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

Mutations of mitochondrial DNA (mtDNA) are associated with a wide spectrum of disorders encompassing the myopathies, encephalopathies and cardiomyopathies, in addition to organ specific presentations such as diabetes mellitus and deafness. The pathogenesis of mtDNA mutations is not fully understood although it is assumed that their final common pathway involves impaired oxidative phosphorylation. The identification of a specific respiratory chain defect (complex I deficiency) in Parkinson's disease (PD) 10 years ago focused attention on the aetiological and pathogenetic roles that mitochondria may play in neurodegenerative diseases. There is evidence now emerging that mtDNA abnormalities may determine the complex I defect in a proportion of PD patients and it may prove possible to use biochemical analysis of platelet and cybrid complex I function to identify those that lie within this group. Respiratory chain defects of a different pattern have been identified in Huntington's disease (HD) (complex II/III deficiency) and Friedreich's ataxia (FA) complex I-III deficiency). In both these disorders, the mitochondrial abnormality is secondary to the primary nuclear mutation:CAG repeat in the huntingtin gene in HD, and GAA repeat in the frataxin gene in FA. Nevertheless, it appears that the mitochondrion may be the target of the biochemical defects that are the consequence of these mutations. There is a close and reciprocal relationship between respiratory chain dysfunction and free radical generation, and there is evidence for oxidative stress and damage in PD, HD and FA, which together with the mitochondrial defect may result in cell damage. Impaired oxidative phosphorylation and free radical generation may independently adversely affect the maintenance of mitochondrial transmembrane potential (Deltapsim). A fall in Deltapsim is an early event (preceding nuclear fragmentation) in the apoptotic pathway. It is possible therefore that mitochondrial dysfunction in the neurodegenerative disorders may result in a fall in the apoptotic threshold of neurones which, in some, may be sufficient to induce cell death whilst, in others, additional factors may be required. In any event, mitochondria present an important target for future strategies for 'neuroprotection' to prevent or retard neurodegeneration.
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PMID:Mitochondrial dysfunction in neurodegenerative disorders. 971 16

To address the problem of the pathogenesis in diabetic neuropathy, rats were made diabetic by streptozotocin administration, and discrete brain regions, such as cortex, cerebellum, brainstem, thalamus, and hypothalamus, were sampled for assay of activities of electron transport chain complexes I-IV at 1 and 3 mo after induction of diabetes. Significant decrease was seen in activities of dinitrophenylhydrazine DNPH-coenzyme Q reductase (complex I), coenzyme Q cytochrome-c reductase (complex III), and cytochrome-c oxidase (complex IV) from discrete brain regions with more pronounced changes in complex I. The decline in the complex I, III, and IV activity was more severe in the 3-mo group. Succinate dehydrogenase (SDH) coenzyme Q reductase (complex II), which is an enzyme shared by tricarboxylic acid (TCA) cycle and electron transport chain, showed a significant increase under the same set of conditions. These results suggest that the bioenergetic impairment has an important role in the pathophysiology of diabetes.
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PMID:The impact of diabetes on CNS. Role of bioenergetic defects. 1034 74

To investigate the prevalence of mitochondrial DNA mutations among Japanese children with IDDM as well as in those with NIDDM, a total of 155 patients with IDDM and 30 patients with NIDDM who were younger than 15 years of age at onset were studied for the following mtDNA mutations: 1) the A-->G mutation at position 3243 of mitochondrial leucine transfer RNA (3243 mutation); 2) the G-->A mutation at position 3316 of mitochondrial leucine transfer RNA (3316 mutation), and 3) The T-->C mutation at position 3394 of the mitochondrial NADH dehydrogenase subunit (3394 mutation). None of the 155 IDDM patients had the 3243 mutation. Although two of the 155 IDDM patients had homoplasmy of 3316 and five had 3394 mutations, these frequencies were not significant compared with healthy controls. None of the 30 NIDDM patients had the 3243, 3316 or 3394 mutation. The presence of these mutations even in control subjects suggests that the effect of the 3316 or 3394 mutation on mitochondrial function is relatively mild. It seems that 3316 and 3394 mutations contribute to the manifestation of diabetes together with other genetic and/or environmental factors.
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PMID:The prevalence of mitochondrial gene mutations in childhood diabetes in Japan. 1039 45

