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)

Polymorphisms within the transcription factor 7-like 2 gene (TCF7L2) have been associated with type 2 diabetes (T2D) in several recent studies. We characterized three of these polymorphisms (rs12255372, rs7903146 and the microsatellite DG10S478) in an admixed sample of 286 patients with T2D and 275 controls from Mexico City. We also analyzed three samples representative of the relevant parental populations: Native Americans from the state of Guerrero (Mexico), Spanish from Valencia and Nigerians (Bini from the Edo region). In order to minimize potential confounding because of the presence of population stratification in the sample, we evaluated the association of the three TCF7L2 polymorphisms with T2D by using the program admixmap to fit a logistic regression model incorporating individual ancestry, sex, age, body mass index and education. The markers rs12255372, rs7903146 and DG10S478 are in tight disequilibrium in the Mexican sample. We observed a significant association between the single-nucleotide polymorphism (SNP) rs12255372 and the microsatellite DG10S478 with T2D in the Mexican sample [rs12255372, odds ratio (OR) = 1.78, p = 0.017; DG10S478, OR = 1.62, p = 0.041]. The SNP rs7903146 shows similar trends, but its association with T2D is not as strong (OR = 1.39, p = 0.152). Analysis of the parental samples, as well as other available data, indicates that there are substantial population frequency differences for these polymorphisms: The frequencies of the T2D risk factors are more than 20% higher in European and West African populations than in East Asian and Native American populations.
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PMID:Association of TCF7L2 polymorphisms with type 2 diabetes in Mexico City. 1747 Jan 38

One thousand thirty-eight normal glucose-tolerant and 1031 type 2 diabetic subjects selected from the Chennai Urban Rural Epidemiology Study were genotyped using polymerase chain reaction-restriction fragment length polymorphism assay to investigate the association of rs12255372(G/T) and rs7903146(C/T) polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene with type 2 diabetes mellitus in Asian Indians. The frequency of the "T" allele of both rs12255372(G/T) and rs7903146(C/T) polymorphisms was significantly higher in diabetic subjects (23% and 33%) compared to that in normal glucose-tolerant subjects (19% and 28%; P = .001 and P = .0001, respectively). Logistic regression analysis of the rs12255372(G/T) polymorphism showed that the odds ratio (adjusted for age, sex, and body mass index) was 1.56 (95% confidence interval [CI], 1.03-2.37; P = .034) for the TT genotype and 1.29 (95% CI, 1.06-1.58; P = .011) for the TG genotype when compared with the GG genotype. Adjusted odds ratios for the TT and TC genotypes of the rs7903146(C/T) polymorphism were found to be 1.50 (95% CI, 1.08-2.08; P = .013) and 1.44 (95% CI, 1.18-1.76; P = .0003), respectively, compared with the CC genotype. Normal glucose-tolerant subjects with the TT genotype of rs12255372(G/T) had significantly higher 2-hour plasma glucose levels (mean +/- SD, 6.1 +/- 1.4 mmol/L) than those with the GG genotype (5.6 +/- 1.0 mmol/L, P = .011). Normal glucose-tolerant subjects with the TT genotype of rs7903146(C/T) polymorphism had significantly higher 2-hour plasma glucose levels (mean +/- SD, 6.0 +/- 1.3 mmol/L) than those with the CC genotype (5.6 +/- 1.0 mmol/L, P = .004). In conclusion, the T allele of the rs12255372(G/T) and rs7903146(C/T) polymorphisms of TCF7L2 gene confer susceptibility to type 2 diabetes mellitus in Asian Indians.
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PMID:The rs12255372(G/T) and rs7903146(C/T) polymorphisms of the TCF7L2 gene are associated with type 2 diabetes mellitus in Asian Indians. 1769 58

The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele was previously associated with type 2 diabetes (T2D) and decreased BMI whereas haplotypes carrying the rs7903146 C and rs10885406 A alleles (HapA) were associated with increased BMI. The functional relevance of TCF7L2 polymorphisms and their effects on T2D and obesity remained to be further investigated. In white European populations, we found that the rs7903146 T allele was more associated with T2D in 3,547 non-obese individuals (odds ratio (OR) = 1.88 (1.69-2.10)) than in 1,110 class III obese subjects (OR = 1.24 (1.03-1.50)). No direct effect of the rs7903146 C allele and HapA was found on any form of obesity in 3,507 normal glucose tolerant (NGT) individuals, 1,106 pedigrees with familial obesity and 5,512 individuals from the French general population. However, in T2D subjects, the rs7903146 C allele was less prevalent in the 1,111 non-obese individuals (55.2%) compared to 659 class III obese subjects (67.5% OR = 1.69 (1.46-1.95)). Functional studies showed that the rs7903146 T allele is less prone to be bound by protein factors than the C allele in 3T3-L1, HepG2 and beta-TC3 cell lines and that TCF7L2 expression decreases in subcutaneous adipose tissue from NGT obese T/T carriers under calorie restriction. In conclusion, TCF7L2 is not a risk factor for obesity in European populations, but its effect on T2D risk is modulated by obesity. Furthermore, our data suggest that the rs7903146 T allele may be possibly functional and associated with a nominal decrease in TCF7L2 expression in adipose tissue of individuals under calorie restriction.
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PMID:Effects of TCF7L2 polymorphisms on obesity in European populations. 1823 63

Variants in the TCF7L2 gene (transcription factor 7-like 2) have shown strong association with type 2 diabetes with two defined risk haplotypes, HapA and HapB(T2D). TCF7L2 may play a role in both glucose homeostasis and adipogenesis. Our aim was to characterize the TCF7L2 mRNA expression and regulation in human adipose tissue. We quantified TCF7L2 mRNA levels in cultured human adipocytes and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissue from 38 obese non-diabetic subjects, using real-time PCR. The influence of haplotype and clinical traits on TCF7L2 mRNA levels were investigated. In vitro, insulin decreased TCF7L2 mRNA expression. This effect was attenuated in cells incubated with the free fatty acids palmitate or oleate. In vivo, we found significantly higher expression in SAT from more insulin resistant subjects. No correlations between TCF7L2 mRNA expression and obesity measures were observed. TCF7L2 expression was higher in VAT than in SAT and when stratifying for haplotype, this difference was seen in HapA carriers but not in non-HapA carriers. In conclusion, TCF7L2 mRNA levels in adipocytes are decreased by insulin and seem to increase in insulin resistant subjects and in HapA carriers.
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PMID:Expression of the transcription factor 7-like 2 gene (TCF7L2) in human adipocytes is down regulated by insulin. 1834 27

After two decades of limited success, the genetic architecture of type 2 diabetes (T2D) is finally being revealed. Within only 2 years, an avalanche of studies identified several genes expressed in pancreatic beta cells and involved in the control of insulin secretion, such as transcription factor 7-like 2 (TCF7L2), a key element of the Wnt signaling pathway. In Europeans, genome-wide association scans showed that TCF7L2 has been the most important locus predisposing to T2D so far. For the first time, a gene is consistently involved in T2D susceptibility in all major ethnic groups. At the individual level, carrying the TCF7L2 risk allele increases T2D risk 50%. However, at the population level, the attributable risk is lower than 25% and varies with the allele frequency. The presence of the TCF7L2 rs7903146 risk allele increases TCF7L2 gene expression in beta cells, possibly impairing glucagon-like peptide-1-induced insulin secretion and/or the production of new mature beta cells. The tremendous association of TCF7L2 polymorphisms with T2D provides new insights into future genetic predisposition tests but remains the tip of the T2D genetic iceberg.
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PMID:TCF7L2 genetic defect and type 2 diabetes. 1844 58

Since the relationship between TCF7L2 (also known as TCF-4) polymorphisms and type 2 diabetes mellitus was identified in 2006, extensive genome-wide association examinations in different ethnic groups have further confirmed this relationship. As a component of the bipartite transcription factor beta-catenin/TCF, TCF7L2 is important in conveying Wnt signaling during embryonic development and in regulating gene expression during adulthood. Although we still do not know mechanistically how the polymorphisms within the intron regions of TCF7L2 affect the risk of type 2 diabetes, this transcriptional regulator was shown to be involved in stimulating the proliferation of pancreatic beta-cells and the production of the incretin hormone glucagon-like peptide-1 in intestinal endocrine L cells. In this review, we introduce background knowledge of TCF7L2 as a component of the Wnt signaling pathway, summarize recent findings demonstrating the association between TCF7L2 polymorphisms and the risk of type 2 diabetes, outline experimental evidence of the potential function of TCF7L2 in pancreatic and intestinal endocrine cells, and present our perspective views.
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PMID:The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus. 1859 16

The promise of nutrigenomics is of personalized nutrition that will lead to optimization or maintenance of good health and/or prevention of the development of chronic diseases. Type 2 diabetes mellitus (T2DM) is a leading health problem throughout the world. Adherence to a Mediterranean-style diet, regulation of carbohydrate intake, and regular exercise may be desirable. Four key genes were originally identified: KCNJ11, potassium inwardly rectifying channel, subfamily J, member 11 gene; PPAR-gamma, peroxisome proliferator activated receptor-gamma; TCF2, transcription factor 2, hepatic; WFS1, Wolfram syndrome 1. However, genome-wide association studies are accelerating our knowledge of the genetics of complex diseases, and have identified seven other key genes in T2DM: CDKAL1, CDK5 regulatory subunit associated protein-like 1; CDKN2, cyclin-dependent kinase inhibitor 2A; FTO, fat mass and obesity associated; HHEX, haematopoietically expressed homeobox; IDE, insulin-degrading enzyme; IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 2; SLC30A8, solute carrier family 30 (zinc transporter), member 8; TCF7L2, transcription factor 7-like 2 (T-cell specific, HMG-box). Gene-nutrient or gene-environment interactions may be important. For example, the PPAR-gamma variant genotype is responsive to different types and levels of lipids, while the effect of the FTO variant can be partly overcome by exercise. Several of these genes act through their effect on the gastrointestinal tract. There are analytical challenges in analyzing the high-dimensional datasets relating genes, nutrients, and other variables to their influence on health and disease processes. An even greater challenge may be in implementing population level changes in diet and behavior to fully exploit the potential of this field.
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PMID:Dissecting the nutrigenomics, diabetes, and gastrointestinal disease interface: from risk assessment to health intervention. 1871 Mar 64

Polymorphisms (rs1801282, rs8192678, rs7903146) of peroxisome proliferator-activated receptor gamma (PPARG), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A) and transcription factor 7-like 2 (TCF7L2) have recently been associated with different diseases, mainly type 2 diabetes. An assay using unlabeled probes and the LightCycler or Rotor-Gene instruments was developed for genotyping of these three polymorphisms. Asymmetric polymerase chain reaction was used, followed by melting analysis of the unlabeled probe/ssDNA amplicon duplex. Samples with the target genotypes were accurately detected and easily distinguishable. Thus, genotyping using unlabeled probes is a rapid, accurate and cost effective closed-tube method. These assays demonstrated 100% specificity and sensitivity for the identification of selected polymorphisms in PPARG, PPARGC1A and TCF7L2 genes.
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PMID:Rapid and cost effective genotyping method for polymorphisms in PPARG, PPARGC1 and TCF7L2 genes. 1899 70

Genetic variants of the transcription factor 7-like 2 (TCF7L2) gene affect the risk of type 2 diabetes in populations with multiple ethnic groups. However, a comprehensive survey of this gene has not been done for a Japanese population. Thus, we conducted this gene-based association study, in which the common genetic variants were analyzed. Using 24 Japanese type 2 diabetic subjects, we first screened a 9.5 kb region, which included the entire coding sequence, to assess potential functional variants of TCF7L2. Sequencing revealed a common coding variant (Pro477Thr) in exon 14 of TCF7L2 that was not enrolled in the public SNP database. Nineteen SNPs and the microsatellite DG10S478 were genotyped across the gene in 2,877 unrelated Japanese subjects. This independent screen identified the previously reported rs7903146 with a strongest association (allele P = 0.0001, odds ratio = 1.59 [95% confidence interval 1.25-2.01]), but there was no significant association between Pro477Thr and type 2 diabetes (allele P = 0.64). Expression of the Pro477Thr variant did not alter TCF7L2 expression in 30 lymphoblast cells. Although a genotypic effect of Pro477Thr on expression of TCF7L2 was not apparent, Pro477Thr was identified as a common variant of TCF7L2 in 2,877 Japanese subjects. Further functional studies are required to determine the possible effect of this coding variant on type 2 diabetes.
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PMID:Common coding variant in the TCF7L2 gene and study of the association with type 2 diabetes in Japanese subjects. 1901 45

Several studies have recently reported strong association between type 2 diabetes and variation in the transcription factor 7-like 2 (TCF7L2) gene, which has been confirmed by several other genome-wide studies. However, the physiological implications of this transcription factor on the pathogenesis of type 2 diabetes is not yet known. The aim of this study was to investigate the alteration in TCF7L2 gene expression in human pancreatic cell line in response to various factors in vitro. MIA Paca-2 cell line (Human Pancreas cell line) was cultured in the presence of curcumin, lipopolysaccaride and glucose (low and high concentration). TCF7L2 gene expression was determined using quantitative real-time RT-PCR. Treatment with curcumin significantly increased TCF7L2 gene expression to 3.24 fold (1.7-log fold) (P = 0.003) compared to the controls while treatment with LPS decreased TCF7L2 gene expression to 0.88-fold (-0.18-log). On the other hand, glucose increased TCF7L2 gene expression in pancreatic cell line. Our data suggest a role for TCF7L2 in glucose homeostasis. The contrary effect of curcumin and LPS on expression of TCF7L2 in pancreatic cells supports a role for TCF7L2 in their survival and function in inflammatory conditions.
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PMID:In vitro modulation of TCF7L2 gene expression in human pancreatic cells. 1915 36


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