Increased Adiposity, Dysregulated Glucose Metabolism and Systemic Inflammation in Galectin-3 KO Mice

PMCID: PMC3579848This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Exploring the use of adjusted body mass index thresholds based on equivalent insulin resistance for defining overweight and obesity in UK South Asian children

Background Body mass index (BMI) overweight/obesity thresholds in South Asian (SA) adults, at equivalent type-2 diabetes risk are lower than for white Europeans (WE). We aimed to define adjusted overweight/obesity thresholds for UK–SA children based on equivalent insulin resistance (HOMA-IR) to WE children. Methods In 1138 WE and 1292 SA children aged 9.0–10.9 years, multi-level regression models quantified associations between BMI and HOMA-IR by ethnic group. HOMA-IR levels for WE children were calculated at established overweight/obesity thresholds (at 9.5 years and 10.5 years), based on UK90 BMI cut-offs. Quantified associations in SA children were then used to estimate adjusted SA weight-status thresholds at the calculated HOMA-IR levels. Results At 9.5 years, current WE BMI overweight and obesity thresholds were 19.2 kg/m2, 21.3 kg/m2 (boys) and 20.0 kg/m2, 22.5 kg/m2 (girls). At equivalent HOMA-IR, SA overweight and obesity thresholds were lower by 2.9 kg/m2 (95% CI: 2.5–3.3 kg/m2) and 3.2 kg/m2 (95% CI: 2.7–3.6 kg/m2) in boys and 3.0 kg/m2 (95% CI: 2.6–3.4 kg/m2) and 3.3 kg/m2 (95% CI: 2.8–3.8 kg/m2) in girls, respectively. At these lower thresholds, overweight/obesity prevalences in SA children were approximately doubled (boys: 61%, girls: 56%). Patterns at 10.5 years were similar. Conclusions SA adjusted overweight/obesity thresholds based on equivalent IR were markedly lower than BMI thresholds for WE children, and defined more than half of SA children as overweight/obese

Welcoming low testosterone as a cardiovascular risk factor

Male hypogonadism now has a new spectrum of complications. They are mainly cardiometabolic in nature. Low serum testosterone levels are a risk factor for diabetes, metabolic syndrome, inflammation and dyslipidemia. These metabolic and inflammatory complications are not without consequences. Recent studies have shown low serum testosterone levels to be an independent risk factor of cardiovascular and all-cause mortality. It is time to welcome low serum testosterone levels as a cardiovascular risk factor

Immunoglobulin E and Mast Cell Proteases Are Potential Risk Factors of Human Pre-Diabetes and Diabetes Mellitus

Recent studies have suggested that mast-cell activation and inflammation are important in obesity and diabetes. Plasma levels of mast cell proteases and the mast cell activator immunoglobulin E (IgE) may serve as novel inflammatory markers that associate with the risk of pre-diabetes and diabetes mellitus. = 0.026) adjustment for common diabetes risk factors.Both IgE and chymase associate with diabetes status. While IgE and hs-CRP are individual risk factors of pre-diabetes and diabetes mellitus, interactions of IgE with hs-CRP or with chymase further increased the risk of pre-diabetes and diabetes mellitus

