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 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Hum Mol Genet 2004 Apr 01
PMID:Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits. 1474 49

Epidemiological studies have revealed strong and internationally reproducible links between early growth restriction and subsequent risk of developing type 2 diabetes and the metabolic syndrome (glucose intolerance, hypertension and hypertriglyceridaemia). This effect can exist independently of genetic factors. There is also direct evidence that poor maternal nutrition and maternal smoking cause both a reduction in birthweight and subsequent loss of glucose tolerance. High rates of growth in childhood may add to these effects. The 'thrifty phenotype' hypothesis attempts to explain these associations in terms of an altered programming of growth and metabolism that aids survival both pre- and postnatally. Type 2 diabetes is envisaged as a consequence of a clash of this programming with adult obesity. Tests of this hypothesis in animal models have shown that both the metabolic syndrome and type 2 diabetes can result from early growth restriction in rats consequent upon rat dams being fed a reduced protein, isocaloric diet (in which the protein is replaced by an equal quantity of nonprotein energy). A variety of other models of early growth restriction in rats lead to a similar phenotype. Several structural and gene expression changes have been shown in many tissues, including pancreas, liver, kidney, muscle and adipose tissue. Changes in gene expression include those concerned with hormone receptors, signalling and glycolytic enzymes. Many important questions remain for future research.
Expert Rev Mol Med 2002 Dec 02
PMID:Pre- and early postnatal nongenetic determinants of type 2 diabetes. 1498 83

Investigating metabolism by unveiling the functions of the nuclear receptors peroxisome proliferator-activated receptors (PPARs) in the numerous intricate pathways ensuring energy homeostasis and fitness has been extremely rewarding. Major lines of research were initially determined by the first-characterized crucial roles of PPARalpha in fatty oxidation and of PPARgamma in adipocyte differentiation and lipid storage. Today, the molecular bases of the functional links between glucose, lipid, and protein metabolism, under the important but nonexclusive control of PPARalpha and PPARgamma, are starting to be uncovered. In addition, in the last couple of years evidence has been provided for an important role of PPARbeta (delta) in lipid metabolism. Inevitably, such actors of metabolic homeostasis are implicated in the physiopathology of complex metabolic disorders, such as those constituting the metabolic syndrome, resulting in atherosclerosis and cardiovascular diseases. This review presents a summary of the recent findings on their dual involvement in health and disease.
Mol Endocrinol 2004 Jun
PMID:Be fit or be sick: peroxisome proliferator-activated receptors are down the road. 1508 71

Protein tyrosine phosphatase 1beta (PTP-1beta) is involved in the regulation of several important physiological pathways. It regulates both insulin and leptin signaling, and interacts with the epidermal- and platelet-derived growth factor receptors. The gene is located on human chromosome 20q13, and several rare single nucleotide polymorphisms (SNPs) have been shown to be associated with insulin resistance and diabetes in different populations. As part of our ongoing investigations into the genetic basis of hypertension, we examined common sequence variants in the gene for association with hypertension, obesity and altered lipid profile in two populations of Japanese and Chinese descent. We re-sequenced all exons, selected intronic sequences and the promoter region in 24 individuals from our cohort. Fourteen SNPs were discovered, and six of these spanning 78 kb were genotyped in 1553 individuals from 672 families. All six SNPs were in linkage disequilibrium, and we found strong association of common risk haplotypes with hypertension in Chinese and Japanese (P<0.0001). In addition, individual SNPs showed association to total plasma cholesterol, LDL-cholesterol and VLDL-cholesterol levels, as well as obesity measures (body mass index). This analysis supports that PTP-1beta affects plasma lipid levels, and may lead to obesity and hypertension in Japanese and Chinese. Given similar associations found in other populations to insulin resistance and diabetes, this gene may play a crucial role in the development of the characteristic metabolic changes seen in patients with the metabolic syndrome.
Hum Mol Genet 2004 Sep 01
PMID:Single nucleotide polymorphisms in protein tyrosine phosphatase 1beta (PTPN1) are associated with essential hypertension and obesity. 1522 88

