Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reported that a change in muscle fibre type distribution is present in two strains of diabetic rats (Otsuka Long-Evans Tokushima Fatty and Goto-Kakizaki rats). In this study, we determined whether the change in soleus muscle fibre type distribution was caused by diabetes, using obese, diabetic (Zucker diabetic fatty, ZDF), obese, non-diabetic (Zucker fatty, ZF) and non-diabetic, non-obese rats (Zucker lean, ZL). Moreover, we investigated whether the gene expression levels of metabolic key molecules, namely the transcriptional factors of metabolic genes, exemplified by peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), and the oxidative enzymes in mitochondria, exemplified by succinate dehydrogenase (SDH), were changed in type I and II muscle fibres in each type of rat, using the new technique of laser capture microdissection (LCM). Both plasma glucose and glucosylated haemoglobin levels were significantly higher in ZDF than in ZL and ZF rats. A lower percentage of type IIA fibres was observed in the muscles of ZDF rats than in those of ZL and ZF rats. The mRNA expression levels of SDH in type II fibres and of PGC-1alpha in type I fibres were significantly lower in ZDF than in ZL and ZF rats as assessed by LCM and real-time PCR analysis. We have shown, for the first time, that a lower percentage of type IIA fibres was observed in ZDF rats. We have also discovered that the expression levels of the oxidative metabolism-related genes, PGC-1alpha and SDH, decreased in type I and type II fibres, respectively, of ZDF rats.
 ...
PMID:Fibre type distribution and gene expression levels of both succinate dehydrogenase and peroxisome proliferator-activated receptor-gamma coactivator-1alpha of fibres in the soleus muscle of Zucker diabetic fatty rats. 1715 79

Diabetes mellitus (DM), which induces alterations in energy metabolism, is the leading cause of cardiovascular disease. We postulated that peroxisome proliferator activated receptor-gamma coactivator 1alpha (PGC-alpha), a transcriptional coactivator that is the primary regulator of oxidative metabolism and mitochondrial biogenesis, and cardiac function are depressive in DM and simvastatin and losartan therapy can improve the affects of DM on mRNA expression of PGC-1alpha and cardiac function. An experimental model of DM (induced by streptozocin 60 mg/kg) in adult male rats (n = 24) was used to investigate the mRNA expression of PGC-1alpha in the left ventricular myocardium. These rats were divided into group I (insulin therapy only, n = 8), group II (insulin plus simvastatin 20 mg/kg/day orally, n = 8), and group III (insulin plus losartan 20 mg/kg/day orally, n = 8). Diabetic rats and 8 healthy rats (group IV) were sacrificed at 3 weeks following DM induction. The mRNA expression of PGC-1alpha was measured using real-time polymerase chain reaction (RT-PCR). Additionally, transthoracic echocardiography was performed on days 0 and 21. The experimental results indicated that the mRNA expression of PGC-1alpha and the left ventricular ejection fraction (LVEF %) were significantly lower in groups I, II and III than in group IV (all P < 0.001). However, the mRNA expression of PGC-1alpha and the LVEF were significantly higher in group III than in groups I and II (both P < 0.01). Conversely, mRNA expression of PGC-1alpha and LVEF did not differ between groups I and II (P > 0.5). In conclusion, DM induces suppression of mRNA expression of PGC-1alpha and LV function in diabetic rats. Losartan and not simvastatin therapy improved the LV function and the expression of this mitochondrial-biogenesis regulator.
 ...
PMID:Downregulation of peroxisme proliferator activated receptor gamma co-activator 1alpha in diabetic rats. 1726 24