It has been hypothesised that mitochondrial dysfunction in pancreatic beta cells could produce hyper-expression of glutamic acid decarboxylase (GAD), a major autoantigen in insulin-dependent diabetes mellitus (IDDM) (Degli Esposti, M. and Mackay, I.R. Diabetologia 40: 352-356, 1997). Here we report that specific inhibition of mitochondrial respiration enhances the expression of GAD in both foetal mouse pancreatic tissue and hamster HIT-T15 cells. Inhibitors of NADH-ubiquinone oxidoreductase (complex I) seem to be particularly effective in increasing the expression of GAD in both foetal mouse pancreas and HIT-T15 hamster beta cells, especially in the presence of nutrients such as arginine and glucose. These results represent the first evidence that GAD expression is enhanced under conditions that are toxic to pancreatic beta cells, and establish a link between mitochondrial dysfunction and expression of IDDM autoantigens.
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PMID:Inhibition of mitochondrial oxidative phosphorylation induces hyper-expression of glutamic acid decarboxylase in pancreatic islet cells. 1043 94

From a family of 16 diabetic patients with typical maternal inheritance, we investigated a 69-year-old woman with type 2 diabetes. The proband showed no major deletions in the mitochondrial DNA (mtDNA). Direct sequencing revealed 7 missense and 5 ribosomal RNA homoplasmic nucleotide substitutions when compared with the Cambridge Sequence and its recent revision. When compared with the control cybrid cells, the proband cybrid cells showed 6 nucleotide substitutions. Among these, 14577 T/C, which turned out to be 98.9% heteroplasmic, is a new missense substitution in the NADH dehydrogenase 6 gene. We also observed 2 other patients with 14577 T/C substitution from another group of 252 unrelated diabetic patients, whereas no individual from a group of 529 control subjects had 14577 T/C substitution. Furthermore, these 6 substitutions were in linkage disequilibrium. Mitochondrial respiratory chain complex I activity and O2 consumption rates of the proband cybrid cells, which were obtained by the fusion of mtDNA-deleted (rho0) HeLa cells and mtDNA from the proband, showed 64.5 and 61.5% reductions, respectively, compared with control cybrid cells. The present study strongly indicates that the new mtDNA mutation at 14577 T/C is probably a major pathogenic mutation for type 2 diabetes in this family.
Diabetes 2000 Jul
PMID:A new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetes. 1090 88

The thiamine transporter gene SLC19A2 was recently found to be mutated in thiamine responsive megaloblastic anaemia with diabetes and deafness (TRMA, Rogers syndrome), an early onset autosomal recessive disorder. We now report a novel G1074A transition mutation in exon 4 of the SLC19A2 gene, predicting a Trp358 to ter change, in a girl with consanguineous parents. In addition to the typical triad of Rogers syndrome, the girl presented with short stature, hepatosplenomegaly, retinal degeneration, and a brain MRI lesion. Both muscle and skin biopsies were obtained before high dose thiamine supplementation. While no mitochondrial abnormalities were seen on morphological examination of muscle, biochemical analysis showed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. In the patient's fibroblasts, the supplementation with high doses of thiamine resulted in restoration of complex I activity. In conclusion, we provide evidence that thiamine deficiency affects complex I activity. The clinical features of TRMA, resembling in part those found in typical mitochondrial disorders with complex I deficiency, may be caused by a secondary defect in mitochondrial energy production.
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PMID:A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I. 1097 58

Treatment of chronic hepatitis with interferon-alpha is an increasingly used successful therapeutic procedure. In the literature in recent years data accumulated on side-effects of interferon therapy, among which relatively frequently insulin dependent diabetes is mentioned. Interferon-alpha enhances the expression of molecules of the histocompatible complex I which may cause in genetically predisposed subjects the clinical manifestation of diabetes. It is therefore recommended to monitor before the onset of treatment and during interferon treatment the auto-antibody formation against islet cells and against insulin which signalizes changes in the pancreas before the clinical disease proper.
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PMID:[Insulin-dependent diabetes mellitus as a possible sequelae of treatment of viral hepatitis with interferon-alpha] . 1118 63

