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)

Over 100 mutations of mitochondrial DNA (mtDNA) have been associated with human disease. The phenotypic manifestation of mtDNA mutations is extremely broad, from oligosymptomatic patients with isolated deafness, diabetes, ophthalmoplegia, etc., to complex encephalomyopathic disorders that may include dementia, seizures, ataxia, stroke-like episodes, etc. The genotype variants are also wide, with rearrangements (deletions, duplications) and point mutations affecting protein coding genes, tRNAs and rRNAs. There are some broad genotype/phenotype correlations but also substantial overlap. The pathogenetic mechanisms involved in the expression of mtDNA mutations are still not yet fully understood. More recently, mutations of nuclear genes encoding subunits of the respiratory chain, particularly those of complex I, have been identified. These predominantly, but not exclusively, involve infant onset disease with early death. Recently it has become clear that the function of the respiratory chain may be impaired by mutations affecting other mitochondrial proteins or as a secondary phenomenon to other intracellular biochemical derangements. Examples include Friedreich ataxia where a mutation of a nuclear encoded protein (frataxin), probably involved in iron homeostasis in mitochondria, results in severe deficiency of the respiratory chain in a pattern indicative of free radical mediated damage. Mutations of nuclear encoded proteins involved in cytochrome oxidase assembly and maintenance have been characterised and, as predicted, are associated with severe deficiency of cytochrome oxidase and, most frequently, Leigh syndrome. Defects of intracellular metabolism, with particularly excess-free radical generation including nitric oxide or peroxynitrite, may cause secondary damage to the respiratory chain. This is probably of relevance in Huntington disease, motor neuron disease (amyotrophic lateral sclerosis) and Wilson disease. These disorders seem to have defective oxidative phosphorylation as a common pathway in their pathogenesis and it may be that treatments designed to improve respiratory chain function may ameliorate the progression of these disorders.
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PMID:Primary and secondary defects of the mitochondrial respiratory chain. 1213 29

A single nucleotide polymorphism of mitochondrial 5178A/C, causing a Met to Leu replacement within the NADH dehydrogenase subunit, is reported to be associated with longevity. The purpose of the present study was to assess the contribution of mitochondrial polymorphisms, particularly the 5178A/C genotype, to the susceptibility to acute myocardial infarction (AMI) in a Japanese study population. There were 4 groups: 150 patients with AMI, 150 with essential hypertension, 100 with diabetes mellitus, and 150 subjects matched for age and sex who served as the control group. Mitochondrial 5178A/C was detected by the polymerase chain reaction restriction fragment length polymorphism method. The allelic frequency of 5178C was significantly higher in the AMI group than in the control group, and this difference was more marked in younger patients. There were differences in allelic frequencies among the essential hypertension group, diabetes mellitus group and control group, but a higher frequency of the C allele was seen in the AMI group compared with the essential hypertension and diabetes mellitus groups. This particular polymorphism was found to be associated with development of AMI, especially in younger patients and constitutes a new risk factor for AMI.
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PMID:Mitochondrial 5178A/C genotype is associated with acute myocardial infarction. 1252 Jan 45

Reactive oxygen species (ROS) have been implicated in the pathogenesis of vascular dysfunction in diabetes mellitus, and NAD(P)H oxidase is known as the most important source of ROS in the vasculatures. To determine whether NAD(P)H oxidase is a major participant in the critical intermediary signaling events in high glucose (HG, 25 mM)-induced proliferation of vascular smooth muscle cells (VSMC), we investigated in explanted aortic VSMC from rats the role of NAD(P)H oxidase on the HG-related cellular proliferation and superoxide production. VSMC under HG condition had increased proliferative capacity that was inhibited by tiron (1 mM), a cell membrane permeable superoxide scavenger, but not by SOD, which is not permeable to cell membrane. The nitroblue tetrazolium staining in the HG-exposed VSMC was more prominent than that of VSMC under normal glucose (5.5 mM) condition, which was significantly inhibited by DPI (10 microM), an NAD(P)H oxidase inhibitor, but not by inhibitors for other oxidases such as NADH dehydrogenase, xanthine oxidase, and nitric oxide synthase. In the VSMC under HG condition, the enhanced NAD(P)H oxidase activity with increased membrane translocation of Rac1 was observed, but the protein expression of p22phox and gp91phox was not increased. These data suggest that HG-induced changes in VSMC proliferation are related to the intracellular production of superoxide through enhanced activity of NAD(P)H oxidase.
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PMID:NAD(P)H oxidase participates in the signaling events in high glucose-induced proliferation of vascular smooth muscle cells. 1267 89

