Health disparities between Whites and Japanese in measures of diabetes and subclinical atherosclerosis in an international population-based study

This dissertation includes three manuscripts focusing on health disparities between whites and Japanese with regard to measures of diabetes and subclinical atherosclerosis in the EBCT and Risk Factor Assessment among Japanese and U.S. Men in the Post World War II Birth Cohort (ERA JUMP) study. The first manuscript compares markers of insulin resistance and insulin secretion between white men in the United States and Japanese men in Japan, adjusting for visceral adipose tissue and other covariates. Whites had significantly higher HOMA-IR, HOMA-β%, and disposition index (DI) than Japanese in Japan. The better compensation of insulin resistance by increased insulin secretion in whites as shown by higher DI may partly explain lower susceptibility of whites to developing type 2 diabetes than Japanese in Japan at similar levels of body-mass index. The second manuscript compares progression of intima-media thickness of the carotid artery (CIMT) between middle-aged Japanese American men and white men, adjusting for baseline cardiovascular risk factors. Japanese Americans had greater progression of CIMT than whites. The third manuscript compares progression of coronary artery calcium (CAC) between Japanese American men and white men. Japanese Americans had similar progression of CAC as whites. This work contributes uniquely to public health significance. Future studies exploring reasons of poorer compensation of increasing insulin resistance by enhanced insulin secretion in Japanese in Japan may help to prevent earlier onset of type 2 diabetes in Japanese than whites at a given level of BMI. The second and third manuscripts identify increasing subclinical atherosclerosis in Japanese Americans that may translate into increased risk of CHD in Japanese Americans in the future. The second and third manuscripts identify Japanese American as a target group for prevention of CHD

Accuracy of 1-Hour Plasma Glucose During the Oral Glucose Tolerance Test in Diagnosis of Type 2 Diabetes in Adults : A Meta-analysis

OBJECTIVE One-hour plasma glucose (1-h PG) during the oral glucose tolerance test (OGTT) is an accurate predictor of type 2 diabetes. We performed a meta-analysis to determine the optimum cutoff of 1-h PG for detection of type 2 diabetes using 2-h PG as the gold standard. RESEARCH DESIGN AND METHODS We included 15 studies with 35,551 participants from multiple ethnic groups (53.8% Caucasian) and 2,705 newly detected cases of diabetes based on 2-h PG during OGTT. We excluded cases identified only by elevated fasting plasma glucose and/or HbA(1c). We determined the optimal 1-h PG threshold and its accuracy at this cutoff for detection of diabetes (2-h PG >= 11.1 mmol/L) using a mixed linear effects regression model with different weights to sensitivity/specificity (2/3, 1/2, and 1/3). RESULTS Three cutoffs of 1-h PG, at 10.6 mmol/L, 11.6 mmol/L, and 12.5 mmol/L, had sensitivities of 0.95, 0.92, and 0.87 and specificities of 0.86, 0.91, and 0.94 at weights 2/3, 1/2, and 1/3, respectively. The cutoff of 11.6 mmol/L (95% CI 10.6, 12.6) had a sensitivity of 0.92 (0.87, 0.95), specificity of 0.91 (0.88, 0.93), area under the curve 0.939 (95% confidence region for sensitivity at a given specificity: 0.904, 0.946), and a positive predictive value of 45%. CONCLUSIONS The 1-h PG of >= 11.6 mmol/L during OGTT has a good sensitivity and specificity for detecting type 2 diabetes. Prescreening with a diabetes-specific risk calculator to identify high-risk individuals is suggested to decrease the proportion of false-positive cases. Studies including other ethnic groups and assessing complication risk are warranted.Peer reviewe

Genome-Wide Association Study and Functional Characterization Identifies Candidate Genes for Insulin-Stimulated Glucose Uptake

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in \u3e55,000 participants from three ancestry groups. We identified ten new loci (P \u3c 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits

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Not AvailableCluster ensemble technique has attracted serious attention in the area of unsupervised learning. It aims at improving robustness and quality of clustering scheme, particularly in scenarios where either randomization or sampling is the part of the clustering algorithm. In this paper, we address the problem of instability and non robustness in K-means clusterings. These problems arise naturally because of random seed selection by the algorithm, order sensitivity of the algorithm and presence of noise and outliers in data. We propose a cluster ensemble method based on Discriminant Analysis to obtain robust clustering using K-means clusterer. The proposed algorithm operates in three phases. The first phase is preparatory in which multiple clustering schemes generated and the cluster correspondence is obtained. The second phase uses discriminant analysis and constructs a label matrix. In the final stage, consensus partition is generated and noise, if any, is segregated. Experimental analysis using standard public data sets provides strong empirical evidence of the high quality of resultant clustering scheme.Not Availabl

Data on alcohol consumption and coronary artery calcification among asymptomatic middle-aged men for the ERA-JUMP study

Data presented in this article are supplementary data to our primary article ‘Association of Alcohol Consumption and Aortic Calcification in Healthy Men Aged 40–49 Years for the ERA JUMP Study’ [1]. In this article, we have presented supplementary tables showing the independent association of alcohol consumption with coronary artery calcification using Tobit conditional regression and ordinal logistic regression. Keywords: Alcohol, Coronary, Atherosclerosis, Calcification, Me

Loci for insulin processing and secretion provide insight into type 2 diabetes risk

Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10$^{-8}$), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease