Pleiotropic effects of TCF7L2 gene variants and its modulation in the metabolic syndrome: from the LIPGENE study

Aims/hypothesis: Variants of the TCF7L2 gene predict the development of type 2 diabetes mellitus (T2DM). We investigated the associations between gene variants of TCF7L2 and clinical features of the metabolic syndrome (MetS) (an entity often preceeding T2DM), and their interaction with non-genetic factors, including plasma saturated fatty acids (SFA) concentration and insulin resistance (IR). Methods: Fasting lipid profiles, insulin sensitivity, insulin secretion, anthropometrics, blood pressure and 10 gene variations of the TCF7L2 gene were determined in 450 subjects with MetS. Results: Several single nucleotide polymorphisms (SNP) showed phenotypic associations independent of SFA or IR. Carriers of the rare T allele of rs7903146, and of three other SNPs in linkage disequilibrium with rs7903146, had lower blood pressure and insulin secretion. High IR and the presence of the T-allele of rs7903146 acted synergistically to define those with reduced insulin secretion. Carriers of the minor allele of rs290481 exhibited an altered lipid profile, with increased plasma levels of apolipoprotein B, non-esterified fatty acids, cholesterol and apolipoprotein B in triglyceride rich lipoproteins, and LDL cholesterol. Carriers of the minor allele of rs11196224 that had higher plasma SFA levels showed elevated procoagulant/proinflammatory biomarkers, impaired insulin secretion and increased IR, whereas carriers of the minor allele of rs17685538 with high plasma SFA levels exhibited higher blood pressure. Conclusions/interpretation: SNP in the TCF7L2 gene are associated with differences in insulin secretion, blood pressure, blood lipids and coagulation in MetS patients, and may be modulated by SFA in plasma or IR.

Calpain-10 interacts with plasma saturated fatty acid concentrations to influence insulin resistance in individuals with the metabolic syndrome

Background: Calpain-10 protein (intracellular Ca2+-dependent cysteine protease) may play a role in glucose metabolism, pancreatic β cell function, and regulation of thermogenesis. Several CAPN10 polymorphic sites have been studied for their potential use as risk markers for type 2 diabetes and the metabolic syndrome (MetS). Fatty acids are key metabolic regulators that may interact with genetic factors and influence glucose metabolism. Objective: The objective was to examine whether the genetic variability at the CAPN10 gene locus is associated with the degree of insulin resistance and plasma fatty acid concentrations in subjects with MetS. Design: The insulin sensitivity index, glucose effectiveness, insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)], insulin secretion (disposition index, acute insulin response, and HOMA of β cell function), plasma fatty acid composition, and 5 CAPN10 single nucleotide polymorphisms (SNPs) were determined in a cross-sectional analysis of 452 subjects with MetS participating in the LIPGENE dietary intervention cohort. Results: The rs2953171 SNP interacted with plasma total saturated fatty acid (SFA) concentrations, which were significantly associated with insulin sensitivity (P < 0.031 for fasting insulin, P < 0.028 for HOMA-IR, and P < 0.012 for glucose effectiveness). The G/G genotype was associated with lower fasting insulin concentrations, lower HOMA-IR, and higher glucose effectiveness in subjects with low SFA concentrations (below the median) than in subjects with the minor A allele (G/A and A/A). In contrast, subjects with the G/G allele with the highest SFA concentrations (above the median) had higher fasting insulin and HOMA-IR values and lower glucose effectiveness than did subjects with the A allele. Conclusion: The rs2953171 polymorphism at the CAPN10 gene locus may influence insulin sensitivity by interacting with the plasma fatty acid composition in subjects with MetS. This trial was registered at clinicaltrials.gov as NCT00429195.

A sequential two meal challenge reveals abnormalities in postprandial TAG but not glucose in men with increasing numbers of metabolic syndrome components

Objective To examine the impact of increasing numbers of metabolic syndrome (MetS) components on postprandial lipaemia. Methods Healthy men (n = 112) underwent a sequential meal postprandial investigation, in which blood samples were taken at regular intervals after a test breakfast (0 min) and lunch (330 min). Lipids and glucose were measured in the fasting sample, with triacylglycerol (TAG), non-esterified fatty acids and glucose analysed in the postprandial samples. Results Subjects were grouped according to the number of MetS components regardless of the combinations of components (0/1, 2, 3 and 4/5). As expected, there was a trend for an increase in body mass index, blood pressure, fasting TAG, glucose and insulin, and a decrease in fasting high-density lipoprotein cholesterol with increasing numbers of MetS components (P≤0.0004). A similar trend was observed for the summary measures of the postprandial TAG and glucose responses. For TAG, the area under the curve (AUC) and maximum concentration (maxC) were significantly greater in men with ≥ 3 than < 3 components (P < 0.001), whereas incremental AUC was greater in those with 3 than 0/1 and 2, and 4/5 compared with 2 components (P < 0.04). For glucose, maxC after the test breakfast (0-330 min) and total AUC (0-480 min) were higher in men with ≥ 3 than < 3 components (P≤0.001). Conclusions Our data analysis has revealed a linear trend between increasing numbers of MetS components and magnitude (AUC) of the postprandial TAG and glucose responses. Furthermore, the two meal challenge discriminated a worsening of postprandial lipaemic control in subjects with ≥ 3 MetS components.

