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

Glomerular hyperfiltration has long been recognized in insulin-dependent diabetes, and has been more recently recognized in patients with non-insulin dependent diabetes mellitus as well. Experimentally, glomerular hyperfiltration has been shown to result from elevations in the glomerular capillary blood flow and the glomerular capillary hydraulic pressure (PGC). Of the hemodynamic determinants of hyperfiltration, it is glomerular hypertension that is most damaging to the glomerulus. Experimental and clinical studies have confirmed that antihypertensive agents that lower PGC more consistently slow the progression of injury than do those that fail to control glomerular hypertension. The pathogenesis of diabetic hyperfiltration is multifactoral. Many mediators have been proposed, including changes due to the altered metabolic milieu, and alterations in endogenous levels of such vasoactive mediators as atrial natriuretic peptide, endothelial-derived relaxing factor, angiotensin II, prostaglandins, thromboxanes, and kinins, among others. It has more recently been suggested that local renal tissue levels, rather than circulating levels, play the more profound role in hemodynamic regulation. For example, the renin-angiotensin system (RAS) appears to be disproportionately active in the renal tissue, potentially explaining the renal vascular responsiveness to angiotensin-converting enzyme inhibition despite absence of systemic RAS activation. Little is yet known of the mechanisms by which glomerular hypertension leads to injury. Innovative new in vitro systems have been developed to address this question. These studies postulate that glomerular hemodynamic factors (shear stress, pulsatile flow) modify the growth and activity of glomerular component cells, inducing the expression of cytokines and other mediators, which then stimulate matrix production and promote structural injury.
 ...
PMID:Current concepts of renal hemodynamics in diabetes. 857 53

beta cell dysfunction is an important component of type 2 diabetes, but the molecular basis for this defect is poorly understood. The transcriptional coactivator PGC-1alpha mRNA and protein levels are significantly elevated in islets from multiple animal models of diabetes; adenovirus-mediated expression of PGC-1alpha to levels similar to those present in diabetic rodents produces a marked inhibition of glucose-stimulated insulin secretion from islets in culture and in live mice. This inhibition coincides with changes in metabolic gene expression associated with impaired beta cell function, including the induction of glucose-6-phosphatase and suppression of GLUT2, glucokinase, and glycerol-3-phosphate dehydrogenase. These changes result in blunting of the glucose-induced rise in cellular ATP levels and membrane electrical activity responsible for Ca(2+) influx and insulin exocytosis. These results strongly suggest that PGC-1alpha plays a key functional role in the beta cell and is involved in the pathogenesis of the diabetic phenotype.
 ...
PMID:Suppression of beta cell energy metabolism and insulin release by PGC-1alpha. 1285 53

Transcriptional coregulators modulate the activity of transcription factors and are required for the proper regulation of gene expression. One transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), plays an important role in the control of energy metabolism and has been associated with type 2 diabetes. A recent paper by Fan et al. provides new information about the posttranslational regulation of PGC-1alpha activity. This Perspective discusses the implications of these findings with respect to diabetes and aging.
 ...
PMID:Regulation of transcriptional coactivator PGC-1alpha. 1499 29

Recent studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression in skeletal muscle of diabetic and prediabetic humans. Moreover, these changes may be mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). By combining PGC-1alpha-induced genome-wide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related receptor alpha (Erralpha) and GA repeat-binding protein alpha as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1alpha-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Erralpha and GA-binding protein a partner with PGC-1alpha in muscle to form a double-positive-feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Erralpha, we demonstrated its key role in PGC-1alpha-mediated effects on gene regulation and cellular respiration. These results illustrate the dissection of gene regulatory networks in a complex mammalian system, elucidate the mechanism of PGC-1alpha action in the OXPHOS pathway, and suggest that Erralpha agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.
 ...
PMID:Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. 1510 Apr 10

Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator implicated in transcriptional programs of hepatic gluconeogenesis, oxidative phosphorylation, and insulin release by beta-cells. To study associations of the PGC-1alpha gene locus with carbohydrate metabolism and type 2 diabetes in humans, we identified several polymorphisms in the promoter region that were located in a haplotype block distinct from a second haplotype block containing part of intron 2 and extending beyond exon 13. Each block contained five common haplotypes. Oral glucose tolerance testing revealed associations of promoter haplotype combinations with 30- and 60-min postload plasma glucose levels, whereas haplotypes in both blocks were associated with indexes of beta-cell function. The associations of promoter haplotypes are supported by functional studies showing that some polymorphisms are located in transcription factor binding sites and affect transactivation in an allele-specific manner. By comparing patients with type 2 diabetes and control subjects, we observed borderline significant differences of four-loci haplotype distributions in the downstream haplotype block. Moreover, the haplotype that was associated with the strongest insulin response to glucose conferred the lowest risk of type 2 diabetes (P < 0.01). Thus, the PGC-1alpha gene locus influences carbohydrate metabolism and contributes to type 2 diabetes in the population studied.
 ...
PMID:Complex haplotypes of the PGC-1alpha gene are associated with carbohydrate metabolism and type 2 diabetes. 1511 10

The Randle cycle, which has been invoked to explain the reciprocal relationship between fatty acid oxidation and glucose oxidation, has long been implicated as a potential mechanism for hyperglycemia and type 2 diabetes mellitus (T2DM). Now genetic, functional genomic, and transgenic approaches have identified PPARgamma coactivators (PGC-1alpha and PGC-1beta) as key regulators of mitochondrial number and function. They regulate adaptive thermogenesis as well as glucose and fat oxidation in muscle and fat tissue, gluconeogenesis in liver, and even glucose-regulated insulin secretion in beta cells. PGC-1alpha and PGC-1beta mRNA levels and the mitochondrial genes they regulate are decreased in muscle of people with prediabetes and T2DM. A new report indicates that PGC-1alpha and PGC-1beta mRNA levels decrease with age in individuals with a genetic variant in PGC-1alpha, and these decreases correlate with alterations in whole-body glucose and fatty acid oxidation. These findings provide insights into how aging modifies genetic susceptibility to alterations in oxidative phosphorylation and T2DM.
 ...
PMID:Genes and pathophysiology of type 2 diabetes: more than just the Randle cycle all over again. 1554 3

Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPARgamma coactivator 1alpha (PGC-1alpha) and PGC-1beta genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1alpha gene. Insulin increased and aging reduced skeletal muscle PGC-1alpha and PGC-1beta mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1alpha Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1alpha in a complex fashion. Whereas expression of PGC-1alpha in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1beta expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1alpha and PGC-1beta expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1alpha and PGC-1beta on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.
 ...
PMID:Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. 1554 92

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.
 ...
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

To investigate whether variations in the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) are associated with essential hypertension and type 2 diabetes in a Chinese population. A case-control study design was applied in a Chinese population. Two single nucleotide polymorphisms (SNPs), +1302G>A and G482S, in the PGC-1alpha gene were genotyped and compared between 494 unrelated Chinese subjects with essential hypertension and type 2 diabetes and 555 normal control subjects with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. These two polymorphisms were in highly significant linkage disequilibrium with each other (p <0.0001). The frequency of the 482S allele was 42.9% in the Chinese population, which was similar to the frequency in the Japanese population (43.7%), but much higher than those of Caucasian populations (30.8% to 38.1%). There were no associations of the G482S and +1302G>A polymorphisms and haplotype combinations with essential hypertension and type 2 diabetes. In addition, no associations were found between these two polymorphisms and blood pressure. In conclusion, these results indicated that these two variations in the PGC-1alpha gene might not contribute to the risk of hypertension and type 2 diabetes in the Chinese population studied here.
 ...
PMID:Peroxisome proliferator-activated receptor-gamma coactivator-1alpha polymorphism is not associated with essential hypertension and type 2 diabetes mellitus in Chinese population. 1582 63

The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)-activated protein kinase]. The deletion of LKB1 in the liver of adult mice resulted in a nearly complete loss of AMPK activity. Loss of LKB1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In LKB1-deficient livers, TORC2, a transcriptional coactivator of CREB (cAMP response element-binding protein), was dephosphorylated and entered the nucleus, driving the expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1alpha expression and normalized blood glucose levels in mice with deleted liver LKB1, indicating that TORC2 is a critical target of LKB1/AMPK signals in the regulation of gluconeogenesis. Finally, we show that metformin, one of the most widely prescribed type 2 diabetes therapeutics, requires LKB1 in the liver to lower blood glucose levels.
 ...
PMID:The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. 1630 21


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