Hyperapobetalipoproteinemia is a common feature of the metabolic syndrome and could result from the interaction between genetic and dietary factors. The objective of this study was to verify whether dietary fat intake interacts with the T94A polymorphism of the liver fatty acid-binding protein (LFABP) gene to modulate plasma apolipoprotein (apo) B levels. Dietary fat and saturated fat intakes were obtained by a dietitian-administered food frequency questionnaire and the LFABP T94A genotype was determined by a PCR-RFLP based method in 623 French-Canadian men recruited through the Chicoutimi Lipid Clinic (279 T94/T94, 285 T94/A94, and 59 A94/A94). The LFABP T94A polymorphism was not associated with plasma apo B levels when fat intake was not taken into consideration. However, in a model including the polymorphism, fat intake expressed as a percentage of total energy intake, the interaction term and covariates, the variance in apo B concentrations was partly explained by the LFABP T94A polymorphism (5.24%, p = 0.01) and by the LFABP T94A*fat interaction (6.25%, p = 0.005). Results were similar when saturated fat replaced fat intake in the model (4.49%, p = 0.02 for LFABP T94A and 6.43%, p = 0.004 for the interaction). Moreover, in men consuming more than 30% of energy from fat, the odds ratio for having plasma apo B levels above 1.04 g/L for A94 carriers was of 0.40 (p = 0.02) compared to T94/T94 homozygotes. Results were similar for carriers of the A94 allele consuming more than 10% of energy from saturated fat (OR: 0.32, p = 0.005). In conclusion, T94/T94 exhibit higher apo B levels whereas carriers of the A94 allele seem to be protected against high apo B levels when consuming a high fat and saturated fat diet. These findings reinforce the importance to take into account gene-diet interactions in the prevention and management of the metabolic syndrome.
Mol Genet Metab 2004 Aug
PMID:Plasma concentrations of apolipoprotein B are modulated by a gene--diet interaction effect between the LFABP T94A polymorphism and dietary fat intake in French-Canadian men. 1530 27

The upstream stimulatory factor (USF) proteins are ubiquitously expressed and, as such, represent unusual candidates for involvement in disorders of carbohydrate and lipid metabolism. Nonetheless, a recent study has reported an association between specific alleles of USF1 and familial combined hyperlipidaemia, a common disorder that substantially increases the risk of premature atherosclerotic cardiovascular disease. USF1 might, therefore, also contribute to the metabolic syndrome. The use of chromatin immunoprecipitation methodologies combined with promoter microarray assays will help to define the transcriptional networks that underlie whole-body glucose and lipid homeostasis.
Trends Mol Med 2004 Aug
PMID:USF1 implicated in the aetiology of familial combined hyperlipidaemia and the metabolic syndrome. 1531 Apr 55

Genetic knockout and null mutations of melanocortin system components lead to phenotypes that recapitulate the metabolic syndrome such as obesity, hypertension and insulin resistance. Since stress is known to modify metabolic and cardiovascular function, we hypothesized the involvement of the neural melanocortin system in the stress response. Male rats were subjected to rapid-eye-movement sleep deprivation stress and the levels of proopiomelanocortin (POMC), MC3R, MC4R and MC5R transcripts in the hypothalamic-pituitary-adrenal axis (HPA) determined by real-time PCR. Increased levels of POMC transcripts were observed in the hypothalamus and adrenal gland tissues but there were no significant changes in the expression of the receptors genes. Whereas MC3R and MC5R are expressed in all HPA tissues, MC4R seems to be restricted mainly to the hypothalamus. It is possible that melanocortin receptors function in different aspects of the neuron. In vitro studies showed similar cellular distribution patterns for MC3R and MC4R and sequence analyses revealed strong conservation of the putative G-protein coupled receptors (GPCR) C-terminal membrane localization signal, EX(3-7)II/L motif, in MC3R, MC4R and MC5R. These data suggest that the physiological roles of neural melanocortin receptors, MC3R and MC4R, are likely determined by distinct tissue distribution patterns and suggest a role for hypothalamic and intra-adrenal melanocortin systems in the manifestation of stress related pathologies.
Cell Mol Biol (Noisy-le-grand) 2004 Sep
PMID:Neural melanocortin receptors are differentially expressed and regulated by stress in rat hypothalamic-pituitary-adrenal axis. 1564 Nov 61

