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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A major reason for the increased incidence of type 2 diabetes mellitus (T2DM) across the world is the so-called obesity epidemic, which occurs both in developed and developing countries. However, a large proportion of patients with T2DM in European and, in particular, Asian countries are non-obese. The non-obese T2DM phenotype is characterized by disproportionally reduced insulin secretion and less insulin resistance, as compared with obese patients with T2DM. Importantly, non-obese patients with T2DM have a similar increased risk of cardiovascular disease as obese T2DM patients. The risk of T2DM in non-obese patients is influenced by genetics as well as factors operating in utero indicated by low birth weight. Furthermore, this phenotype is slightly more prevalent among patients with latent autoimmune diabetes in adults, characterized by positive anti-GAD antibodies. The recently identified TCF7L2 gene polymorphism resulting in low insulin secretion influences the risk of T2DM in both obese and non-obese subjects, but is relatively more prevalent among non-obese patients with T2DM. Furthermore, the Pro12Ala polymorphism of the PPAR gamma gene influencing insulin action increases the risk of T2DM in non-obese subjects. Despite a "normal" body mass index, non-obese patients with T2DM are generally characterized by a higher degree of both abdominal and total fat masses (adiposity). Prevention of T2DM with lifestyle intervention is at least as effective in non-obese as in obese prediabetic subjects, and recent data suggest that metformin treatment targeting insulin resistance and non-glycemic cardiovascular disease risk factors is as beneficial in non-obese as in obese patients with T2DM. Nevertheless, non-obese patients with T2DM may progress to insulin treatment more rapidly as compared with obese patients with T2DM.
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PMID:Non-obese patients with type 2 diabetes and prediabetic subjects: distinct phenotypes requiring special diabetes treatment and (or) prevention? 1805 16

Obesity results from the complex interaction of environmental factors that act on a genetic background that determines the susceptibility to obesity. The identification of such obesity susceptibility genes can provide important insights into the mechanism underlying this condition. While candidate gene approaches have not been tremendously successful in identifying relevant genetic contributors to obesity, except PPAR , the advent of genome-wide strategies has recently revealed novel and unexpected genetic factors with strong associations with obesity and/or diabetes, i.e. FTO, TCF7L2, INSIG2, ENPP1, or FASN (reviewed herein), although some of them are not undebated. Considering the function of the encoded proteins, it will now be of interest to investigate the cellular and molecular mechanisms, how these genetic variations affect body weight, energy metabolism and/or obesity-associated morbidity.
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PMID:Polygenic contribution to obesity: genome-wide strategies reveal new targets. 1823 Aug 92

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

Polymorphism RS7903146 in transcription factor 7-like2 gene ( TCF7L2) is associated with type 2-diabetes mellitus (T2DM) in adults. Concerned with predisposition for diabetes mellitus in obese children, we tested if risk genotypes TC and TT of rs7903146 are more common in obese children with increased homeostasis model assessment insulin resistance index (HOMA-IR) compared to obese controls with normal HOMA-IR. As exploratory analysis, we also calculated beta-cell function for these risk genotypes and measured glucagon-like peptide 1 (GLP-1) in a subgroup. The cohort was 401 obese children (BMI > 2SDS; 211 female; 59% presenting increased HOMA-IR) from two German outpatient obesity referral centers. Genotype distributions in patients presenting increased HOMA-IR (TT: 10.18%, CT: 35.65%, CC: 54.17%) and in patients with normal HOMA-IR (TT: 8.66%, CT: 42.67%, CC: 48.67%) provided no significant effect of these two risk genotypes (p > 0.2). Correction for possible confounder's gender, age, pubertal stage, and BMI revealed no association with glucose metabolism parameters including GLP-1. However, exploratory HOMA-B% index was comparatively higher in TT-homozygotes (p=0.021) as compared to CC-homozygotes. We conclude that even though TT and CT genotypes were not higher in patients presenting elevated HOMA-IR, the higher HOMA-B% index in TT-homozygotes indicates TCF7L2 to be a susceptibility gene for the development of impaired glucose tolerance in obese children as demonstrated in several adult cohort studies.
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PMID:TCF7L2 polymorphism rs7903146 and predisposition for type 2 diabetes mellitus in obese children. 1854 86

The WNT signalling pathway is involved in many physiological and pathophysiological activities. WNT ligands bind to Frizzled receptors and co-receptors (LDL receptor-related protein 5/6), triggering a cascade of signalling events. The major effector of the canonical WNT signalling pathway is the bipartite transcription factor beta-catenin/T cell transcription factor (beta-cat/TCF), formed by free beta-cat and one of the four TCFs. The WNT pathway is involved in lipid metabolism and glucose homeostasis, and mutations in LRP5 may lead to the development of diabetes and obesity. beta-Cat/TCF is also involved in the production of the incretin hormone glucagon-like peptide-1 in the intestinal endocrine L cells. More recently, genome-wide association studies have identified TCF7L2 as a diabetes susceptibility gene, and individuals carrying certain TCF7L2 single nucleotide polymorphisms could be more susceptible to the development of type 2 diabetes. Furthermore, beta-cat is able to interact with forkhead box transcription factor subgroup O (FOXO) proteins. Since FOXO and TCF proteins compete for a limited pool of beta-cat, enhanced FOXO activity during ageing and oxidative stress may attenuate WNT-mediated activities. These observations shed new light on the pathogenesis of type 2 diabetes as an age-dependent disease.
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PMID:The WNT signalling pathway and diabetes mellitus. 1866 46

Variants in the TCF7L2 gene have been associated with type 2 diabetes mellitus (T2DM), but the causal variant(s) is still unknown. We studied the TCF7L2 messenger RNA (mRNA) expression in paired samples of visceral and subcutaneous adipose tissue from 49 subjects using quantitative real-time polymerase chain reaction and its relation to obesity and T2DM. All subjects were genotyped for the previously described TCF7L2 diabetes risk variants. Independent of age, sex, obesity, and diabetes status, we found >3-fold higher TCF7L2 mRNA expression in subcutaneous compared with visceral adipose tissue. There was no correlation between visceral and subcutaneous TCF7L2 expression. No differences in adipose tissue TCF7L2 mRNA expression levels were found between diabetic and nondiabetic subjects, or between lean and obese subjects (all Ps > .05). In addition, there was no association between TCF7L2 genetic variants and mRNA expression. Based on our data, TCF7L2 mRNA expression is fat-depot specific but does not seem to provide the mechanistic link explaining genetic association with T2DM.
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PMID:TCF7L2 gene expression in human visceral and subcutaneous adipose tissue is differentially regulated but not associated with type 2 diabetes mellitus. 1870 48

Type 2 diabetes is one of the fastest growing public health problems worldwide. Both environmental (e.g. physical activity, obesity, and diet) and genetic factors are involved in the development of type 2 diabetes. The associations between physical activity and diabetes risk have been assessed by a number of prospective studies and clinical trials. The results from these studies consistently indicate that the regular physical activity during occupation, commuting, leisure time or daily life reduces the risk of type 2 diabetes by 15-60%; and lifestyle intervention, including counselling for physical activity, nutrition, and body weight, can reduce the risk of type 2 diabetes by 40-60% among adults with impaired glucose tolerance and by about 20% among general individuals. In the past decade, studies using traditional linkage analysis and candidate-gene association approach have found dozens of genes harboring common variants that were related to the common-form type 2 diabetes. However, most reported associations are lack of reproducibility, except TCF7L2, PPARG, CAPN10, and KCNJ11. Since 2007, seven genome-wide association (GWA) studies emerged to generate a list of new diabetes genes. The genetic effects are largely of moderate size. These findings provide novel insight into the diabetes etiology and pave new avenue for predicting the disease risk using genetic information. In addition, data especially those from intervention trials display preliminary but promising evidence that the genetic variants might interact with physical activity in predisposing to type 2 diabetes. The gene-environment interactions merit extensive exploration in large, prospective studies.
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PMID:Genes, environment, and interactions in prevention of type 2 diabetes: a focus on physical activity and lifestyle changes. 1878 59

