a key role in regulating insulin secretion and, thus, may be potential targets for therapeutic intervention aimed at preserving or improving beta-cell function. As a first step, we have characterized morphology, insulin secretion, and pattern of gene expression in islets from prediabetic and diabetic ZDF rats. The development of diabetes was associated with changes in islet morphology, and the islets of diabetic animals were markedly hypertrophic with multiple irregular projections into the surrounding exocrine pancreas. In addition, there were multiple defects in the normal pattern of insulin secretion. The islets of prediabetic ZDF rats secreted significantly more insulin at each glucose concentration tested and showed a leftward shift in the dose-response curve relating glucose concentration and insulin secretion. Islets of prediabetic animals also demonstrated defects in the normal oscillatory pattern of insulin secretion, indicating the presence of impairment of the normal feedback control between glucose and insulin secretion. The islets from diabetic animals showed further impairment in the ability to respond to a glucose stimulus. Changes in gene expression were also evident in islets from prediabetic and diabetic ZDF rats compared with age-matched control animals. In prediabetic animals, there was no change in insulin mRNA levels. However, there was a significant 30-70% reduction in the levels of a large number of other islet mRNAs including glucokinase, mitochondrial glycerol-3-phosphate dehydrogenase, voltage-dependent Ca2+ and K+ channels, Ca(2+)-ATPase, and transcription factor Islet-1 mRNAs. In addition, there was a 40-50% increase in the levels of glucose-6-phosphatase and 12-lipoxygenase mRNAs. There were further changes in gene expression in the islets from diabetic ZDF rats, including a decrease in insulin mRNA levels that was associated with reduced islet insulin levels. Our results indicate that multiple defects in beta-cell function can be detected in islets of prediabetic animals well before the development of hyperglycemia and suggest that changes in the normal pattern of gene expression contribute to the development of beta-cell dysfunction.
Diabetes 1995 Dec
PMID:Evolution of beta-cell dysfunction in the male Zucker diabetic fatty rat. 758 53

Goto-Kakizaki (GK) rat, a rodent model of spontaneously occurring non-insulin dependent diabetes mellitus (NIDDM), exhibits impaired glucose-stimulated insulin secretion. To explore the background of the beta-cell dysfunction in NIDDM, we investigated whether and how the expression pattern of factors that would potentially be involved in the glucose-stimulated insulin secretion machinery is changed in GK rats. Using quantitative reverse transcription-PCR (RT-PCR) method, we found that the gene expression of CD38, a type 2 membrane protein which has ADP-ribosyl cyclase activity, is reduced by approximately 50% in islets of GK rats. Despite previous studies showing reduction in the FAD-linked mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) activity in GK rats, the mGPDH mRNA amounts were equal to those in the control Wistar rats, suggesting a difference that arose post-transcriptionally. These observations support the idea that multiple defects of the glucose-responsive insulin secreting machinery are involved in the development of diabetes in GK rats.
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PMID:Expression of CD38 gene, but not of mitochondrial glycerol-3-phosphate dehydrogenase gene, is impaired in pancreatic islets of GK rats. 766 44

This study aimed to compare the metabolic and secretory responses of pancreatic islets from animals with non-insulin-dependent diabetes to D-glucose with the effects of the methyl esters of succinic acid (SME) and glutamic acid (GME). The insulin secretory response to D-glucose was impaired in islets from rats with diabetes which was either inherited (Goto-Kakizaki (GK) rats) or acquired (streptozotocin-treated (STZ) rats). This coincided with a preferential alteration of oxidative relative to total glycolysis in intact islets and a selective defect of FAD-linked mitochondrial glycerophosphate dehydrogenase (m-GDH) in islet homogenates. This enzymatic defect was also found in purified B cells from STZ rats. It contrasted both with unaltered activities of glutamate dehydrogenase and succinate dehydrogenase in the islets of diabetic animals and with a normal or even increased activity of m-GDH in the livers of GK and STZ rats. The oxidation of [1,4-14C]SME and [U-14C]GME appeared decreased in islets of GK or STZ animals when compared with control rats, but no significant difference between control and diabetic rats was observed when the oxidative data were expressed relative to the rate of [U-14C]GME hydrolysis. Nevertheless, the absolute values for insulin release evoked by a non-metabolized analogue of L-leucine (BCH), by SME and by the association of BCH with either SME or GME were invariably lower in islets of GK and STZ rats than in those of control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pancreatic islet response to dicarboxylic acid esters in rats with type 2 diabetes: enzymatic, metabolic and secretory aspects. 784 32

Pancreatic beta-cell mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) plays a major role in glucose-induced insulin secretion. Decreased activity of this enzyme has thus been proposed to play a role in the pathogenesis of NIDDM. Cloning of human insulinoma mGPDH cDNAs disclosed the existence of two variant transcripts with different 5' ends. Reverse transcription polymerase chain reaction (PCR) confirmed the presence of both mGPDH mRNAs in purified native human pancreatic islets and other tissues. A major 6.5-Kb mGPDH transcript was detected by Northern blot analysis in RNA from human and rat pancreatic islets, with distinctly lower levels in other human tissues, indicating that previously reported high mGPDH enzymatic activity in beta-cells is determined by high transcript levels. The mGPDH gene was mapped to chromosome 2 by PCR analysis of genomic DNA from human/rodent somatic cell hybrids, and five independent overlapping yeast artificial chromosome (YAC) clones containing the mGPDH sequence were identified from the Centre d'Etude du Polymorphisme Humain YAC library. Analysis of these YAC clones identified a highly polymorphic chromosome 2q21-q33 dinucleotide repeat genetic marker (D2S141) physically linked to the mGPDH gene. These studies provide the means to investigate the role of the human mGPDH gene in the pathogenesis of NIDDM and illustrate the value of a novel strategy to identify genetic markers for diabetes candidate genes.
Diabetes 1996 Feb
PMID:Mitochondrial glycerol-3-phosphate dehydrogenase. Cloning of an alternatively spliced human islet-cell cDNA, tissue distribution, physical mapping, and identification of a polymorphic genetic marker. 854 72

Mitochondrial glycerol phosphate dehydrogenase (mtGPD) is the rate-limiting enzyme in the glycerol phosphate shuttle, which is thought to play an important role in cells that require an active glycolytic pathway. Abnormalities in mtGPD have been proposed as a potential cause for non-insulin-dependent diabetes mellitus. To facilitate genetic studies, we have isolated genomic clones containing the coding regions of the human mtGPD-encoding gene (GPDM). The gene contains 17 exons and is estimated to span more than 80 kb. All splice junctions contain GT/AG consensus sequences. Introns interrupt the sequences encoding the leader peptide, the FAD-binding site, the calcium-binding regions, and a conserved central element postulated to play a role in glycerol phosphate binding. Fluorescence in situ hybridization was used to map this gene to chromosome 2, band q24.1. A retropseudogene was identified and mapped to chromosome 17.
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PMID:Structural organization and mapping of the human mitochondrial glycerol phosphate dehydrogenase-encoding gene and pseudogene. 868 23

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

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

The efficacy of reverse-electron-transport therapy of obesity should be promoted by agents which up-regulate hepatocyte enzymes that are potentially rate-limiting for mitochondrial fatty acid oxidation and electron shuttles. Peroxisome proliferator drugs, including the fibrates used to treat hyperlipidemia, may be useful in this regard, as they induce malic enzyme, the mitochondrial glycerol-3-phosphate dehydrogenase, and carnitine palmitoyl transferase I in rodent hepatocytes. An agent of this class, MEDICA 16, has the additional property of potently inhibiting both citrate lyase and acetyl-CoA carboxylase. As a result, methyl-substituted diacarboxylic acids (MEDICA) 16 can be expected to disinhibit hepatic fatty acid oxidation while up-regulating electron shuttle mechanisms, and thus should stimulate reverse electron transport. This may explain the remarkable 40% increase in basal metabolic rate observed in normal rats ingesting MEDICA 16--an effect not associated with any compensatory increase in food intake. Relative to controls, the MEDICA 16-treated rats achieved a 50% reduction in body fat and a modest increase in lean mass, such that weight and growth were not changed. In other rodent strains, MEDICA 16 has prevented obesity diabetes and atherogenesis. However, whether MEDICA 16 and other peroxisome proliferator drugs will have clinical utility in reverse-electron-transport therapy may hinge on their ability to induce key enzymes in human hepatocytes; cell culture studies to evaluate this are required.
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PMID:Peroxisome proliferators as adjuvants for the reverse-electron-transport therapy of obesity: an explanation for the large increase in metabolic rate of MEDICA 16-treated rats. 1060 61


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