Using RNase protection analysis, we found a novel C to G mutation at nucleotide position 3093 of mitochondrial DNA (mtDNA) in a previously reported 35-year-old woman exhibiting clinical features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome together with diabetes mellitus, hyperthyroidism and cardiomyopathy. The patient also had an A3243G mutation in the tRNA(Leu(UUR)) gene and a 260-base pair duplication in the D-loop of mtDNA. The fibroblasts of the patient were cultured and used for the construction of cybrids using cytoplasmic transfer of the patient's mtDNA to the mtDNA-less rho(0) cells. RNA isolated from the cybrids was subjected to RNase protection analysis, and a C3093G transversion at the 16S rRNA gene and a MELAS-associated A3243G mutation of mtDNA were detected. The novel C3093G mutation together with the A3243G transition were found in muscle biopsies, hair follicles and blood cells of this patient and also in her skin fibroblasts and cybrids. The proportion of the C3093G mutant mtDNA in muscle biopsies of the patient was 51%. In contrast, the mutation was not detected in three sons of the proband. To characterize the impact of the mtDNA mutation-associated defects on mitochondrial function, we determined the respiratory enzyme activities of the primary culture of fibroblasts established from the proband, her mother and her three sons. The proportions of mtDNA with the C3093G transversion and the A3243G transition in the fibroblasts of the proband were 45 and 58%, respectively. However, the fibroblasts of the proband's mother and children harbored lower levels of mtDNA with the A3243G mutation but did not contain the C3093G mutation. The complex I activity in the proband's fibroblasts was decreased to 47% of the control but those of the fibroblasts of the mother and three sons of the proband were not significantly changed. These findings suggest that the C3093G transversion together with the A3243G transition of mtDNA impaired the respiratory function of mitochondria and caused the atypical MELAS syndrome associated with diabetes mellitus, hyperthyroidism and cardiomyopathy in this patient.
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PMID:A novel mutation in the mitochondrial 16S rRNA gene in a patient with MELAS syndrome, diabetes mellitus, hyperthyroidism and cardiomyopathy. 1145 95

The protean manifestations of a novel maternally inherited point mutation of the mitochondrial genome are reported. The proband showed isolated, spastic paraparesis. A brother, who had suffered from a multisystem progressive disorder, ultimately died of cardiomyopathy. Another brother is healthy. The proband's mother showed truncal ataxia, dysarthria, severe hearing loss, mental regression, ptosis, ophthalmoparesis, distal cyclones, and diabetes mellitus. A muscle biopsy performed in the proband failed to show the morphological abnormalities typical of mitochondrial disorders; the activities of respiratory chain complexes were normal. However, complex I and IV activities were low in the muscle homogenate of the affected mother and brother. Sequence analysis of mtDNA showed a heteroplasmic mutation of the tRNA(Ile) gene (G4284A). The mutation load was approximately 55%, 80%, and 90% in the muscle mtDNA of the proband, his mother, and his affected brother, respectively. Mutation was undetected in the healthy brother, as well as in 100 control samples. Several cybrid clones containing homoplasmic mutant mtDNA from the proband showed significant reductions of complex IV activity and maximum oxygen consumption rate, compared with homoplasmic wild-type clones derived from the same subject.
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PMID:Novel heteroplasmic mtDNA mutation in a family with heterogeneous clinical presentations. 1178 91

A number of novel genes that are up-regulated in diabetic kidneys have been identified. Recently, transforming growth factor-beta (TGF-beta)--driven secreted proteins, i.e., connective tissue growth factor (CTGF) and gremlin, were identified. They are up-regulated in kidneys of diabetic animals and modulate the biology of mesangial cells. CTGF mediates TGF-beta--induced matrix overproduction by the mesangial cells. Gremlin is a putative antagonist of bone morphogenetic protein-2 that blocks mesangial cell proliferation. Thus, gremlin may modulate the biology of mesangium by stimulating mesangial cell proliferation and in turn production of matrix. In addition, transcriptionally regulated kinases, serum glucocorticoid-regulated kinase and munc-13 have been identified. The former stimulates renal tubular Na+ transport and is involved in hyperfiltraion of diabetic kidneys by a Na+ transport feedback mechanism. Munc-13 has been shown to induce apoptosis in hyperglycemic state via diacylglycerol-activated, PKC-independent signaling pathway. Another pathway relevant to diabetic nephropathy is polyol pathway, where glucose is reduced to sorbitol by aldose reductase. Recently, a renal-specific reductase of the aldo-keto reductase family was isolated. It is up-regulated in diabetic mice, and this could serve as a suitable target for gene therapy in renal complications of diabetes. Several mitochondrial genome-encoded genes, such as, cytochrome oxidase and NADH dehydrogenase, are up-regulated in diabetic kidneys. A novel nuclear-encoded mitochondrial gene, i.e., translocase inner mitochondrial membrane 44 (Tim44), is up-regulated in diabetic kidneys, and it may also serve as another target for molecular therapeutic intervention at the core storage energy sites, i.e., mitochondria. In this review, these novel differentially regulated genes that respond to hyperglycemic stress are described, and they may serve as possible targets for gene therapy in the treatment of diabetic nephropathy.
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PMID:Gene expression and identification of gene therapy targets in diabetic nephropathy. 1184 17


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