Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thoroughbred horses have been selected for exceptional racing performance resulting in system-wide structural and functional adaptations contributing to elite athletic phenotypes. Because selection has been recent and intense in a closed population that stems from a small number of founder animals Thoroughbreds represent a unique population within which to identify genomic contributions to exercise-related traits. Employing a population genetics-based hitchhiking mapping approach we performed a genome scan using 394 autosomal and X chromosome microsatellite loci and identified positively selected loci in the extreme tail-ends of the empirical distributions for (1) deviations from expected heterozygosity (Ewens-Watterson test) in Thoroughbred (n = 112) and (2) global differentiation among four geographically diverse horse populations (F(ST)). We found positively selected genomic regions in Thoroughbred enriched for phosphoinositide-mediated signalling (3.2-fold enrichment; P<0.01), insulin receptor signalling (5.0-fold enrichment; P<0.01) and lipid transport (2.2-fold enrichment; P<0.05) genes. We found a significant overrepresentation of sarcoglycan complex (11.1-fold enrichment; P<0.05) and focal adhesion pathway (1.9-fold enrichment; P<0.01) genes highlighting the role for muscle strength and integrity in the Thoroughbred athletic phenotype. We report for the first time candidate athletic-performance genes within regions targeted by selection in Thoroughbred horses that are principally responsible for fatty acid oxidation, increased insulin sensitivity and muscle strength: ACSS1 (acyl-CoA synthetase short-chain family member 1), ACTA1 (actin, alpha 1, skeletal muscle), ACTN2 (actinin, alpha 2), ADHFE1 (alcohol dehydrogenase, iron containing, 1), MTFR1 (mitochondrial fission regulator 1), PDK4 (pyruvate dehydrogenase kinase, isozyme 4) and TNC (tenascin C). Understanding the genetic basis for exercise adaptation will be crucial for the identification of genes within the complex molecular networks underlying obesity and its consequential pathologies, such as type 2 diabetes. Therefore, we propose Thoroughbred as a novel in vivo large animal model for understanding molecular protection against metabolic disease.
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PMID:A genome scan for positive selection in thoroughbred horses. 1950 17

The hypothesis that PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) has potential as a target for the treatment of type 2 diabetes was tested by feeding wild-type and PDHK4 knockout mice a high saturated fat diet that induces hyperglycemia, hyperinsulinaemia, glucose intolerance, hepatic steatosis and obesity. Previous studies have shown that PDHK4 deficiency lowers blood glucose by limiting the supply of three carbon gluconeogenic substrates to the liver. There is concern, however, that the increase in glucose oxidation caused by less inhibition of the pyruvate dehydrogenase complex by phosphorylation will inhibit fatty acid oxidation, promote ectopic fat accumulation and worsen insulin sensitivity. This was examined by feeding wild-type and PDHK4 knockout mice a high saturated fat diet for 8 months. Fasting blood glucose levels increased gradually in both groups but remained significantly lower in the PDHK4 knockout mice. Hyperinsulinaemia developed in both groups, but glucose tolerance was better and body weight was lower in the PDHK4 knockout mice. At termination, less fat was present in the liver and skeletal muscle of the PDHK4 knockout mice. Higher amounts of PGC-1alpha [PPARgamma (peroxisome proliferator-activated receptor gamma) coactivator 1alpha] and PPARalpha and lower amounts of fatty acid synthase and acetyl-CoA carboxylase isoenzyme 1 were present in the liver of the PDHK4 knockout mice. These findings suggest PDHK4 deficiency creates conditions that alter upstream signalling components involved in the regulation of lipid metabolism. The findings support the hypothesis that PDHK4 is a viable target for the treatment of type 2 diabetes.
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PMID:Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates the long-term negative effects of a high-saturated fat diet. 1962 55

Meta-analysis methods exist for combining multiple microarray datasets. However, there are a wide range of issues associated with microarray meta-analysis and a limited ability to compare the performance of different metaanalysis methods. Using cDNA microarray technology (Partek Genomics Suite 6.6) and global pathway analysis with Ingenuity Pathway Analysis tool (IPA, Inc), we examined the transcript level in type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) patients and controls. To understand the molecular link between T2DM and AD, we compared the gene expression pattern and pathway involved. Microarray analysis identified 235 differentially expressed genes between T2DM patients and controls; and 834 between AD and controls at two fold change and a false discovery rate of 0.05. Significantly changed expression of "myeloid leukemia cell differentiation protein 1; RAS guanyl releasing protein 1; S100 calcium-binding protein A8; prostaglandin- endoperoxide synthase 2; parvalbumin; endoplasmic reticulum aminopeptidase 1; phosphoglycerate kinase 1; Eukaryotic translation initiation factor 3 subunit F; Interleukin-1 beta; tubulin, beta 2A; glycine receptor alpha 1 and ribosomal protein S24" genes were highly associated with T2DM, whereas "neuronal differentiation 6; G-protein coupled receptor 83; phosphoserine phosphatase; bobby sox homolog or HMG box -containing protein 2; Glutathione S-transferase theta 1; alpha-2-glycoprotein 1 zinc-binding; Heat shock 70kDa protein 1B; transportin 1, Acidic leucine-rich nuclear phosphoprotein 32 family member B; Nuclear factor of activated T-cells 5; inositol 1,4,5-trisphosphate 3-kinase B; prenylcysteine oxidase 1 like" were found to be strongly related with AD. We also found a set of differentially expressed genes; "ARP2 actin-related protein 2; Cell division control protein 42; cytoplasmic polyadenylation element binding protein 4; Early growth response protein 1; ectonucleotide pyrophosphatase/phosphodiesterase 5; folate receptor 1; glutamate-ammonia ligase; hydroxy-3-methylglutaryl-Coenzyme A reductase; 3-hydroxy-3- methylglutaryl-CoA synthase; interleukin 1 receptor- like 1; leukemia inhibitory factor receptor; metastasis associated lung adenocarcinoma transcript 1; pyruvate dehydrogenase kinase, isozyme 4; phosphoserine phosphatase, parvalbumin, and tubulin, beta 2A" to be present in both dataset. Altered regulation of intracellular signaling pathways, including Ephrin receptor, liver X receptor/ retinoid X receptor; interleukin 6; insulinlike growth factor 1; interleukin 10 and 14-3-3-mediated signaling pathways were associated with T2DM as well as Alzheimer-type pathology. Our findings implicate diabetic disorders in the pathogenesis of AD, and provide a basis for future candidate studies based on specific pathways.
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PMID:Establishing genomic/transcriptomic links between Alzheimer's disease and type 2 diabetes mellitus by meta-analysis approach. 2405 8