Exercise training decreases insulin resistance and increases glucose tolerance in conditions of prediabetes and overt Type 2 diabetes. However, the adaptive responses in skeletal muscle at the molecular and genetic level for these effects of exercise training have not been clearly established in an animal model of prediabetes. The present study identifies alterations in muscle gene expression that occur with exercise training in prediabetic, insulin-resistant obese Zucker rats and insulin-sensitive lean Zucker rats and are associated with a well-defined metabolic outcome. Treadmill running for up to 4 wk caused significant enhancements of glucose tolerance as assessed by the integrated area under the curve for glucose (AUCg) during an oral glucose tolerance test. Using microarray analysis, we identified a set of only 12 genes as both significantly altered by exercise training (>1.5-fold change; P < 0.05) and significantly correlated (P < 0.05) with the AUCg. Two genes, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) and protein kinase C-zeta (PKC-zeta), are involved in the regulation of muscle glucose transport, and we provide the first evidence that PKC-zeta gene expression is enhanced by exercise training in insulin-resistant muscle. Protein expression of PGC-1alpha and PKC-zeta were positively correlated with the mRNA expression for these two genes. Overall, we have identified a limited number of genes in soleus muscle of lean and obese Zucker rats that are associated with both decreased insulin resistance and increased glucose tolerance following endurance exercise training. These findings could guide the development of pharmaceutical "exercise mimetics" in the treatment of insulin-resistant, prediabetic, or Type 2 diabetic individuals.
 ...
PMID:Alterations in soleus muscle gene expression associated with a metabolic endpoint following exercise training by lean and obese Zucker rats. 1728 68

Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation of AMPK is unaffected in lean (BMI approximately 25 kg/m(2)) subjects with type 2 diabetes. However, most type 2 diabetic subjects are obese (BMI >30 kg/m(2)), and exercise stimulation of AMPK is blunted in obese rodents. We examined whether obese type 2 diabetic subjects have impaired exercise stimulation of AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to the putative AMPK targets, AS160 and peroxisome proliferator-activated receptor coactivator (PGC)-1alpha, involved in glucose transport regulation and mitochondrial biogenesis, respectively. Twelve type 2 diabetic, eight obese, and eight lean subjects exercised on a cycle ergometer for 40 min. Muscle biopsies were done before, during, and after exercise. Subjects underwent this protocol on two occasions, at low (50% Vo(2max)) and moderate (70% Vo(2max)) intensities, with a 4-6 week interval. Exercise had no effect on LKB1 activity. Exercise had a time- and intensity-dependent effect to increase AMPK activity and AS160 phosphorylation. Obese and type 2 diabetic subjects had attenuated exercise-stimulated AMPK activity and AS160 phosphorylation. Type 2 diabetic subjects had reduced basal PGC-1 gene expression but normal exercise-induced increases in PGC-1 expression. Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects.
Diabetes 2007 Mar
PMID:Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study. 1732 55

In mammals, maintenance of energy and nutrient homeostasis during food deprivation is accomplished through an increase in mitochondrial fatty acid oxidation in peripheral tissues. An important component that drives this cellular oxidative process is the transcriptional coactivator PGC-1alpha. Here, we show that fasting induced PGC-1alpha deacetylation in skeletal muscle and that SIRT1 deacetylation of PGC-1alpha is required for activation of mitochondrial fatty acid oxidation genes. Moreover, expression of the acetyltransferase, GCN5, or the SIRT1 inhibitor, nicotinamide, induces PGC-1alpha acetylation and decreases expression of PGC-1alpha target genes in myotubes. Consistent with a switch from glucose to fatty acid oxidation that occurs in nutrient deprivation states, SIRT1 is required for induction and maintenance of fatty acid oxidation in response to low glucose concentrations. Thus, we have identified SIRT1 as a functional regulator of PGC-1alpha that induces a metabolic gene transcription program of mitochondrial fatty acid oxidation. These results have implications for understanding selective nutrient adaptation and how it might impact lifespan or metabolic diseases such as obesity and diabetes.
 ...
PMID:Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. 1734 48

