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

Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy. We have examined restriction fragment length polymorphisms (RFLPs) near "candidate diabetogenic genes" as one approach to identify molecular markers for GDM genes. Genotypes for insulin hypervariable region (HVR), insulin-like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity. Logistic regression analysis was used to explore the relationship between genotypes at these candidate gene loci and GDM, while adjusting for the effects of potential confounding variables. Among black subjects, the INSR allele 1 (P = 0.001) and interactions between INSR allele 1 with body mass index (BMI) (P = 0.002) and history of DM in subject's mother (P = 0.004) contributed significantly to GDM risk. Among Caucasian subjects, a similar relationship between the INSR allele 1 (P = 0.007) and INSR allele 1-BMI interactions (P = 0.011) on GDM risk were observed. In Caucasians, an additional significant risk factor was determined by an INSR allele 1-IGF2 allele 2 interaction (P = 0.018). No risk factors were identified in Hispanic subjects. These data continue to support the hypothesis that GDM is a heterogeneous disorder with respect to phenotypic and genotypic features. Furthermore, our data suggest that risk for GDM in black and Caucasian subjects is not due to obesity perse but to interactions between obesity and INSR alleles. In Caucasian women, INSR and IGF2 alleles interact to confer additional risk for GDM. Thus genes underlying susceptibility to GDM in some women may be similar to genes conferring risk to NIDDM, while in others novel genes may contribute to GDM risk.
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PMID:Increased risk for gestational diabetes mellitus associated with insulin receptor and insulin-like growth factor II restriction fragment length polymorphisms. 257 27

Insulin-like growth factor II (IGF-II) plays a key role in mammalian growth, influencing foetal cell division and differentiation and possibly metabolic regulation. The mature 67 amino acid peptide shares sequence homology with both insulin and IGF-I. The liver is the main endocrine source of IGFs, but autocrine/paracrine activity is found in most tissues. The type 1 receptor mediates most of the biological effects of IGF-I and IGF-II; the type 2 receptor is involved with IGF-II degradation. Binding proteins may both localise IGFs to the receptors and regulate their activities. The IGF2 gene is maternally imprinted in mouse and human. Relaxation of IGF2 imprinting occurs in the Beckwith-Wiedemann syndrome of somatic overgrowth, sporadic Wilms' tumour and a number of other cancers. In the general adult population, the IGF2-INS gene cluster may also influence body weight, in which case IGF-II function could become a target for therapeutic intervention in obesity.
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PMID:Insulin-like growth factor II (IGF-II). 972 81

The subtelomeric region of 11p harbours three closely linked genes, TH, INS and IGF2, that have been associated with obesity, size at birth, type I diabetes, polycystic ovary syndrome, overgrowth in Beckwith-Wiedemann syndrome and possibly hypertension. We have previously shown that the IGF2 ApaI single nucleotide polymorphism (SNP) associates with weight and body mass index in middle-aged Caucasian males but that there is no such association with the INS -23/ HphI site that marks INS 5' variable number of tandem repeats (VNTR) class I vs class III VNTR alleles. We report here the examination of three SNP markers in IGF2: 6815 A/T in the P1 promoter, AluI in exon 3 and ApaI in the 3' untranslated region (UTR), INS 5'VNTR class I alleles and the TH01 tetranucleotide microsatellite in a population sample. The analysis has taken into account the possibility that typing failure and the number of parameters required to model multiallelic loci could create spurious significance. We have exercised Hardy-Weinberg equilibrium tests, dichotomised multiallelic series to impose parsimony, and examined the data with failures modelled or excluded. Regression analysis infers that three markers, IGF2 ApaI, TH01 and subclasses of INS VNTR class I independently predict derived weight indices (combined P<10(-8) and accounting up to 2% of population weight variance), with no evidence of interaction. This establishes that there must be multiple causal sites impacting on weight in this genomic region.
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PMID:Evidence of multiple causal sites affecting weight in the IGF2-INS-TH region of human chromosome 11. 1193 24

We studied a previously reported association between the IGF2 gene's ApaI polymorphism and obesity in 500 healthy men and women (19-90 y). We hypothesized that individuals homozygous for the IGF2 A allele (A/A) would exhibit lower body mass, BMI and DEXA-measured fat mass compared to G/G homozygotes. Subjects were categorized as exhibiting the G/G (n = 241), G/A (n = 197) or A/A (n = 62) genotype. Contrary to our hypothesis, no difference was observed in body mass, body mass index (BMI) or fat mass between the G/G and A/A genotype groups in the entire cohort. Surprisingly, Caucasian A/A individuals (n = 427) exhibited significantly higher fat mass compared to Caucasian G/G individuals (P < 0.05). In summary, individuals homozygous for the IGF2 G allele do not exhibit higher body mass, BMI or fat mass compared to A/A individuals; however, Caucasians with the A/A genotype exhibit higher fat mass than G/G individuals.
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PMID:IGF2 genotype and obesity in men and women across the adult age span. 1207 89

The IGF2-INS-TH genomic region has been implicated in various common disorders including the metabolic syndrome, type 2 diabetes and coronary heart disease (CHD). Here we present detailed haplotype analysis of 2743 males 51-62 years old in relation to body weight and composition, blood pressure (BP) and plasma triglycerides (TG). Use of the total data set was complicated by the number of loci typed, missing data, multi-allelic markers and continuous trait phenotypes. Different algorithms and subsets of the data were analysed using the programmes haplotype trend regression, haplo.score, evolutionary-based haplotype analysis package and Phase, in conjunction with SPSS. Ten haplotypes designated in frequency order *1(20.0%) to *10(3.4%) represented 89% of all haplotypes. Haplotype *5 protected against obesity. Haplotype *4 carriers exhibited elevated BP and fat mass, haplotype *6 was associated with raised plasma TG levels. Haplotype *8 also showed similar magnitude effects as *4. These cohort trait analyses and detailed haplotypic analyses enable integration with published case data. Haplotypes *4, *6 and *8 are the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displays unique features in all three genes (with significant commonality with type 1 diabetes-predisposition haplotypes). We propose that long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, predisposes to the metabolic syndrome features of elevated BP, fat mass or TG level, therefore appearing more frequently in type 2 diabetic, polycystic ovary syndrome and CHD cases. The functional element(s) of *5 for weight-lowering could reside in any of the three genes.
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PMID:Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits. 1474 49

We have evaluated the possible association of polycystic ovary syndrome (PCOS) with 15 genomic variants previously described to influence insulin resistance, obesity, and/or type 2 diabetes mellitus. Seventy-two PCOS patients and 42 healthy controls were genotyped for 15 variants in the genes encoding for paraoxonase (three variants), plasma cell differentiation antigen glycoprotein, human sorbin and SH3 domain containing 1, plasminogen activator inhibitor-1, peroxisome proliferator-activated receptor-gamma2, protein tyrosine phosphatase 1B (two variants), adiponectin (two variants), IGF1, IGF2, IGF1 receptor, and IGF2 receptor. Compared with controls, PCOS patients were more frequently homozygous for the -108T variant in paraoxonase (36.6% vs. 9.5%; P = 0.002) and homozygous for G alleles of the ApaI variant in IGF2 (62.9% vs. 38.1%; P = 0.018). Paraoxonase is a serum antioxidant enzyme and, because -108T alleles result in decreased paraoxonase expression, this increase in oxidative stress might result in insulin resistance. G alleles of the ApaI variant in IGF2 may increase IGF2 expression, and IGF2 stimulates adrenal and ovarian androgen secretion. In conclusion, the paraoxonase -108 C-->T variant and the ApaI polymorphism in the IGF2 gene are associated with PCOS and might contribute to increased oxidative stress, insulin resistance, and hyperandrogenism in this prevalent disorder.
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PMID:Association of the polycystic ovary syndrome with genomic variants related to insulin resistance, type 2 diabetes mellitus, and obesity. 1518 Oct 35

Insulin-like growth factor II (IGF-II) is a polypeptide that plays a key role in mammalian growth, influencing fetal cell division, differentiation, and possibly metabolic regulation. In adult humans, polymorphisms of the IGF2 gene have been associated with predisposition to obesity. In the present study, we tested the association between IGF2/ApaI genotype and Body Mass Index (BMI) in 294 healthy volunteers (95 men and 199 women; 18-30y) and correlated the results with their birth weights (BW) in order to investigate the relationship between this polymorphic site, fetal life and adult BMI. Blood samples were obtained for DNA extraction, PCR and genotyping. The statistical analyses were performed by the Chi-square, Kolmogorov-Smirnov normality, and Tukey post hoc tests. Although the IGF2 genotype was not significantly associated with BMI and/or BW, we observed a statistically significant correlation of 0.33 (p < 0.023) between BW and BMI in GG subjects whose BW was higher than 3.5 kg (n = 47). We hypothesize that high BWs associated with homozygosis for the G allele of IGF2/ApaI is not a null factor and might be associated with predisposition to high BMI in young adults.
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PMID:Association between birth weight, body mass index and IGF2/ApaI polymorphism. 1610 92

Interindividual variation of the IGF2-INS-TH region influences risk of a variety of diseases and complex traits. Previous studies identified a haplotype (designated IGF2-INS-TH(*)5 and tagged by allele A of IGF2 ApaI, allele 9 of TH01 and class I alleles of INS VNTR) associated with low body mass index (BMI) in a cohort of UK men. We aimed here both to study whether previous findings relating (*)5 with weight are replicated in a different cohort of men (East Hertfordshire) characterised in more phenotypic detail and to test the effect of this haplotype on related subphenotypes. The PHASE program was used to identify (*)5 and not(*)5 haplotypes. A total of 490 haplotypes were derived from 131 men and 114 women, the frequency of (*)5 being around 9%. Specific tests of (*)5 haplotype (vs not(*)5 haplotypes) conducted included Student's t-test and multiple regression analyses. We observed replication of weight effect for the (*)5 haplotype in men: significant associations with lower BMI (-1.81 kg/m(2), P=0.009), lower waist circumference (-6.3 cm, P=0.001) and lower waist-hip ratio (-5%, P<0.001). This haplotype also marks nearly two-fold lower 120 min insulin (P=0.004) as well as low baseline insulin (-11.02 pmol/l, P=0.043) and low 30 min insulin (-64.44 pmol/l, P=0.072) in a glucose tolerance test. No association between (*)5 and these traits was found in women. Our results, taken together with other data on IGFII levels and TH activity, point to the importance of (*)5 as an integrated polygenic haplotype relevant to obesity and insulin response to glucose in men.
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PMID:Replication of IGF2-INS-TH*5 haplotype effect on obesity in older men and study of related phenotypes. 1625 97

Understanding the molecular mechanisms underlying fatty liver disease (FLD) in humans is of major importance. We used high-density oligonucleotide microarrays (22.3 K) to assess the mechanisms responsible for the development of human liver steatosis. We compared global gene expression in normal (n=9) and steatotic (n=9) livers without histological signs of inflammation or fibrosis. A total of 34 additional human samples including normal (n=11), steatosis (n=11), HCV-related steatosis (n=4) or steatohepatitis associated with alcohol consumption (n=4) or obesity (n=4) were used for immunohistochemistry or quantitative real-time PCR studies. With unsupervised classification (no gene selection), all steatotic liver samples clustered together. Using step-down maxT multiple testing procedure for controlling the Family-Wise Error-Rate at level 5%, 110 cDNAs (100 over- and 10 underexpressed) were found to be differentially expressed in steatotic and normal livers. Of them were genes involved in mitochondrial phosphorylative and oxidative metabolism. The mean ratio of mitochondrial DNA to nuclear DNA content was higher in liver steatosis compared to normal liver biopsies (1.12+/-0.14 vs 0.67+/-0.10; P=0.01). An increased expression of genes involved in inflammation (IL-1R family, TGFB) was also observed and confirmed by quantitative RT-PCR or immunochemistry. In steatohepatitis, an increase of the protein expression of mitochondrial antigens, IL-1R1, IGF2 and TGFB1 was also observed, interleukin 1 receptor being always strongly expressed in steatohepatitis linked to alcohol or obesity. In conclusion, mitochondrial alterations play a major role in the development of steatosis per se. Activation of inflammatory pathways is present at a very early stage of steatosis, even if no morphological sign of inflammation is observed.
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PMID:Exploration of global gene expression in human liver steatosis by high-density oligonucleotide microarray. 1634 56

Overexpression of fatty acid synthase (FASN), a key enzyme for de novo lipogenesis, is observed in many cancers including colorectal cancer and is associated with poor clinical outcomes. Cellular FASN expression is physiologically upregulated in a state of energy excess. Obesity and excess energy balance have been known to be risk factors for colorectal cancer. High degree of microsatellite instability (MSI-H) is a distinct phenotype in colorectal cancer, associated with CpG island methylator phenotype (CIMP). Previous data suggest that obesity or altered energy balance may potentially modify risks for MSI-H cancers and microsatellite stable (MSS) cancers differently. However, the relationship between MSI and FASN overexpression has not been investigated. Using 976 cases of population-based colorectal cancer samples from 2 large prospective cohort studies, we correlated FASN expression (by immunohistochemistry) with MSI, KRAS and BRAF mutations, p53 expression (by immunohistochemistry), and CIMP status [determined by MethyLight for 8 CIMP-specific gene promoters including CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1]. Marked (2+) FASN overexpression was observed in 110 (11%) of the 976 tumors and was significantly more common in MSI-H tumors (21% [28/135]) than MSI-low (5.6% [4/72], P = .004) and MSS tumors (11% [72/678], P = .001). The association between FASN overexpression and MSI-H persisted even after stratification by CIMP status. In contrast, FASN overexpression was not correlated with CIMP after stratification by MSI status. Fatty acid synthase overexpression was not significantly correlated with sex, tumor location, p53, or KRAS/BRAF status. In conclusion, FASN overexpression in colorectal cancer is associated with MSI-H, independent of CIMP status.
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PMID:Fatty acid synthase overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype. 1735 Jun 69


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