Insulin receptor substrate-2 gene variants in subjects with metabolic syndrome: association with plasma fatty acid levels and insulin resistance

Several insulin receptor substrate-2 (IRS-2) polymorphisms have been studied in relation to insulin resistance and type 2 diabetes. To examine whether the genetic variability at the IRS-2 gene locus was associated with the degree of insulin resistance and plasma fatty acid levels in metabolic syndrome (MetS) subjects. Methods and results: Insulin sensitivity, insulin secretion, glucose effectiveness, plasma fatty acid composition and three IRS-2 tag-single nucleotide polymorphisms (SNPs) were determined in 452 MetS subjects. Among subjects with the lowest level of monounsaturated (MUFA) (below the median), the rs2289046 A/A genotype was associated with lower glucose effectiveness (p<0.038), higher fasting insulin concentrations (p<0.028) and higher HOMA IR (p<0.038) as compared to subjects carrying the minor G-allele (A/G and G/G). In contrast, among subjects with the highest level of MUFA (above the median), the A/A genotype was associated with lower fasting insulin concentrations and HOMA-IR, whereas individuals carrying the G allele and with the highest level of ω-3 polyunsaturated fatty acids (above the median) showed lower fasting insulin (p<0.01) and HOMA-IR (p<0.02) as compared with A/A subjects. Conclusion: The rs2289046 polymorphism at the IRS2 gene locus may influence insulin sensitivity by interacting with certain plasma fatty acids in MetS subjects.

Greater impairment of postprandial triacylglycerol than glucose response in metabolic syndrome subjects with fasting hyperglycaemia

Abstract Objective: Studies have started to question whether a specific component or combinations of metabolic syndrome (MetS) components may be more important in relation to cardiovascular disease risk. Our aim was to examine the impact of the presence of raised fasting glucose as a MetS component on postprandial lipaemia. Methods: Men classified with the MetS underwent a sequential test meal investigation, in which blood samples were taken at regular intervals after a test breakfast (t=0 min) and lunch (t=330 min). Lipids, glucose and insulin were measured in the fasting and postprandial samples. Results: MetS subjects with 3 or 4 components were subdivided into those without (n=34) and with (n=23) fasting hyperglycaemia (≥ 5.6 mmol/l), irrespective of the combination of components. Fasting lipids and insulin were similar in the two groups, with glucose significantly higher in the men with glucose as a MetS component (P<0.001). Following the test meals, there was a higher maximum concentration (maxC), area under the curve (AUC) and incremental AUC (P≤0.016) for the postprandial triacylglycerol (TAG) response in men with fasting hyperglycaemia. Greater glucose AUC (P<0.001) and insulin maxC (P=0.010) was also observed in these individuals after the test meals. Multivariate regression analysis revealed fasting glucose to be an important predictor of the postprandial TAG and glucose response. Conclusion: Our data analysis has revealed a greater impairment of postprandial TAG than glucose response in MetS subjects with raised fasting glucose. The worsening of postprandial lipaemic control may contribute to the greater CVD risk reported in individuals with MetS component combinations which include hyperglycaemia.

Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome

Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic Mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons oil samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. Oil the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect oil interferon regulatory factor 6 function. Genet Med 2009:11(4):241-247.

Lung ultrasound in acute respiratory distress syndrome and acute lung injury

Purpose of reviewLung ultrasound at the bedside can provide accurate information on lung status in critically ill patients with acute respiratory distress syndrome.Recent findingsLung ultrasound can replace bedside chest radiography and lung computed tomography for assessment of pleural effusion, pneumothorax, alveolar- interstitial syndrome, lung consolidation, pulmonary abscess and lung recruitment/de-recruitment. It can also accurately determine the type of lung morphology at the bedside (focal or diffuse aeration loss), and therefore it is useful for optimizing positive end-expiratory pressure. The learning curve is brief, so most intensive care physicians will be able to use it after a few weeks of training.SummaryLung ultrasound is noninvasive, easily repeatable and allows assessment of changes in lung aeration induced by the various therapies. It is among the most promising bedside techniques for monitoring patients with acute respiratory distress syndrome.

Unilateral Facial Paralysis Caused by Ramsay Hunt Syndrome

The Ramsay Hunt syndrome is a rare disease caused by an infection of the geniculate ganglion by the varicella-zoster virus. The main clinical features of the syndrome are as follows: Bell palsy unilateral or bilateral, vesicular eruptions on the ears, ear pain, dizziness, preauricular swelling, tingling, tearing, loss of taste sensation, and nystagmus. We describe a 23-year-old white woman, who presented with facial paralysis on the left side of the face, pain, fever, ear pain, and swelling in the neck and auricular region on the left side. She received appropriate treatment with acyclovir, vitamin B complex, and CMP nucleus. After 30 days after presentation, the patient did not show any signs or symptoms of the syndrome. At follow-up at 1 year, she showed no relapse of the syndrome.

Perfil da fluência da fala na síndrome de Williams-Beuren: estudo preliminar

TEMA: o padrão de fala fluente atribuído aos indivíduos com a síndrome de Williams-Beuren sustenta-se pela efetividade da alça fonológica. Alguns estudos citaram a ocorrência de disfluências decorrentes de prejuízos léxico-semânticos, entretanto, a quebra de fluência não foi bem especificada quanto ao tipo e freqüência de ocorrência. OBJETIVO: obter o perfil da fluência da fala de indivíduos com a SWB e comparar com um grupo controle pareado por gênero e idade mental semelhante. MÉTODO: foram avaliados 12 sujeitos com síndrome de Williams-Beuren a com idade cronológica entre 6,6 a 23,6 e idade mental de 4,8 a 14,3 anos que foram comparados a outros 12 sujeitos de idade mental semelhante com ausência de dificuldades de linguagem/aprendizagem. Para avaliação da fluência foi utilizado o Teste de Linguagem Infantil - ABFW, na área de fluência, que possibilitou classificar, quantificar e comparar os dois grupos quanto às tipologias e freqüência de rupturas e velocidade de fala. RESULTADOS: o grupo com a síndrome de Williams-Beuren (SWB) apresentou maior porcentagem de descontinuidade de fala e freqüência aumentada para disfluências comuns do tipo hesitação e repetição de palavras quando comparados aos indivíduos com idade mental semelhante e com desenvolvimento típico de fala e linguagem. CONCLUSÃO: O perfil da fluência da fala apresentado pelos indivíduos com a SWB neste estudo mostrou a presença de disfluências que podem ser decorrentes de prejuízo no processamento léxico-semântico e sintático da informação verbal; ressaltando-se, pois a necessidade de investigações mais sistemáticas sobre este tema.

Genética e linguagem na síndrome de Williams-Beuren: uma condição neuro-cognitiva peculiar

TEMA: aspectos genéticos, cognitivos e de linguagem na Síndrome de Williams-Beuren (SWB). OBJETIVO: revisar a literatura sobre a SWB, destacando aspectos genéticos, cognitivos e de linguagem. CONCLUSÕES: a literatura mostrou que a etiologia da SWB é conhecida, embora o diagnóstico precoce pode ser difícil pela variabilidade de manifestações clínicas dessa condição. O fenótipo variável tem sido atribuído a deleção de vários genes na região 7q11.23. que inclui o gene da elastina. A deleção desse gene é identificada pelo estudo citogenético molecular denominado Hibridização in situ por Fluorescência (FISH). A freqüência populacional desta síndrome é de 1 em 20,000 nascimentos e é resultante de uma alteração genética de novo. O quadro da SWB é caracterizado principalmente por fácies típica conhecida como face de duende, alterações cardíacas, prejuízos cognitivos e aspectos comportamentais que incluem a linguagem. A característica falante e sociável associada as dificuldades viso-construtivas conferem a esta síndrome um quadro neuro-cognitivo peculiar. A deficiência mental é variável e pode ou não estar presente. Estudos que descreveram as habilidades de linguagem nesta síndrome destacaram que a habilidade sintática pode estar íntegra ou parcialmente íntegra, a produção verbal pode ser precisa e inteligível, mostrando a integridade do sistema fonológico. O vocabulário receptivo-auditivo é citado em alguns estudos como adequado e em outros como prejudicado para a idade mental. Pesquisas na área têm produzido, resultados incongruentes com respeito ao perfil de habilidades cognitivas e lingüísticas nos portadores dessa condição. A correlação entre as habilidades de linguagem e a cognição e a divergência de achados na literatura serão abordadas neste artigo.

Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome

Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic Mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons oil samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. Oil the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect oil interferon regulatory factor 6 function. Genet Med 2009:11(4):241-247.