The purpose of this study was to determine whether benign hereditary leukopenia-neutropenia in Yemenites may be reflective of an absent or a lesser degree of chronic low grade inflammation that has been documented to exist in most apparently healthy subjects. The white blood cell count (WBCC), fibrinogen as well as high sensitivity C-reactive protein (hs-CRP) concentrations were determined in a group of apparently healthy individuals during their routine health screening program. These inflammatory biomarkers in a group of 82 Yemenite Jews were compared to those measured in a group of 1817 individuals whose parents immigrated to Israel from Central and East Europe, from countries surrounding the Mediterranean Sea as well as the Middle East. The two study groups were matched for possible confounding factors that may have an influence on the intensity of the microinflammatory response including age, gender, body mass index, components of the metabolic syndrome and the Ten Year Calculated Coronary Heart Disease Framingham Risk Score. The expected reduced WBCC was noted in the group of Yemenite Jews (6.99 +/- 1.64 versus 5.88 +/- 2.06 x 10(3)/microL cells, P = 0.001). However, they had significantly enhanced concentrations of hs-CRP, the respective values being 2.1 +/- 2 versus 1.4 +/- 2.4 mg/L in men (P = 0.002) and 2.5 +/- 2.2 versus 1.4 +/- 2.9 in women (P < 0.0005). An increased concentration of fibrinogen was found in the Yemenite Jews, although the difference was not statistically significant in men. Thus, the leukopenia-neutropenia in Yemenite Jews is probably not an expression of an absent or lesser degree of chronic low grade inflammation. These findings shed more light on the potential mechanisms that are responsible for the low WBCC in this particular ethnic group.
Blood Cells Mol Dis
PMID:Benign hereditary leukopenia-neutropenia does not result from lack of low grade inflammation. A new look in the era of microinflammation. 1572 95

Rheumatoid arthritis (RA) associates with increased cardiovascular mortality. This appears to be predominantly due to ischaemic causes, such as myocardial infarction and congestive heart failure. The higher prevalence of cardiac ischaemia in RA is thought to be due to the accelerated development of atherosclerosis. There are two main reasons for this, which might be inter-related: the systemic inflammatory load, characteristic of RA; and the accumulation in RA of classical risk factors for coronary heart disease, which is reminiscent of the metabolic syndrome. We describe and discuss in the context of RA the involvement of local and systemic inflammatory processes in the development and rupture of atherosclerotic plaques, as well as the role of individual risk factors for coronary heart disease. We also present the challenges facing the clinical and scientific communities addressing this problem, which is receiving increasing attention.
Expert Rev Mol Med 2005 May 06
PMID:Inflammation and atherosclerosis in rheumatoid arthritis. 1587 61

Type 2 diabetes carries a 2-6-fold increased risk of cardiovascular disease (CVD) and death. Indeed, the risk of major cardiovascular events in Type 2 diabetic patients without history of coronary heart disease (CHD) is equivalent to that observed in non-diabetic subjects with CHD. However, atherosclerosis may also precede the development of diabetes, suggesting that both disorders share common genetic and environmental antecedent factors ("common soil" hypothesis). One such a possible ancestor is insulin resistance which constitutes both a major feature of Type 2 diabetes and an independent risk factor for CHD. It is well documented that inflammatory processes play an important role in the causation of atherosclerotic CVD. Inflammatory mediators play a paramount role in the initiation, progression, and rupture of atherosclerotic plaques. Thus, markers of inflammation and endothelial dysfunction may provide additional information about a patient's risk of developing CVD and may become new targets for treatment. On the other hand, evidence has emerged suggesting that inflammation is also involved in the development of Type 2 diabetes. Prospective studies have demonstrated that increased levels of pro-inflammatory markers such as CRP or reduced levels of anti-inflammatory markers such as adiponectin predict the development of Type 2 diabetes. Thus, there is accumulating evidence suggesting that inflammation is the bridging link between atherosclerosis and the metabolic syndrome. Interventions by lifestyle modification or agents with anti-inflammatory properties may reduce the risk of both conditions. Drugs exerting anti-inflammatory and vascular effects have future potential to be used within an array of interventions aimed at reducing the enormous cardiovascular burden associated with Type 2 diabetes.
Curr Mol Med 2005 May
PMID:Type 2 diabetes as an inflammatory cardiovascular disorder. 1589 50


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