To investigate candidate genes involved in human type 2 diabetes (T2D) for obesity-related phenotypes in pigs. Statistical association analyses of genes with fat deposition were realized in a pig reference family constructed by two breeds, Berkshire and Yorkshire. Extensive sequencing was then attempted to discover the causative polymorphism. Genes implied in human T2D development, TCF7L2, WFS1, FTO, SLC30A8, and GCKR, were mapped on Sus scrofa chromosomes 14, 8, 6, 4, and 3, respectively. Only TCF7L2 was significantly associated with five fat traits in pigs. Further investigation demonstrated that one haplotype (HapB), but not the HapA (homologous to the region for human T2D susceptibility where single-nucleotide polymorphism (SNP) rs7903146 is located), is significantly associated with the fat-related traits. In HapB, two SNPs in TCF7L2 exon 8 and intron 10 are significantly associated with five fat traits, and may be in linkage disequilibrium with the causative variant with additive effects on all four backfat traits, and the total lipid percentage. Pigs of genotype TT for the SNP in exon 8 have only one transcript isoform (the one without exon 4), and lower backfat depth. Candidate gene analyses could provide novel ideas about how these genes function in T2D susceptibility in human, and support that the pig can be a suitable model for human obesity and T2D research. Further replication of this research in other pig populations should be considered, so that the possibility of utilizing these genetic markers in pig breeding or in animal model research can be explored.
Obesity (Silver Spring) 2009 Feb
PMID:Association analyses between type 2 diabetes genes and obesity traits in pigs. 1905 25

The changing social and economic conditions and the increase of the life span induced a progressive increase of the general prevalence of DMT2, particularly in the elderly population of the highly evoluted countries. Up to now 18 genetic loci have been identified, each of them consisting of several single nucleotide polymorphisms (SNPs). The evidence that the DMT2 is regulated by a high number of genes, demonstrate the pathogenetic complexity of this disease. The onset of diabetes mellitus (DM) in medium age is a consequence of the breakdown of the glycemic homeostasis in correlation with the genetic factors, such as the variants of the TCF7L2, obesity, etc., and the environmental factors, such as the life-style, the evolution of chronic-degenerative diseases, etc. In case of DM that onsets in old age we have to add the deterioration of the anti-aging defense mechanisms, characterized by the antagonistic action of the genes of longevity and aging. One can observe several clinical and therapeutic differences; therefore, the authors of this review propose the reinsertion of three forms into the DMT2 correlated with the age of onset and with the actual age of the subjects: the maturity onset diabetes (MOD), the maturity onset diabetes in elderly (MODE), and the senile diabetes (DS).
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PMID:Revision of the ADA-classification of diabetes mellitus type 2 (DMT2): the importance of maturity onset diabetes (MOD), and senile diabetes (DS). 2080 Mar

Twenty-two single-nucleotide polymorphisms (SNPs) in 10 gene regions previously identified in obesity and type 2 diabetes (T2D) genome-wide association studies (GWAS) were evaluated for association with metabolic traits in a sample from an island population of European descent. We performed a population-based study using 18 anthropometric and biochemical traits considered as continuous variables in a sample of 843 unrelated subjects (360 men and 483 women) aged 18-80 years old from the island of Hvar on the eastern Adriatic coast of Croatia. All eight GWAS SNPs in FTO were significantly associated with weight, body mass index, waist circumference and hip circumference; 20 of the 32 nominal P-values remained significant after permutation testing for multiple corrections. The strongest associations were found between the two TCF7L2 GWAS SNPs with fasting plasma glucose and HbA1c levels, all four P-values remained significant after permutation tests. Nominally significant associations were found between several SNPs and other metabolic traits; however, the significance did not hold after permutation tests. Although the sample size was modest, our study strongly replicated the association of FTO variants with obesity-related measures and TCF7L2 variants with T2D-related traits. The estimated effect sizes of these variants were larger or comparable to published studies. This is likely attributable to the homogenous genetic background of the relatively isolated study population.
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PMID:Replication of genetic variants from genome-wide association studies with metabolic traits in an island population of the Adriatic coast of Croatia. 2115 Aug 82


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