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)

Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.
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PMID:A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. 2495 67

Human geneticists are currently in the middle of a race. Thanks to a new technology in the form of 'genome-wide chips', investigators can potentially find many novel disease genes in one large experiment. Type 2 diabetes has been hot out of the blocks with six recent publications that together provide convincing evidence for six new gene regions involved in the condition. Together with candidate approaches, these studies have identified 11 confirmed genomic regions that alter the risk of type 2 diabetes in the European population. One of these regions, the fat mass and obesity associated gene (FTO), represents by far the best example of an association between common variation and fat mass in the general population.
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PMID:Genome-wide association studies provide new insights into type 2 diabetes aetiology. 1770 36

Until recently, progress in identification of the genetic variants influencing predisposition to common forms of diabetes and obesity has been slow, a sharp contrast to the large number of genes implicated in rare monogenic forms of both conditions. Recent advances have transformed the situation, however, enabling researchers to undertake well-powered scans able to detect association signals across the entire genome. For type 2 diabetes, the six high-density genome-wide association studies so far performed have extended the number of loci harboring common variants implicated in diabetes susceptibility into double figures. One of these loci, mapping to the fat mass and obesity associated gene (FTO), influences diabetes risk through a primary effect on fat mass, making this the first common variant known to influence weight and individual risk of obesity. These findings offer two main avenues for clinical translation. First, the identification of new pathways involved in disease predisposition-for example, those influencing zinc transport and pancreatic islet regeneration in the case of type 2 diabetes-offers opportunities for development of novel therapeutic and preventative approaches. Second, with continuing efforts to identify additional genetic variants, it may become possible to use patterns of predisposition to tailor individual management of these conditions.
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PMID:Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity. 1821 65

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

Recent studies indicate that obesity may play a key role in modulating genetic predispositions to type 2 diabetes (T2D). This study examines the main effects of both single-locus and multilocus interactions among genetic variants in Taiwanese obese and nonobese individuals to test the hypothesis that obesity-related genes may contribute to the etiology of T2D independently and/or through such complex interactions. We genotyped 11 single nucleotide polymorphisms for 10 obesity candidate genes including adrenergic beta-2-receptor surface, adrenergic beta-3-receptor surface, angiotensinogen, fat mass and obesity associated gene, guanine nucleotide binding protein beta polypeptide 3 (GNB3), interleukin 6 receptor, proprotein convertase subtilisin/kexin type 1 (PCSK1), uncoupling protein 1, uncoupling protein 2, and uncoupling protein 3. There were 389 patients diagnosed with T2D and 186 age- and sex-matched controls. Single-locus analyses showed significant main effects of the GNB3 and PCSK1 genes on the risk of T2D among the nonobese group (p = 0.002 and 0.047, respectively). Further, interactions involving GNB3 and PCSK1 were suggested among the nonobese population using the generalized multifactor dimensionality reduction method (p = 0.001). In addition, interactions among angiotensinogen, fat mass and obesity associated gene, GNB3, and uncoupling protein 3 genes were found in a significant four-locus generalized multifactor dimensionality reduction model among the obese population (p = 0.001). The results suggest that the single nucleotide polymorphisms from the obesity candidate genes may contribute to the risk of T2D independently and/or in an interactive manner according to the presence or absence of obesity.
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PMID:Gene-gene interactions among genetic variants from obesity candidate genes for nonobese and obese populations in type 2 diabetes. 1959 64

The heritability of obesity and body weight in general is high. A small number of confirmed monogenic forms of obesity-the respective mutations are sufficient by themselves to cause the condition in food abundant societies-have been identified by molecular genetic studies. The elucidation of these genes, mostly based on animal and family studies, has led to the identification of important pathways to the disorder and thus to a deeper understanding of the regulation of body weight. The identification of inborn deficiency of the mostly adipocyte-derived satiety hormone leptin in extremely obese children from consanguineous families paved the way to the first pharmacological therapy for obesity based on a molecular genetic finding. The genetic predisposition to obesity for most individuals, however, has a polygenic basis. A polygenic variant by itself has a small effect on the phenotype; only in combination with other predisposing variants does a sizeable phenotypic effect arise. Common variants in the first intron of the 'fat mass and obesity associated' gene (FTO) result in an elevated body mass index (BMI) equivalent to approximately +0.4 kg/m(2) per risk allele. The FTO variants were originally detected in a genome wide association study (GWAS) pertaining to type 2 diabetes mellitus. Large meta-analyses of GWAS have subsequently identified additional polygenic variants. Up to December 2009, polygenic variants have been confirmed in a total of 17 independent genomic regions. Further study of genetic effects on human body weight regulation should detect variants that will explain a larger proportion of the heritability. The development of new strategies for diagnosis, treatment and prevention of obesity can be anticipated.
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PMID:From monogenic to polygenic obesity: recent advances. 2012 79

Common variants in the fat mass and obesity associated (FTO) gene are associated with obesity and type 2 diabetes. Fto-deficient mice develop hepatic insulin resistance, leading to the hypothesis that hepatic Fto plays a role in the regulation of glucose metabolism and that hepatic Fto expression is regulated by metabolic states. We found that hepatic Fto mRNA levels were increased by fasting in mice. Intraperitoneal glucose injection reduced hepatic Fto mRNA levels without significant changes in body weight in fasted mice. The inverse correlation between Fto mRNA and glucose remained significant after adjusting for body weight. There were positive correlations between hepatic Fto mRNA expression and gluconeogenic gene expression. These data support the hypothesis that hepatic Fto expression changes in response to metabolic states and glucose reduces hepatic Fto mRNA expression independently of body weight. Hepatic Fto may participate in the feedback regulation of glucose metabolism via gluconeogenesis.
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PMID:Relationship between blood glucose levels and hepatic Fto mRNA expression in mice. 2081 34

Recent genome-wide association studies have showed that common variant (rs9939609) in fat mass and obesity associated (FTO) gene was significantly associated with type 2 diabetes through an effect on human body mass index/obesity. Further studies have suggested that this variant was also involved in the development of metabolic syndrome (MetS). However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association between rs9939609 polymorphism and the risk of MetS. Published literature from PubMed, EMBASE and other databases were searched. All studies assessing the association between rs9939609 polymorphism and the risk of MetS were identified. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed-effects model. Thirteen studies (8,370 cases and 23,156 controls) using NCEP ATPIII criteria for MetS were pooled with a meta-analysis. The overall result showed that there was a statistically significant association between rs9939609 polymorphism and MetS risk (OR = 1.11, 95% CI = 1.06-1.17). Subgroup analysis based on ethnicity showed that effect size was only statistically significant in Europeans (OR = 1.11, 95% CI = 1.05-1.16). Eight studies (1,256 cases and 2,551 controls) using IDF criteria for MetS were pooled with a meta-analysis. The overall analysis suggested that rs9939609 polymorphism was significantly associated with MetS risk (OR = 1.32, 95% CI = 1.13-1.54). Subgroup analysis stratified by ethnicity suggested that effect size was only statistically significant in Asians (OR = 1.33, 95% CI = 1.10-1.61). Our results suggested that FTO rs9939609 polymorphism was significantly associated with the increased risk of MetS in European and Asian populations. Mechanistic investigation is also needed to clarify the effect of FTO gene in the predisposition to MetS.
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PMID:Common variant (rs9939609) in the FTO gene is associated with metabolic syndrome. 2231 Oct 15

The prevalence of childhood obesity is increasing in many countries and confers risks for early type 2 diabetes, cardiovascular disease and metabolic syndrome. In the presence of potent 'obesogenic' environments not all children become obese, indicating the presence of susceptibility and resistance. Taking an energy balance approach, susceptibility could be mediated through a failure of appetite regulation leading to increased energy intake or via diminished energy expenditure. Evidence shows that heritability estimates for BMI and body fat are paralleled by similar coefficients for energy intake and preferences for dietary fat. Twin studies implicate weak satiety and enhanced food responsiveness as factors determining an increase in BMI. Single gene mutations, for example in the leptin receptor gene, that lead to extreme obesity appear to operate through appetite regulating mechanisms and the phenotypic response involves overconsumption and a failure to inhibit eating. Investigations of robustly characterized common gene variants of fat mass and obesity associated (FTO), peroxisome proliferator-activated receptor (PPARG) and melanocortin 4 receptor (MC4R) which contribute to variance in BMI also influence the variance in appetite factors such as measured energy intake, satiety responsiveness and the intake of palatable energy-dense food. A review of the evidence suggests that susceptibility to childhood obesity involving specific allelic variants of certain genes is mediated primarily through food consumption (appetite regulation) rather than through a decrease in activity-related energy expenditure. This conclusion has implications for early detection of susceptibility, and for prevention and management of childhood obesity.
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PMID:Obesity and eating behaviour in children and adolescents: contribution of common gene polymorphisms. 2272 41

Treatment with several antipsychotic drugs can result in weight gain, which may lead to further morbidity such as type 2 diabetes and cardiovascular disease via the development of metabolic syndrome. These important and problematic metabolic consequences of antipsychotic drug treatment probably reflect a pharmacological disruption of the mechanisms involved in control of food intake and body weight. The extent of weight gain following antipsychotic drug treatment shows substantial variability between individuals, due in part to genetic factors. Common functional polymorphisms in many candidate genes implicated in the control of body weight and various aspects of energy and lipid metabolism have been investigated for association with weight gain in subjects receiving antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia. Perhaps the strongest and most replicated findings are the associations with promoter polymorphisms in the 5-HT2C receptor and leptin genes, although many other possible genetic risk factors, including polymorphisms in the fat mass and obesity associated (FTO) gene and genes for the alpha2A adrenoceptor and melanocortin4 receptor, have been reported. Genome-wide association studies (GWAS) have also addressed antipsychotic-induced weight gain and other indicators of metabolic disturbances. However there is as yet little consistency between these studies or between GWAS and classical candidate gene approaches. Identifying common genetic factors associated with drug-induced weight gain and its metabolic consequences may provide opportunities for personalized medicine in the predictive assessment of metabolic risk as well as indicating underlying physiological mechanisms.
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PMID:Pharmacogenetic Aspects of Antipsychotic Drug-induced Weight Gain - A Critical Review. 2343 Oct 82


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