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

Transcriptional coactivators can be important targets for physiologic regulation. PPARgamma coactivator-1alpha (PGC-1alpha), in cooperation with several transcription factors, has emerged as a key regulator of several aspects of mammalian energy metabolism including mitochondrial biogenesis, adaptive thermogenesis in brown adipose tissue, glucose uptake, fiber type-switching in skeletal muscle, gluconeogenesis in liver and insulin secretion from pancreas. Recent studies have shown a reduced expression of PGC-1alpha in skeletal muscle of diabetic and prediabetic humans. Moreover, expression of PGC-1alpha in white fat cells activates a broad program of adaptive thermogenesis characteristic of brown fat cells. PGC-1alpha could be a target for antiobesity or diabetes drugs. The aim of this article was to summarize the molecular mechanisms and biological programs controlled by the transcriptional coactivator PGC-1alpha.
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PMID:[PGC-1alpha, a transcriptional coactivator involved in metabolism]. 1563 20

The peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) is a novel transcriptional co-activator that holds an important role in lipid and glucose metabolism. PGC-1alpha is a candidate gene for the metabolic syndrome (MS) as well as type 2 diabetes. Recent studies suggested linkage between the chromosomal region of PGC-1alpha and fasting serum insulin levels, and associates a Gly482Ser polymorphism of the gene with type 2 diabetes and hypertension. In this study, we investigated whether the Gly482Ser variant is associated with the MS per se or other phenotypic traits related to this syndrome. The variant was examined, using PCR-RFLP, in the DanMONICA cohort comprising a population-based sample of 2349 subjects. MS was defined using the National Cholesterol Education Program -- Adult Treatment Panel III (NCEP-ATPIII) criteria. The allelic frequency of the Ser482 allele was 35.8% in the MS group and 35.6% in the non-MS group (P = 0.74). There were no significant differences across the three groups of genotypes with respect to any of the examined variables, including BMI, waist, fasting serum lipids, plasma glucose, serum insulin, HOMA estimates of insulin resistance and insulin secretion, 24-ambulatory blood pressure or left ventricular mass index. In conclusion, the Gly482Ser polymorphism of the PGC-1alpha gene is not associated with the metabolic syndrome, related quantitative traits or cardiac hypertrophy among Danish Caucasian subjects.
Diabetes Res Clin Pract 2005 Feb
PMID:Studies of the Gly482Ser polymorphism of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) gene in Danish subjects with the metabolic syndrome. 1564 78

Metabolic pathways are controlled at different levels in response to environmental or hormonal stimuli. This control is achieved, at least in part, at the transcriptional level of gene expression. The regulation of gene expression is executed by specific transcription factors, but there is another level of regulation by a set of proteins that modulate these factors called transcriptional coactivators. In mammals, one of the most characterized examples of regulation of metabolic pathways by transcriptional coactivators is peroxisome proliferator-activated receptors gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha). PGC-1alpha is activated by signals that control energy and nutrient homeostasis. Notably, PGC-1alpha induces and coordinates gene expression that stimulates mitochondrial biogenesis and a thermogenic program in brown fat, fiber-type switching in skeletal muscle, and metabolic pathways linked to the fasted response in the liver. PGC-1alpha activates gene expression through specific interaction with transcription factors that bind to the promoters of metabolic genes. These transcription factors can be ubiquitous such as the nuclear respiratory factors or tissue-enriched factors such as PPARgamma (brown fat), hepatocyte nuclear factor (HNF4alpha) (liver and pancreas) and muscle enhancer factor (MEF2s). The fact that PGC-1alpha controls important metabolic pathways in several tissues suggests that it can be a therapeutic target for antiobesity or diabetes drugs.
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PMID:Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-alpha. 1571 83

PGC-1alpha mRNA and protein are elevated in islets from multiple animal models of diabetes. Overexpression of PGC-1alpha impairs glucose-stimulated insulin secretion (GSIS). However, it is not well known which metabolic events lead to upregulation of PGC-1alpha in the beta-cells under pathophysiological condition. In present study, we have investigated effects of chronic hyperlipidemia and hyperglycemia on PGC-1alpha mRNA expression in isolated rat islets. Isolated rat islets are chronically incubated with 0, 0.2 and 0.4 mM oleic acid/palmitic acid (free fatty acids, FFA) or 5.5 and 25 mM glucose for 72 h. FFA dose-dependently increases PGC-1alpha mRNA expression level in isolated islets. FFA also increases PGC-1alpha expression in mouse beta-cell-derived beta TC3 cell line. In contrast, 25 mM glucose decreases expression level of PGC-1alpha. Inhibition of PGC-1alpha by siRNA improves FFA-induced impairment of GSIS in islets. These data suggest that hyperlipidemia and hyperglycemia regulate PGC-1alpha expression in islets differently, and elevated PGC-1alpha by FFA plays an important role in chronic hyperlipidemia-induced beta-cell dysfunction.
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PMID:Free fatty acids increase PGC-1alpha expression in isolated rat islets. 1573 55

Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1--which modulates ageing in several species--controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.
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PMID:Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. 1574 10

The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the metabolism of glucose to acetyl-CoA. Phosphorylation of pyruvate dehydrogenase by the pyruvate dehydrogenase kinases (PDK) inhibits pyruvate dehydrogenase complex activity. There are four PDK isoforms, and expression of PDK4 and PDK2 genes is elevated in starvation and diabetes, allowing glucose to be conserved while fatty acid oxidation is increased. In these studies we have investigated the transcriptional mechanisms by which the expression of the PDK4 gene is increased. The peroxisome proliferator-activated receptor gamma coactivator (PGC-1alpha) stimulates the expression of genes involved in hepatic gluconeogenesis and mitochondrial fatty acid oxidation. We have found that PGC-1alpha will induce the expression of both the PDK2 and PDK4 genes in primary rat hepatocytes and ventricular myocytes. We cloned the promoter for the rat PDK4 gene. Hepatic nuclear factor 4 (HNF4), which activates many genes in the liver, will induce PDK4 expression. Although HNF4 and PGC-1alpha interact to stimulate several genes encoding gluconeogenic enzymes, the induction of PDK4 does not involve interactions of PGC-1alpha with HNF4. Using the chromatin immunoprecipitation assay, we have demonstrated that HNF4 and PGC-1alpha are associated with the PDK4 gene in vivo. Our data suggest that by inducing PDK genes PGC-1alpha will direct pyruvate away from metabolism into acetyl-CoA and toward the formation of oxaloacetate and into the gluconeogenic pathway.
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PMID:Cloning of the rat pyruvate dehydrogenase kinase 4 gene promoter: activation of pyruvate dehydrogenase kinase 4 by the peroxisome proliferator-activated receptor gamma coactivator. 1596 3

Physical activity enhances muscle mitochondrial gene expression, while inactivity and mitochondrial dysfunction are both risk factors for developing diabetes. Defective activation of the transcriptional coactivator PGC-1alpha may contribute to the gene expression pattern observed in diabetic and insulin-resistant skeletal muscle. We proposed that greater insight into the mitochondrial component of skeletal muscle "diabetes" would be possible if the clinical transcriptome data were contrasted with local muscle inactivity-induced modulation of mitochondrial genes in otherwise healthy subjects. We studied PPARGC1A (PGC-1alpha), PPARGC1B (PGC-1beta), NRF1, and a variety of mitochondrial DNA (mtDNA) and nuclear-encoded mitochondrial genes critical for oxidative phosphorylation in soleus muscle biopsies obtained from six healthy men and women before and after 5 weeks of local muscle inactivity. Muscle inactivity resulted in a coordinated down-regulation of PGC-1alpha and genes involved with mitochondrial metabolism, including muscle substrate delivery genes. Decreased expression of the mtDNA helicase Twinkle was related to the decline in mitochondrial RNA polymerase (r = 0.83, p < 0.04), suggesting that mtDNA transcription and replication are coregulated in human muscle tissue. In contrast to the situation in diabetes, PGC-1beta expression was not significantly altered, while NRF1 expression was actually up-regulated following muscle inactivity. We can conclude that reduced PGC-1alpha expression described in Type 2 diabetes may be partly explained by muscle inactivity. Further, although diabetes patients are typically inactive, our analysis indicates that local muscle inactivity may not be expected to contribute to the decreased NRF1 and PGC-1beta expression noted in insulin-resistant and Type 2 diabetes patients, suggesting these changes may be more disease specific.
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PMID:Expression profiling following local muscle inactivity in humans provides new perspective on diabetes-related genes. 1632 70

