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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance is common and plays a central role in the pathogenesis of type 2 diabetes mellitus (T2DM). Precedents in biomedical research indicate that evaluation of monogenic syndromes can help to understand a common complex phenotype. Monogenic forms of insulin resistance, such as familial partial lipodystrophy, which results from mutations in either LMNA (encoding lamin A/C) or PPARG (encoding peroxisome proliferator-activated receptor gamma), and congenital generalized lipodystrophy, which results from mutations in either AGPAT2 (encoding 1-acylglycerol-3-phosphate O-acyltransferase) or BSCL2 (encoding seipin), can display features seen in the common metabolic syndrome. In addition, insulin resistance is seen in disorders associated with insulin receptor mutations, progeria syndromes and in inherited forms of obesity. Although insulin resistance in such rare monogenic syndromes could simply be secondary to fat redistribution and/or central obesity, the products of the causative genes might also produce insulin resistance directly, and might illuminate new causative mechanisms for insulin resistance in such common disorders as T2DM and obesity.
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PMID:Monogenic forms of insulin resistance: apertures that expose the common metabolic syndrome. 1451 35

The metabolic syndrome (MetS) is a common multiplex cluster of phenotypes strongly related to cardiovascular disease that includes central obesity with hypertension, dyslipidemia, and type 2 diabetes. The core molecular defect of the MetS is insulin resistance; indeed, the terms "MetS" and "insulin resistance syndrome" often are used interchangeably. The successful translation to clinical medicine of molecular genetic research on other rare monogenic metabolic disorders has stimulated the evaluation of such rare monogenic forms of insulin resistance as partial lipodystrophy resulting from mutations in either LMNA or PPARG genes. Careful phenotypic evaluation of carriers of monogenic insulin resistance using a range of diagnostic methods--an approach sometimes called "phenomics"--may help to find early presymptomatic biomarkers of cardiovascular disease, which, in turn, may uncover new pathways and targets for interventions for the common MetS, diabetes, and atherosclerosis.
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PMID:Phenomics, lipodystrophy, and the metabolic syndrome. 1517 63

Familial partial lipodystrophy (FPLD) results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in PPARG, encoding peroxisome proliferator-activated receptor gamma (PPARgamma). The LMNA form is called FPLD2 (MIM 151660), and the PPARG form is called FPLD3 (MIM 604367). We now report a 21-yr-old female with FPLD and no coding sequence mutations in either LMNA or PPARG. She was heterozygous for a novel A>G mutation at position -14 of intron B upstream of PPARG exon 1 within the promoter of the PPARgamma4 isoform. Her less severely affected father, who had features of the metabolic syndrome and a paucity of limb and gluteal fat, was also heterozygous for -14A>G. This mutation was absent among 600 alleles from normal Caucasians. A minimal promoter sequence bearing the mutation had significantly reduced promoter activity when used to drive reporter expression in in vitro expression in two cell lines, compared with the wild-type sequence. This is the first report of a human mutation in the promoter of a PPARgamma isoform. Because the mutation affects PPARgamma4 expression and is associated with FPLD, this implies that PPARgamma4 might be important for fat depot distribution and metabolism in vivo.
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PMID:A single-base mutation in the peroxisome proliferator-activated receptor gamma4 promoter associated with altered in vitro expression and partial lipodystrophy. 1553 25