The beta(3)-adrenergic receptor gene (BAR-3) allelic variant (Trp64Arg and Arg64Arg) is correlated with obesity or non-insulin-dependent diabetes mellitus. The mitochondrial NADH dehydrogenase subunit-2 gene (ND2) variant (Mt5178A) is associated with longevity or less susceptibility to adult-onset diseases. The frequencies of both the variants are high among the Japanese population. Cross-sectional analysis of these variants was conducted to determine if they correlated well with life-style-related phenotypes and nutrient intake. The body fat rate in the BAR-3 variant+ND2 variant group was higher than those rates in the BAR-3 normal+ND2 variant, BAR-3 normal+ND2 normal. The BAR-3 normal+ND2 variant group preferred much carbohydrate and less animal protein compared with other three groups. A combination of SNPs of the nuclear BAR-3 and the mitochondrial ND2 genes may affect eating behavior besides the biochemical and metabolic process of signal transduction and electron transfer system.
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PMID:Phenotypic linkage between single-nucleotide polymorphisms of beta3-adrenergic receptor gene and NADH dehydrogenase subunit-2 gene, with special reference to eating behavior. 1294 91

Type 2 diabetes has been related to a decrease of mitochondrial DNA (mtDNA) content. In this study, we show increased expression of the peroxisome proliferator-activated receptor-alpha (PPARalpha) and its target genes involved in fatty acid metabolism in skeletal muscle of Zucker Diabetic Fatty (ZDF) (fa/fa) rats. In contrast, the mRNA levels of genes involved in glucose transport and utilization (GLUT4 and phosphofructokinase) were decreased, whereas the expression of pyruvate dehydrogenase kinase 4 (PDK-4), which suppresses glucose oxidation, was increased. The shift from glucose to fatty acids as the source of energy in skeletal muscle of ZDF rats was accompanied by a reduction of subunit 1 of complex I (NADH dehydrogenase subunit 1, ND1) and subunit II of complex IV (cytochrome c oxidase II, COII), two genes of the electronic transport chain encoded by mtDNA. The transcript levels of PPARgamma Coactivator 1 (PGC-1) showed a significant reduction. Treatment with troglitazone (30 mg/kg/day) for 15 days reduced insulin values and reversed the increase in PDK-4 mRNA levels, suggesting improved insulin sensitivity. In addition, troglitazone treatment restored ND1 and PGC-1 expression in skeletal muscle. These results suggest that troglitazone may avoid mitochondrial metabolic derangement during the development of diabetes mellitus 2 in skeletal muscle.
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PMID:Impaired expression of NADH dehydrogenase subunit 1 and PPARgamma coactivator-1 in skeletal muscle of ZDF rats: restoration by troglitazone. 1456 25

Metformin and thiazolidinediones (TZDs) are believed to exert their antidiabetic effects via different mechanisms. As evidence suggests that both impair cell respiration in vitro, this study compared their effects on mitochondrial functions. The activity of complex I of the respiratory chain, which is known to be affected by metformin, was measured in tissue homogenates that contained disrupted mitochondria. In homogenates of skeletal muscle, metformin and TZDs reduced the activity of complex I (30 mmol/l metformin, -15 +/- 2%; 100 micromol/l rosiglitazone, -54 +/- 7; and 100 micromol/l pioglitazone, -12 +/- 4; P < 0.05 each). Inhibition of complex I was confirmed by reduced state 3 respiration of isolated mitochondria consuming glutamate + malate as substrates for complex I (30 mmol/l metformin, -77 +/- 1%; 100 micromol/l rosiglitazone, -24 +/- 4; and 100 micromol/l pioglitazone, -18 +/- 5; P < 0.05 each), whereas respiration with succinate feeding into complex II was unaffected. In line with inhibition of complex I, 24-h exposure of isolated rat soleus muscle to metformin or TZDs reduced cell respiration and increased anaerobic glycolysis (glucose oxidation: 270 micromol/l metformin, -30 +/- 9%; 9 micromol/l rosiglitazone, -25 +/- 8; and 9 micromol/l pioglitazone, -45 +/- 3; lactate release: 270 micromol/l metformin, +84 +/- 12; 9 micromol/l rosiglitazone, +38 +/- 6; and 9 micromol/l pioglitazone, +64 +/- 11; P < 0.05 each). As both metformin and TZDs inhibit complex I activity and cell respiration in vitro, similar mitochondrial actions could contribute to their antidiabetic effects.
Diabetes 2004 Apr
PMID:Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? 1504 21