We previously proposed that the production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) is a key event in the development of diabetes complications. The association between the pathogenesis of diabetes and its complications and mitochondrial biogenesis has been recently reported. Because metformin has been reported to exert a possible additional benefit in preventing diabetes complications, we investigated the effect of metformin and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) on mtROS production and mitochondrial biogenesis in cultured human umbilical vein endothelial cells. Treatment with metformin and AICAR inhibited hyperglycemia-induced intracellular and mtROS production, stimulated AMP-activated protein kinase (AMPK) activity, and increased the expression of peroxisome proliferator-activated response-gamma coactivator-1alpha (PGC-1alpha) and manganese superoxide dismutase (MnSOD) mRNAs. The dominant negative form of AMPKalpha1 diminished the effects of metformin and AICAR on these events, and an overexpression of PGC-1alpha completely blocked the hyperglycemia-induced mtROS production. In addition, metformin and AICAR increased the mRNA expression of nuclear respiratory factor-1 and mitochondrial DNA transcription factor A (mtTFA) and stimulated the mitochondrial proliferation. Dominant negative-AMPK also reduced the effects of metformin and AICAR on these observations. These results suggest that metformin normalizes hyperglycemia-induced mtROS production by induction of MnSOD and promotion of mitochondrial biogenesis through the activation of AMPK-PGC-1alpha pathway.
Diabetes 2006 Jan
PMID:Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. 1638 Apr 84

Among the putative candidate genes for insulin resistance, the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator of PPARgamma and alpha, regulating a wide range of processes involved in energy production and utilization, such as thermogenesis, liver gluconeogenesis, glucose uptake in muscle. In population studies a Gly482Ser substitution in PGC-1alpha has been reported to be associated with increased risk of type diabetes 2 and insulin resistance. In the present study we have analysed the association between the Gly482Ser missense mutation of the PGC-1alpha gene and insulin sensitivity and glucose tolerance in a population of obese non-diabetic subjects. The Gly482Ser SNPs was detected by PCR-RFLP in a cohort of 358 Caucasian obese subjects (223 with normal glucose tolerance (NGT) and 125 with impaired glucose tolerance (IGT). We observed a significant association (p <0.007) between carriers of the Gly482Ser variant of the PGC-1alpha gene and insulin resistance measured by HOMAIR. Multivariate analysis confirmed that the Gly482Ser SNP was a significant (p < 0.02) determinant of decreased insulin sensitivity, independently from other well-known modulators of insulin action. In conclusion, we have found significant association between the Gly482Ser variant of the PGC-1alpha gene and reduced insulin sensitivity in obese subjects. This association resulted independent from all other known modulators of insulin resistance, and suggests a primary role for the PGC-1alpha gene on the genetic susceptibility to insulin resistance in obesity.
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PMID:The Gly482Ser missense mutation of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) gene associates with reduced insulin sensitivity in normal and glucose-intolerant obese subjects. 1640 52

Dietary restriction of calories (caloric restriction [CR]) increases longevity in phylogenetically diverse species. CR retards or prevents age-dependent deterioration of tissues and an array of spontaneous and chemically induced diseases associated with obesity including cardiovascular disease, diabetes, and cancer. An understanding of the molecular mechanisms that underlie the beneficial effects of CR will help identify novel dietary, pharmacological, and lifestyle strategies for slowing the rate of aging and preventing these diseases as well as identify factors which modulate chemical toxicity. Here, we review the involvement of transcriptional coactivator proteins, peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 (PGC-1) alpha and beta, and regulated nuclear receptors (NR) in mediating the phenotypic changes found in models of longevity which include rodent CR models and mouse mutants in which insulin and/or insulin-like growth factor-I signaling is attenuated. PGC-1alpha is transcriptionally or posttranslationally regulated in mammals by: 1) forkhead box "other" (FoxO) transcription factors through an insulin/insulin-like growth factor-I -dependent pathway, 2) glucagon-stimulated cellular AMP (cAMP) response element binding protein, 3) stress-activated kinase signaling through p38 mitogen-activated protein kinase, and 4) the deacetylase and longevity factor sirtuin 1 (SIRT1). PGC-1alpha and PGC-1beta regulate the ligand-dependent and -independent activation of a large number of NR including PPARalpha and constitutive activated receptor (CAR). These NR regulate genes involved in nutrient and xenobiotic transport and metabolism as well as resistance to stress. CR reverses age-dependent decreases in PGC-1alpha, PPARalpha, and regulated genes. Strategies that target one or multiple PGC-1-regulated NR could be used to mimic the beneficial health effects found in models of longevity.
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PMID:Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. 1642 81


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