Familial partial lipodystrophy (FPLD) is characterized by adipose tissue repartitioning with multiple metabolic disturbances, including insulin resistance and dyslipidemia. Classical FPLD results from mutations in LMNA encoding nuclear lamin A/C (FPLD2), but recently some families with partial lipodystrophy and normal LMNA sequence were found to have germline mutations in PPARgamma (FPLD3). For instance, all four affected subjects in a three-generation Canadian FPLD3 kindred ascertained based upon a clinical diagnosis of partial lipodystrophy were heterozygous for the PPARgamma F388L mutation, which altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPARgamma. The mutation was absent from normal subjects, and functional studies showed that the mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by rosiglitazone, with no evidence of a dominant-negative mechanism. Other reported FPLD3 patients with mutant PPARgamma were ascertained either directly based on a clinical diagnosis of lipodystrophy (R425C mutation), or based on insulin resistance with subsequent demonstration of lipodystrophy (V290M and P467L mutations). Compared to subjects with mutant LMNA, lipodystrophic subjects with mutant PPARgamma had less severe adipose involvement, together with more severe clinical and biochemical manifestations of insulin resistance, and more variable response to treatment with thiazolidinediones. Thus, rare natural mutations affecting PPARgamma ligand binding and/or transactivation functions cause partial lipodystrophy, with associated components that resemble the metabolic syndrome.
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PMID:Lessons from human mutations in PPARgamma. 1571 81

The metabolic syndrome (MetS) is a common phenotype that is clinically defined by threshold values applied to measures of central obesity, dysglycemia, dyslipidemia, and/or elevated blood pressure, which must be present concurrently in any one of a variety of combinations. Insulin resistance, although not a defining component of the MetS, is nonetheless considered to be a core feature. MetS is important because it is rapidly growing in prevalence and is strongly related to the development of cardiovascular disease. To define etiology, pathogenesis and expression of MetS, we have studied patients, specifically Canadian families and communities. One example is familial partial lipodystrophy (FPLD), a rare monogenic form of insulin resistance caused by mutations in either LMNA, encoding nuclear lamin A/C (subtype FPLD2), or in PPARG, encoding peroxisomal proliferator-activated receptor-gamma (subtype FPLD3). Because it evolves slowly and recapitulates key clinical and biochemical attributes, FPLD seems to be a useful monogenic model of MetS. A second example is the disparate MetS prevalence between two Canadian aboriginal groups that is mirrored by disparate prevalence of diabetes and cardiovascular disease. Careful phenotypic evaluation of such special cases of human MetS by using a wide range of diagnostic methods, an approach called "phenomics," may help uncover early presymptomatic disease biomarkers, which in turn might reveal new pathways and targets for interventions for MetS, diabetes, and atherosclerosis.
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PMID:Genetic and physiological insights into the metabolic syndrome. 1589 Jul 90

Laminopathies are a group of diseases due to mutations of type A-lamins, a group of proteins lining the inner aspect of cell nuclei. These diseases illustrate the complexity of the genotype-phenotype relationship characteristic of same genetic diseases. Since the discovery of the causal role of LMNA gene mutations in the genesis of Emery Dreifuss muscular dystrophy in 1999, no less than eight other diseases have been associated with mutations of this same gene! The tissue-specific nature of the clinical manifestations, contrasting with the ubiquitous expression of these proteins, has incited much research concerning the physiological role of lamins, considered to be much broader than the structural function initially put forward. Certain laminopathies, which combine insulin resistance, android distribution of adipose tissue, dyslipidemia, early atherosclerosis, and hepatic steatosis, appear very similar though more severe to the frequent dysmetabolism syndrome. The relationships of laminopathies with accelerated aging syndrome, Hutchinson-Gilford progeria, or progeroid syndromes, which are also related to A/C lamin anomalies, could provide new avenues of research on the pathogenesis of the metabolic syndrome. In addition, clinicians have to be aware of atypical and milder forms of laminopathies, that require specific investigations and molecular screening of relatives allowing an adequate medical management.
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PMID:[Laminopathies: lipodystrophies, insulin resistance, syndromes of accelerated ageing... and others]. 1598 90

Human lipodystrophies represent a group of diseases characterized by altered body fat amount and/or repartition and major metabolic alterations with insulin resistance leading to diabetic complications and increased cardiovascular and hepatic risk. Genetic forms of lipodystrophies are rare. Congenital generalized lipodystrophy or Berardinelli-Seip syndrome, autosomal recessive, is characterized by a complete early lipoatrophy and severe insulin resistance and results, in most cases, from mutations either in the seipin gene of unknown function or AGPAT2 encoding an enzyme involved in triacylglycerol synthesis. The Dunnigan syndrome [FPLD2 (familial partial lipodystrophy of the Dunnigan type)] is due to mutations in LMNA encoding the lamin A/C, belonging to the complex group of laminopathies that could comprise muscular and cardiac dystrophies, neuropathies and syndromes of premature aging. Some FPLDs are linked to loss-of-function mutations in the PPAR-gamma gene (peroxisome-proliferator-activated receptor gamma; FPLD3) with severe metabolic alterations but a less severe lipodystrophy compared with FPLD2. The metabolic syndrome, acquired, represents the most common form of lipodystrophy. HIV-infected patients often present lipodystrophies, mainly related to side effects of antiretroviral drugs together with insulin resistance and metabolic alterations. Such syndromes help to understand the mechanisms involved in insulin resistance resulting from altered fat repartition and could benefit from insulin-sensitizing effects of lifestyle modifications or of specific medications.
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PMID:Diseases of adipose tissue: genetic and acquired lipodystrophies. 1624 48

Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001).
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PMID:Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes: association analyses in 9,518 subjects. 1732 60

Mutations in the LMNA gene, encoding the nuclear envelope protein lamin A/C, are responsible for a number of distinct disease entities including Dunnigan-type familial partial lipodystrophy. Dunningan-type lipodystrophy is characterized by loss of subcutaneous adipose tissue, insulin resistance, dyslipidemia, and type 2 diabetes and shares many of the features of the metabolic syndrome. Furthermore, several genome-wide linkage scans for type 2 diabetes have found evidence of linkage at chromosome 1q21.2, the region that harbors the LMNA gene. Therefore, LMNA is a biological and positional candidate for type 2 diabetes susceptibility. Previous studies have reported association between a common LMNA variant (1908C>T; rs4641) and adverse metabolic traits in ethnically diverse populations from Asia and North America. In the present study, we characterized the common variation across the LMNA gene (including rs4641) and tested for association with type 2 diabetes in two large case-control studies (n = 2,052) and with features of the metabolic syndrome in a separate cohort study (n = 1,572). Despite our study being sufficiently powered to detect effects similar and even smaller in magnitude than those previously reported, none of the LMNA single nucleotide polymorphisms were statistically significantly associated with type 2 diabetes or the metabolic syndrome. Thus, it appears unlikely that variation at LMNA substantially increases the risk of type 2 diabetes or related traits in U.K. Europids.
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PMID:Lamin A/C polymorphisms, type 2 diabetes, and the metabolic syndrome: case-control and quantitative trait studies. 1732 61

Systematic correlation of phenotype with genotype is a key goal of the emerging field of phenomics, which is expected to help define complex diseases. Careful evaluation of phenotype-genotype associations in monogenic disorders, such as laminopathies, might provide new hypotheses to be tested with molecular and cellular studies and might also suggest potential new intervention strategies. For instance, evaluation of the clinical features of carriers of mutant LMNA in kindreds with familial partial lipodystrophy suggests rational, staged intervention using established pharmaceutical agents to prevent cardiovascular complications not just for patients with lipodystrophy but by extension for patients with the common metabolic syndrome. Careful non-invasive imaging shows phenotypic differences between partial lipodystrophy due to mutant LMNA and not due to mutant LMNA. Furthermore, hierarchical cluster analysis detects systematic relationships between organ involvement in laminopathies and mutation position in the LMNA genomic sequence. However, sometimes the same LMNA mutation can underlie markedly different clinical phenotypes; cellular and molecular experiments can help to explain the mechanistic basis for such differences. Finally, promising novel treatment modalities for laminopathies, such as farnesyl transferase inhibition and gene-based therapies, might help not only to illuminate mechanisms that link genotype to phenotype, but also to provide hope for patients suffering with laminopathies, since these treatments are designed to modulate key early or proximal steps in the pathogenesis of these disorders.
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PMID:Phenomics and lamins: from disease to therapy. 1746 74


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