Peroxisome proliferator activator receptor-gamma coactivator 1 (PGC-1) is a major candidate gene for diabetes-related metabolic phenotypes, contributing to decreased expression of nuclear-encoded mitochondrial genes in muscle and adipose tissue. We have demonstrated that muscle expression of PGC-1alpha and -beta is reduced in both genetic (Lep(ob)/Lep(ob)) and acquired obesity (high fat diet). In C57BL6 mice, muscle PGC-1alpha expression decreased by 43% (p < 0.02) after 1 week of a high fat diet and persisted more than 11 weeks. In contrast, PGC-1alpha reductions were not sustained in obesity-resistant A/J mice. To identify mediators of obesity-linked reductions in PGC-1, we tested the effects of cellular nutrients in C2C12 myotubes. Although overnight exposure to high insulin, glucose, glucosamine, or amino acids had no effect, saturated fatty acids potently reduced PGC-1alpha and -beta mRNA expression. Palmitate decreased PGC-1alpha and -beta expression by 38% (p = 0.01) and 53% (p = 0.006); stearate similarly decreased expression of PGC-1alpha and -beta by 22% (p = 0.02) and 39% (p = 0.02). These effects were mediated at a transcriptional level, as indicated by an 11-fold reduction of PGC-1alpha promoter activity by palmitate and reversal of effects by histone deacetylase inhibition. Palmitate also (a) reduced expression of tricarboxylic acid cycle and oxidative phosphorylation mitochondrial genes and (b) reduced oxygen consumption. These effects were reversed by overexpression of PGC-1alpha or -beta, indicating PGC-1 dependence. Palmitate effects also required p38 MAPK, as demonstrated by 1) palmitate-induced increase in p38 MAPK phosphorylation, 2) reversal of palmitate effects on PGC-1 and mitochondrial gene expression by p38 MAPK inhibitors, and 3) reversal of palmitate effects by small interfering RNA-mediated decreases in p38alpha MAPK. These data indicate that obesity and saturated fatty acids decrease PGC-1 and mitochondrial gene expression and function via p38 MAPK-dependent transcriptional pathways.
 ...
PMID:Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. 1741 3

The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a peroxisome proliferator-activated receptor (PPAR) gamma agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type 2 diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db, high-fat diet-fed C57BL/6 (HFD) and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. In db/db and HFD mice, gene transcripts associated with mitochondrial ATP production, energy uncoupling, mitochondrial ribosomal proteins, outer and inner membrane translocases, and mitochondrial heat-shock proteins were decreased in abundance, compared with db/+ and standard-fat diet-fed control mice, respectively. RSG dose-dependently increased these transcripts in both db/db and HFD mice and induced transcription of mitochondrial structural proteins and cellular antioxidant enzymes responsible for removal of reactive oxygen species generated by increased mitochondrial activity. Transcription factors, including PPAR coactivator (PGC)-1beta, PGC-1alpha, estrogen-related receptor alpha, and PPARalpha, were suppressed in both models and induced by RSG. The effects of RSG on adipose mitochondrial genes were confirmed by quantitative RT-PCR and further supported by mitochondrial staining, mitochondrial DNA quantification, and citrate synthase activity. Adipose mitochondrial biogenesis was overwhelmingly suppressed in both mouse models of diabetes/obesity and globally induced by RSG. These findings suggest an important role of adipose mitochondria in diabetes/obesity and the potential for new treatment approaches targeting adipose mitochondria.
Diabetes 2007 Jul
PMID:Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone. 1745 54

The objective of the study was to test for an association between type 2 diabetes mellitus (T2DM) and body mass index (BMI) and three single nucleotide polymorphisms (SNP)s in the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) gene. We were also interested in whether these associations differed by tertiles of diet, physical activity or presence of polymorphisms in the peroxisome proliferator-activated receptor gamma (PPAR-gamma) gene among Hispanics and Non-Hispanic Whites (NHW) from Colorado. We studied 216 Hispanic pedigrees (1850 nuclear families) and 236 NHW pedigrees (1240 families) from the San Luis Valley and Denver. We genotyped the Gly482Ser, Thr528Thr and Thr612Met polymorphisms in the PGC-1alpha gene and the Pro12Ala polymorphism of the PPAR-gamma gene. Historical physical activity (average METS/week) as well as average dietary intake over the past year was assessed by self-report. Data were analyzed using the Family Based Association Test (FBAT) as well as generalized estimating equations (GEE). We did not find any significant association between three SNPs in the PGC-1alpha gene and T2DM in Hispanics or NHW; however, using FBAT, we found the common Thr612Thr allele of the PGC-1alpha gene to be associated with T2DM among Hispanic subjects carrying the rare Pro12Ala allele of the PPAR-gamma gene (p=.003). We found similar associations when we considered a haplotype containing that allele (p=.002). However, the results of the GEE analysis did not confirm these findings: odds ratio (OR)=1.68, 95% CI (0.5, 5.2) suggesting these results may due to chance. BMI also did not show any consistent associations with the PGC-1alpha gene. In conclusion, we did not find an association between the PGC-1alpha gene and T2DM or BMI and there were no consistent interactions with diet, physical activity or the Pro12Ala polymorphism of the PPAR-gamma gene.
Exp Clin Endocrinol Diabetes 2007 Apr
PMID:The peroxisome proliferator-activated receptor gamma coactivator-1 alpha gene (PGC-1alpha) is not associated with type 2 diabetes mellitus or body mass index among Hispanic and non Hispanic Whites from Colorado. 1747 45

Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). In patients with type 2 diabetes, insulin resistance in skeletal muscle is associated with abnormalities in insulin signaling, fatty acid metabolism, and mitochondrial oxidative phosphorylation (OXPHOS). In PCOS patients, the molecular mechanisms of insulin resistance are, however, less well characterized. To identify biological pathways of importance for the pathogenesis of insulin resistance in PCOS, we compared gene expression in skeletal muscle of metabolically characterized PCOS patients (n = 16) and healthy control subjects (n = 13) using two different approaches for global pathway analysis: gene set enrichment analysis (GSEA 1.0) and gene map annotator and pathway profiler (GenMAPP 2.0). We demonstrate that impaired insulin-stimulated total, oxidative and nonoxidative glucose disposal in PCOS patients are associated with a consistent downregulation of OXPHOS gene expression using GSEA and GenMAPP analysis. Quantitative real-time PCR analysis validated these findings and showed that reduced levels of peroxisome proliferator-activated receptor gamma coactivator alpha (PGC-1alpha) could play a role in the downregulation of OXPHOS genes in PCOS. In these women with PCOS, the decrease in OXPHOS gene expression in skeletal muscle cannot be ascribed to obesity and diabetes. This supports the hypothesis of an early association between insulin resistance and impaired mitochondrial oxidative metabolism, which is, in part, mediated by reduced PGC-1alpha levels. These abnormalities may contribute to the increased risk of type 2 diabetes observed in women with PCOS.
Diabetes 2007 Sep
PMID:Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome. 1756 58

Obesity is associated with oxidative stress and mitochondrial and myocardial dysfunction, although interaction among which remains elusive. This study was designed to evaluate the impact of the free radical scavenger metallothionein on high-fat diet-induced myocardial, intracellular Ca(2+), and mitochondrial dysfunction. FVB and metallothionein transgenic mice were fed a high- or low-fat diet for 5 months to induce obesity. Echocardiography revealed decreased fractional shortening, increased end-systolic diameter, and cardiac hypertrophy in high-fat-fed FVB mice. Cardiomyocytes from high-fat-fed FVB mice displayed enhanced reactive oxygen species (ROS) production, contractile and intracellular Ca(2+) defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and reduced intracellular Ca(2+) rise and clearance. Transmission microscopy noted overt mitochondrial damage with reduced mitochondrial density. Western blot analysis revealed enhanced phosphorylation of nuclear factor Foxo3a without changes in Foxo3a, Foxo1a, pFoxo1a, silent information regulator (Sirt), and Akt and pAkt in hearts of high-fat diet-fed FVB mice. The peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a key regulator of mitochondrial biogenesis, was significantly depressed by high-fat diet feeding and in vitro palmitic acid treatment. RT-PCR further depicted reduced levels of the PGC-1alpha downstream nuclear respiratory factors 1 and 2, mitochondrial transcription factor A, and mitochondrial DNA copy number in hearts of high-fat-fed FVB mice. Intriguingly, the high-fat diet-induced alterations in ROS, myocardial contractile, and mitochondrial and cell signaling were negated by metallothionein, with the exception of pFoxo3a. These data suggest that metallothionein may protect against high-fat diet-induced cardiac dysfunction possibly associated with upregulation of PGC-1alpha and preservation of mitochondrial biogenesis.
Diabetes 2007 Sep
PMID:Metallothionein prevents high-fat diet induced cardiac contractile dysfunction: role of peroxisome proliferator activated receptor gamma coactivator 1alpha and mitochondrial biogenesis. 1757 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>