Insulin Resistance is Associated with Gallstones Even in Non-obese, Non-diabetic Korean Men

It remains unclear as to whether insulin resistance alone or in the presence of well-known risk factors, such as diabetes or obesity, is associated with gallstones in men. The aim of this study was to determine whether insulin resistance is associated independently with gallstone disease in non-diabetic men, regardless of obesity. Study subjects were 19,503 Korean men, aged 30-69 yr, with fasting blood glucose level <126 mg/dL and without a documented history of diabetes. Gallbladder status was assessed via abdominal ultrasonography after overnight fast. Body mass index and waist circumference were measured. Insulin resistance was estimated by the Homeostasis Model Assessment of insulin resistance (HOMA-IR). The prevalence of obesity, abdominal obesity, and metabolic syndrome in the subjects with gallstones were higher than in those without. The prevalence of elevated HOMA (>75 percentile) in subjects with gallstones was significantly higher than in those without, and this association remained even after the obesity stratification was applied. In multiple logistic regression analyses, only age and HOMA proved to be independent predictors of gallstones. Insulin resistance was positively associated with gallstones in non-diabetic Korean men, and this occurred regardless of obesity. Gallstones appear to be a marker for insulin resistance, even in non-diabetic, non-obese men

Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity

Characteristics of Type 2 Diabetes in Terms of Insulin Resistance in Korea

The aim of this study was to assess the implications of insulin resistance on the clinical and biochemical profiles of Korean type 2 diabetic patients. 122 patients with type 2 diabetes underwent a short insulin tolerance test to assess insulin resistance. Subjects were classified in tertiles according to ISI (insulin sensitivity index), and the tertile I (the insulin-resistant group) and tertile III (the insulin-sensitive group) clinical and biochemical parameters were compared. Age, waist circumference (WC), systolic blood pressure (SBP), HbA1c, body fat content, and fasting plasma glucose were significantly higher in tertile I than tertile III (all p < 0.05). The frequency of hypertension and family history of cerebrovascular disease (CVD) were greater in tertile I than III (p < 0.05). To evaluate the factors affecting ISI, multiple regression was performed, and age, WC, SBP, HbA1c, and body fat content were found to be independently related to insulin resistance (p < 0.05). Old age, hypertension, central obesity, and poor glycemic control were identified as clinical parameters of insulin resistance in Korean type 2 diabetic patients

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c

Does vimentin help to delineate the so-called 'basal type breast cancer'?

<p>Abstract</p> <p>Background</p> <p>Vimentin is one of the cytoplasmic intermediate filament proteins which are the major component of the cytoskeleton. In our study we checked the usefulness of vimentin expression in identifying cases of breast cancer with poorer prognosis, by adding vimentin to the immunopanel consisting of basal type cytokeratins, estrogen, progesterone, and HER2 receptors.</p> <p>Methods</p> <p>179 tissue specimens of invasive operable ductal breast cancer were assessed by the use of immunohistochemistry. The median follow-up period for censored cases was 90 months.</p> <p>Results</p> <p>38 cases (21.2%) were identified as being vimentin-positive. Vimentin-positive tumours affected younger women (p = 0.024), usually lacked estrogen and progesterone receptor (p < 0.001), more often expressed basal cytokeratins (<0.001), and were high-grade cancers (p < 0.001). Survival analysis showed that vimentin did not help to delineate basal type phenotype in a triple negative (ER, PgR, HER2-negative) group. For patients with 'vimentin or CK5/6, 14, 17-positive' tumours, 5-year estimated survival rate was 78.6%, whereas for patients with 'vimentin, or CK5/6, 14, 17-negative' tumours it was 58.3% (log-rank p = 0.227).</p> <p>Conclusion</p> <p>We were not able to better delineate an immunohistochemical definition of basal type of breast cancer by adding vimentin to the immunopanel consisted of ER, PgR, HER2, CK5/6, 14 and 17 markers, when overall survival was a primary end-point.</p

Stepwise screening for diabetes identifies people with high but modifiable coronary heart disease risk. The ADDITION study

AIMS/HYPOTHESIS: The Anglo-Danish-Dutch study of intensive treatment in people with screen-detected diabetes in primary care (ADDITION) is a pragmatic randomised controlled trial of the effectiveness of intensified multi-factorial treatment on 5 year cardiovascular morbidity and mortality rates in people with screen-detected type 2 diabetes in the Netherlands, UK and Denmark. This paper describes the baseline characteristics of the study population, their estimated risk of coronary heart disease and the extent to which that risk is potentially modifiable. METHODS: Stepwise screening strategies were performed using risk questionnaires and routine general practice data plus random blood glucose, HbA(1c) and fasting blood glucose measurement. Diabetes was diagnosed using the 1999 World Health Organization criteria and estimated 10 year coronary heart disease risk was calculated using the UK Prospective Diabetes Study risk engine. RESULTS: Between April 2001 and December 2006, 3,057 people with screen-detected diabetes were recruited to the study (mean age 59.7 years, 58% men) after a stepwise screening programme involving 76,308 people screened in 334 general practices in three countries. Their median estimated 10 year risk of coronary heart disease was 11% in women (interquartile range 7-16%) and 21% (15-30%) in men. There were differences in the distribution of risk factors by country, linked to differences in approaches to screening and the extent to which risk factors had already been detected and treated. The mean HbA(1c) at recruitment was 7.0% (SD 1.6%). Of the people recruited, 73% had a blood pressure >/=140/90 and of these 58% were not on antihypertensive medication. Cholesterol levels were above 5.0 mmol/l in 70% of participants, 91% of whom were not being treated with lipid-lowering drugs. CONCLUSIONS/INTERPRETATION: People with type 2 diabetes detected by screening and included in the ADDITION study have a raised and potentially modifiable risk of CHD. ClinicalTrials.gov ID no.: NCT 00237549

Glucose-Raising Genetic Variants in MADD and ADCY5 Impair Conversion of Proinsulin to Insulin

Recent meta-analyses of genome-wide association studies revealed new genetic loci associated with fasting glycemia. For several of these loci, the mechanism of action in glucose homeostasis is unclear. The objective of the study was to establish metabolic phenotypes for these genetic variants to deliver clues to their pathomechanism.) and insulin resistance (HOMA-IR, Matsuda-Index) were assessed.. on proinsulin-to-insulin conversion. These effects may also be related to neighboring regions of the genome

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes