Current Issue : October - December Volume : 2011 Issue Number : 1 Articles : 9 Articles
Background\nWe present a potentially useful alternative approach based on support vector machine (SVM) techniques to classify persons with and without common diseases. We illustrate the method to detect persons with diabetes and pre-diabetes in a cross-sectional representative sample of the U.S. population.\n \nMethods\nWe used data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to develop and validate SVM models for two classification schemes: Classification Scheme I (diagnosed or undiagnosed diabetes vs. pre-diabetes or no diabetes) and Classification Scheme II (undiagnosed diabetes or pre-diabetes vs. no diabetes). The SVM models were used to select sets of variables that would yield the best classification of individuals into these diabetes categories.\n \nResults\nFor Classification Scheme I, the set of diabetes-related variables with the best classification performance included family history, age, race and ethnicity, weight, height, waist circumference, body mass index (BMI), and hypertension. For Classification Scheme II, two additional variables--sex and physical activity--were included. The discriminative abilities of the SVM models for Classification Schemes I and II, according to the area under the receiver operating characteristic (ROC) curve, were 83.5% and 73.2%, respectively. The web-based tool-Diabetes Classifier was developed to demonstrate a user-friendly application that allows for individual or group assessment with a configurable, user-defined threshold.\n \nConclusions\nSupport vector machine modeling is a promising classification approach for detecting persons with common diseases such as diabetes and pre-diabetes in the population. This approach should be further explored in other complex diseases using common variables....
Background\nPatients with diabetes mellitus (DM) have high risk of heart failure. Whether some of the risk is directly linked to metabolic derangements in the myocardium or whether the risk is primarily caused by coronary artery disease (CAD) and hypertension is incompletely understood. Echocardiographic tissue Doppler imaging was therefore performed in DM patients without significant CAD to examine whether DM per se influenced cardiac function.\n \nMethods\nPatients with a left ventricular (LV) ejection fraction (EF) > 35% and without significant CAD, prior myocardial infarction, cardiac pacemaker, atrial fibrillation, or significant valve disease were identified from a tertiary invasive center register. DM patients were matched with controls on age, gender and presence of hypertension.\n \nResults\nIn total 31 patients with diabetes and 31 controls were included. Mean age was 58 �± 12 years, mean LVEF was 51 �± 7%, and 48% were women. No significant differences were found in LVEF, left atrial end systolic volume, or left ventricular dimensions. The global longitudinal strain was significantly reduced in patients with DM (15.9 �± 2.9 vs. 17.7 �± 2.9, p = 0.03), as were peak longitudinal systolic (S') and early diastolic (E') velocities (5.7 �± 1.1 vs. 6.4 �± 1.1 cm/s, p = 0.02 and 6.1 �± 1.7 vs. 7.7 �± 2.0 cm/s, p = 0.002). In multivariable regression analyses, DM remained significantly associated with impairments of S' and E', respectively.\n \nConclusion\nIn patients without significant CAD, DM is associated with an impaired systolic longitudinal LV function and global diastolic dysfunction. These abnormalities are likely to be markers of adverse prognosis....
Background\nInsulin gene (INS) mutations have recently been described as a common cause of permanent neonatal diabetes (PNDM) and a rare cause of diabetes diagnosed in childhood or adulthood.\n \nMethods\nINS was sequenced in 116 maturity-onset diabetes of the young (MODYX) patients (n = 48 Danish and n = 68 Czech), 83 patients with gestational diabetes mellitus (GDM), 34 type 1 diabetic patients screened negative for glutamic acid decarboxylase (GAD), and 96 glucose tolerant individuals. The control group was randomly selected from the population-based sampled Inter99 study.\n \nResults\nOne novel heterozygous mutation c.17G>A, R6H, was identified in the pre-proinsulin gene (INS) in a Danish MODYX family. The proband was diagnosed at 20 years of age with mild diabetes and treated with diet and oral hypoglycaemic agent. Two other family members who carried the INS R6H were diagnosed with diabetes when 51 years old and with GDM when 27 years old, respectively. A fourth mutation carrier had normal glucose tolerance when 20 years old. Two carriers of INS R6H were also examined twice with an oral glucose tolerance test (OGTT) with 5 years interval. They both had a ~30% reduction in beta-cell function measured as insulinogenic index. In a Czech MODYX family a previously described R46Q mutation was found. The proband was diagnosed at 13 years of age and had been treated with insulin since onset of diabetes. Her mother and grandmother were diagnosed at 14 and 35 years of age, respectively, and were treated with oral hypoglycaemic agents and/or insulin.\n \nConclusion\nMutations in INS can be a rare cause of MODY and we conclude that screening for mutations in INS should be recommended in MODYX patients....
Background\nDevelopment of Type 2 diabetes, like obesity, is promoted by a genetic predisposition. Although several genetic variants have been identified they only account for a small proportion of risk. We have asked if genetic risk is associated with abnormalities in storing excess lipids in the abdominal subcutaneous adipose tissue.\n\nMethodology/Principal Findings\nWe recruited 164 lean and 500 overweight/obese individuals with or without a genetic predisposition for Type 2 diabetes or obesity. Adipose cell size was measured in biopsies from the abdominal adipose tissue as well as insulin sensitivity (HOMA index), HDL-cholesterol and Apo AI and Apo B. 166 additional non-obese individuals with a genetic predisposition for Type 2 diabetes underwent a euglycemic hyperinsulinemic clamp to measure insulin sensitivity. Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, was associated with inappropriate expansion of the adipose cells, reduced insulin sensitivity and a more proatherogenic lipid profile in non-obese individuals. However, obesity per se induced a similar expansion of adipose cells and dysmetabolic state irrespective of genetic predisposition.\n\nConclusions/Significance\nGenetic predisposition for Type 2 diabetes, but not obesity, is associated with an impaired ability to recruit new adipose cells to store excess lipids in the subcutaneous adipose tissue, thereby promoting ectopic lipid deposition. This becomes particularly evident in non-obese individuals since obesity per se promotes a dysmetabolic state irrespective of genetic predisposition. These results identify a novel susceptibility factor making individuals with a genetic predisposition for Type 2 diabetes particularly sensitive to the environment and caloric excess....
Background\nRecent evidence suggests that there is a link between metabolic diseases and bacterial populations in the gut. The aim of this study was to assess the differences between the composition of the intestinal microbiota in humans with type 2 diabetes and non-diabetic persons as control.\n\nMethods and Findings\nThe study included 36 male adults with a broad range of age and body-mass indices (BMIs), among which 18 subjects were diagnosed with diabetes type 2. The fecal bacterial composition was investigated by real-time quantitative PCR (qPCR) and in a subgroup of subjects (N = 20) by tag-encoded amplicon pyrosequencing of the V4 region of the 16S rRNA gene. The proportions of phylum Firmicutes and class Clostridia were significantly reduced in the diabetic group compared to the control group (P = 0.03). Furthermore, the ratios of Bacteroidetes to Firmicutes as well as the ratios of Bacteroides-Prevotella group to C. coccoides-E. rectale group correlated positively and significantly with plasma glucose concentration (P = 0.04) but not with BMIs. Similarly, class Betaproteobacteria was highly enriched in diabetic compared to non-diabetic persons (P = 0.02) and positively correlated with plasma glucose (P = 0.04).\n\nConclusions\nThe results of this study indicate that type 2 diabetes in humans is associated with compositional changes in intestinal microbiota. The level of glucose tolerance should be considered when linking microbiota with metabolic diseases such as obesity and developing strategies to control metabolic diseases by modifying the gut microbiota....
Background\nRecent genome-wide association studies (GWASs) have reported several genetic variants to be reproducibly associated with type 2 diabetes. Additional variants have also been detected from a metaanalysis of three GWASs, performed in populations of European ancestry. In the present study, we evaluated the influence of 17 genetic variants from 15 candidate loci, identified in type 2 diabetes GWASs and the metaanalysis, in a Han Chinese cohort.\n\nMethodology/Principal Findings\nSelected type 2 diabetesââ?¬â??associated genetic variants were genotyped in 1,165 type 2 diabetic patients and 1,136 normoglycemic control individuals of Southern Han Chinese ancestry. The OR for risk of developing type 2 diabetes was calculated using a logistic regression model adjusted for age, sex, and BMI. Genotype-phenotype associations were tested using a multivariate linear regression model. Genetic variants in CDKN2A/B, CDKAL1, TCF7L2, TCF2, MC4R, and PPARG showed a nominal association with type 2 diabetes (P=0.05), of whom the three first would stand correction for multiple testing: CDKN2A/B rs10811661, OR: 1.26 (1.12ââ?¬â??1.43) P = 1.8*10-4; CDKAL1 rs10946398, OR: 1.23 (1.09ââ?¬â??1.39); P = 7.1*10-4, and TCF7L2 rs7903146, OR: 1.61 (1.19ââ?¬â??2.18) P = 2.3 * 10-3. Only nominal phenotype associations were observed, notably for rs8050136 in FTO and fasting plasma glucose (P = 0.002), postprandial plasma glucose (P = 0.002), and fasting C-peptide levels (P = 0.006) in the diabetic patients, and with BMI in controls (P = 0.033).\n\nConclusions/Significance\nWe have identified significant association between variants in CDKN2A/B, CDKAL1 and TCF7L2, and type 2 diabetes in a Han Chinese cohort, indicating these genes as strong candidates conferring susceptibility to type 2 diabetes across different ethnicities....
Background\nAccurate molecular diagnosis of monogenic non-autoimmune neonatal diabetes mellitus (NDM) is critical for patient care, as patients carrying a mutation in KCNJ11 or ABCC8 can be treated by oral sulfonylurea drugs instead of insulin therapy. This diagnosis is currently based on Sanger sequencing of at least 42 PCR fragments from the KCNJ11, ABCC8, and INS genes. Here, we assessed the feasibility of using the next-generation whole exome sequencing (WES) for the NDM molecular diagnosis.\n\nMethodology/Principal Findings\nWe carried out WES for a patient presenting with permanent NDM, for whom mutations in KCNJ11, ABCC8 and INS and abnormalities in chromosome 6q24 had been previously excluded. A solution hybridization selection was performed to generate WES in 76 bp paired-end reads, by using two channels of the sequencing instrument. WES quality was assessed using a high-resolution oligonucleotide whole-genome genotyping array. From our WES with high-quality reads, we identified a novel non-synonymous mutation in ABCC8 (c.1455G>C/p.Q485H), despite a previous negative sequencing of this gene. This mutation, confirmed by Sanger sequencing, was not present in 348 controls and in the patient's mother, father and young brother, all of whom are normoglycemic.\n\nConclusions/Significance\nWES identified a novel de novo ABCC8 mutation in a NDM patient. Compared to the current Sanger protocol, WES is a comprehensive, cost-efficient and rapid method to identify mutations in NDM patients. We suggest WES as a near future tool of choice for further molecular diagnosis of NDM cases, negative for chr6q24, KCNJ11 and INS abnormalities....
Background\nConcomitant with the rise in childhood obesity there has been a significant increase in the number of adolescents with clinical features of insulin resistance and prediabetes. Clinical insulin resistance and prediabetes are likely to progress to type 2 diabetes and early atherosclerosis if not targeted for early intervention. There are no efficacy trials of lifestyle intervention in this group to inform clinical practice. The primary aim of this randomised control trial (RCT) is to determine the efficacy and effectiveness of two different structured lifestyle interventions differing in diet composition on insulin sensitivity, in adolescents with clinical insulin resistance and/or prediabetes treated with metformin.\n \nMethods/design\nThis study protocol describes the design of an ongoing RCT. We are recruiting 108 (54 each treatment arm) 10 to 17 year olds with clinical features of insulin resistance and/or prediabetes, through physician referral, into a multi-centred RCT. All participants are prescribed metformin and participate in a diet and exercise program. The lifestyle program is the same for all participants except for diet composition. The diets are a high carbohydrate, low fat diet and a moderate carbohydrate, increased protein diet.\nThe program commences with an intensive 3 month dietary intervention, implemented by trained dietitians, followed by a 3 month intensive gym and home based exercise program, supervised by certified physical trainers. To measure the longer term effectiveness, after the intensive intervention trial participants are managed by either their usual physician or study physician and followed up by the study dietitians for an additional 6 months. The primary outcome measure, change in insulin sensitivity, is measured at 3, 6 and 12 months.\n \nDiscussion\nClinical insulin resistance and prediabetes in the paediatric population are rapidly emerging clinical problems with serious health outcomes. With appropriate management these conditions are potentially reversible or at least their progression can be delayed. This research study is the first trial designed to provide much needed data on the effective dietary management for this cohort. This study will inform clinical practice guidelines for adolescents with clinical insulin resistance and may assist in preventing metabolic complications, type 2 diabetes and early cardiovascular disease....
Background\nDiabetes mellitus (DM) is associated with microvascular complications, such as diabetic retinopathy (DR). DR is one of the main causes of visual loss in individuals aged 20-64 years old. This study aims to investigate the independent associations between the stage of DR and a variety of possible risk factors, including years since DM diagnosis, HbA1c levels, the coexistence of hypertension, age and gender.\n\nFindings\n120 patients were recruited in the Department of Internal Medicine, Veroia General Hospital, Veroia, Greece, and the DR stage was defined by an ophthalmologist. Afterwards, the DR association with the aforementioned factors was examined. Univariate and multivariate analysis (multivariate ordinal logistic regression) was performed. At the univariate analysis, there was a positive association between DR severity and age (Spearman's rho = 0.4869, p < 0.0001), years since DM diagnosis (Spearman's rho = 0.6877, p < 0.0001), HbA1c levels (Spearman's rho = 0.6315, p < 0.0001), history of hypertension (2.47 �± 1.37 vs. 0.50 �± 0.80 for patients without hypertension; p < 0.0001) and male sex (2.56 �± 1.41 vs. 2.05 �± 1.45 for female patients; p = 0.045, MWW). All these factors, except for age, retained their statistical significance at the multivariate ordinal logistic model.\n\nConclusions\nYears since DM diagnosis, hypertension, HbA1c levels and male sex are independently associated with severe DR. The effect of age seems to reflect a confounding association....
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