Many diabetic patients suffer from a cardiomyopathy that cannot be explained by poor coronary perfusion. Reactive oxygen species (ROS) have been proposed to contribute to this cardiomyopathy. Consistent with this we found evidence for induction of the antioxidant genes for catalase in diabetic OVE26 hearts. To determine whether increased antioxidant protection could reduce diabetic cardiomyopathy, we assessed cardiac morphology and contractility, Ca(2+) handling, malondialdehyde (MDA)-modified proteins, and ROS levels in individual cardiomyocytes isolated from control hearts, OVE26 diabetic hearts, and diabetic hearts overexpressing the antioxidant protein catalase. Diabetic hearts showed damaged mitochondria and myofibrils, reduced myocyte contractility, slowed intracellular Ca(2+) decay, and increased MDA-modified proteins compared with control myocytes. Overexpressing catalase preserved normal cardiac morphology, prevented the contractile defects, and reduced MDA protein modification but did not reverse the slowed Ca(2+) decay induced by diabetes. Additionally, high glucose promoted significantly increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of catalase or acute in vitro treatment with rotenone, an inhibitor of mitochondrial complex I, or thenoyltrifluoroacetone, an inhibitor of mitochondrial complex II, eliminated excess ROS production in diabetic cardiomyocytes. The structural damage to diabetic mitochondria and the efficacy of mitochondrial inhibitors in reducing ROS suggest that mitochondria are a source of oxidative damage in diabetic cardiomyocytes. We also found that catalase overexpression protected cardiomyocyte contractility in the agouti model of type 2 diabetes. These data show that both type 1 and type 2 diabetes induce damage at the level of individual myocytes, and that this damage occurs through mechanisms utilizing ROS.
Diabetes 2004 May
PMID:Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. 1511 4

A key adaptation enabling the fetus to survive in a limited energy environment may be the reprogramming of mitochondrial function, which can have deleterious effects. Critical questions are whether mitochondrial dysfunction progressively declines after birth, and if so, what mechanism might underlie this process. To address this, we developed a model of intrauterine growth retardation (IUGR) in the rat that leads to diabetes in adulthood. Reactive oxygen species (ROS) production and oxidative stress gradually increased in IUGR islets. ATP production was impaired and continued to deteriorate with age. The activities of complex I and III of the electron transport chain progressively declined in IUGR islets. Mitochondrial DNA point mutations accumulated with age and were associated with decreased mitochondrial DNA content and reduced expression of mitochondria-encoded genes in IUGR islets. Mitochondrial dysfunction resulted in impaired insulin secretion. These results demonstrate that IUGR induces mitochondrial dysfunction in the fetal beta-cell, leading to increased production of ROS, which in turn damage mitochondrial DNA. A self-reinforcing cycle of progressive deterioration in mitochondrial function leads to a corresponding decline in beta-cell function. Finally, a threshold in mitochondrial dysfunction and ROS production is reached, and diabetes ensues.
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PMID:Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to beta-cell failure. 1594 49

Obesity and type 2 diabetes have been associated with a high-fat diet (HFD) and reduced mitochondrial mass and function. We hypothesized a HFD may affect expression of genes involved in mitochondrial function and biogenesis. To test this hypothesis, we fed 10 insulin-sensitive males an isoenergetic HFD for 3 days with muscle biopsies before and after intervention. Oligonucleotide microarray analysis revealed 297 genes were differentially regulated by the HFD (Bonferonni adjusted P < 0.001). Six genes involved in oxidative phosphorylation (OXPHOS) decreased. Four were members of mitochondrial complex I: NDUFB3, NDUFB5, NDUFS1, and NDUFV1; one was SDHB in complex II and a mitochondrial carrier protein SLC25A12. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1) alpha and PGC1beta mRNA were decreased by -20%, P < 0.01, and -25%, P < 0.01, respectively. In a separate experiment, we fed C57Bl/6J mice a HFD for 3 weeks and found that the same OXPHOS and PGC1 mRNAs were downregulated by approximately 90%, cytochrome C and PGC1alpha protein by approximately 40%. Combined, these results suggest a mechanism whereby HFD downregulates genes necessary for OXPHOS and mitochondrial biogenesis. These changes mimic those observed in diabetes and insulin resistance and, if sustained, may result in mitochondrial dysfunction in the prediabetic/insulin-resistant state.
Diabetes 2005 Jul
PMID:A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. 1598 91

Since it was first realized that biological energy transduction involves oxygen and ATP, opinions about the amount of ATP made per oxygen consumed have continually evolved. The coupling efficiency is crucial because it constrains mechanistic models of the electron-transport chain and ATP synthase, and underpins the physiology and ecology of how organisms prosper in a thermodynamically hostile environment. Mechanistically, we have a good model of proton pumping by complex III of the electron-transport chain and a reasonable understanding of complex IV and the ATP synthase, but remain ignorant about complex I. Energy transduction is plastic: coupling efficiency can vary. Whether this occurs physiologically by molecular slipping in the proton pumps remains controversial. However, the membrane clearly leaks protons, decreasing the energy funnelled into ATP synthesis. Up to 20% of the basal metabolic rate may be used to drive this basal leak. In addition, UCP1 (uncoupling protein 1) is used in specialized tissues to uncouple oxidative phosphorylation, causing adaptive thermogenesis. Other UCPs can also uncouple, but are tightly regulated; they may function to decrease coupling efficiency and so attenuate mitochondrial radical production. UCPs may also integrate inputs from different fuels in pancreatic beta-cells and modulate insulin secretion. They are exciting potential targets for treatment of obesity, cachexia, aging and diabetes.
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PMID:The efficiency and plasticity of mitochondrial energy transduction. 1624 6


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