The Prevalence and Cost of Unapproved Uses of Top-Selling Orphan Drugs

Introduction: The Orphan Drug Act encourages drug development for rare conditions. However, some orphan drugs become top sellers for unclear reasons. We sought to evaluate the extent and cost of approved and unapproved uses of orphan drugs with the highest unit sales. Methods We assessed prescription patterns for four top-selling orphan drugs: lidocaine patch (Lidoderm) approved for post-herpetic neuralgia, modafinil (Provigil) approved for narcolepsy, cinacalcet (Sensipar) approved for hypercalcemia of parathyroid carcinoma, and imatinib (Gleevec) approved for chronic myelogenous leukemia and gastrointestinal stromal tumor. We pooled patient-specific diagnosis and prescription data from two large US state pharmaceutical benefit programs for the elderly. We analyzed the number of new and total patients using each drug and patterns of reimbursement for approved and unapproved uses. For lidocaine patch, we subcategorized approved prescriptions into two subtypes of unapproved uses: neuropathic pain, for which some evidence of efficacy exists, and non-neuropathic pain. Results: We found that prescriptions for lidocaine patch, modafinil, and cinacalcet associated with non-orphan diagnoses rose at substantially higher rates (average monthly increases in number of patients of 14.6, 1.45, and 1.58) than prescriptions associated with their orphan diagnoses (3.12, 0.24, and 0.03, respectively (p75%). Increases in lidocaine patch use for non-neuropathic pain far exceeded neuropathic pain (10.2 vs. 3.6 patients, p<0.001). Discussion In our sample, three of four top-selling orphan drugs were used more commonly for non-orphan indications. These orphan drugs treated common clinical symptoms (pain and fatigue) or laboratory abnormalities. We should continue to monitor orphan drug use after approval to identify products that come to be widely used for non-FDA approved indications, particularly those without adequate evidence of efficacy

Role of TMPRSS2-ERG Gene Fusion in Negative Regulation of PSMA Expression

Prostate specific membrane antigen (PSMA) is overexpressed in prostatic adenocarcinoma (CaP), and its expression is negatively regulated by androgen stimulation. However, it is still unclear which factors are involved in this downregulation. TMPRSS2-ERG fusion is the most common known gene rearrangement in prostate carcinoma. Androgen stimulation can increase expression of the TMPRSS2-ERG fusion in fusion positive prostate cancer cells. The purpose of this investigation is to determine whether PSMA expression can be regulated by the TMPRSS2-ERG gene fusion. We employed two PSMA positive cell lines: VCaP cells, which harbor TMPRSS2-ERG fusion, and LNCaP cells, which lack the fusion. After 24 hours of androgen treatment, TMPRSS2-ERG mRNA level was increased in VCaP cells. PSMA mRNA level was dramatically decreased in VCaP cells, while it only has moderate change in LNCaP cells. Treatment with the androgen antagonist flutamide partially restored PSMA expression in androgen-treated VCaP cells. Knocking down ERG by siRNA in VCaP cells enhances PSMA expression both in the presence and absence of synthetic androgen R1881. Overexpressing TMPRSS2-ERG fusions in LNCaP cells downregulated PSMA both in the presence or absence of R1881, while overexpressing wild type ERG did not. Using PSMA-based luciferase reporter assays, we found TMPRSS2-ERG fusion can inhibit PSMA activity at the transcriptional level. Our data indicated that downregulation of PSMA in androgen-treated VCaP cells appears partially mediated by TMPRSS2-ERG gene fusion

Physical activity, cardiorespiratory fitness, and metabolic syndrome in adolescents: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>In adults, there is a substantial body of evidence that physical inactivity or low cardiorespiratory fitness levels are strongly associated with the development of metabolic syndrome. Although this association has been studied extensively in adults, little is known regarding this association in adolescents. The aim of this study was to analyze the association between physical activity and cardiorespiratory fitness levels with metabolic syndrome in Brazilian adolescents.</p> <p>Methods</p> <p>A random sample of 223 girls (mean age, 14.4 ± 1.6 years) and 233 boys (mean age, 14.6 ± 1.6 years) was selected for the study. The level of physical activity was determined by the Bouchard three-day physical activity record. Cardiorespiratory fitness was estimated by the Leger 20-meter shuttle run test. The metabolic syndrome components assessed included waist circumference, blood pressure, HDL-cholesterol, triglycerides, and fasting plasma glucose levels. Independent Student <it>t</it>-tests were used to assess gender differences. The associations between physical activity and cardiorespiratory fitness with the presence of metabolic syndrome were calculated using logistic regression models adjusted for age and gender.</p> <p>Results</p> <p>A high prevalence of metabolic syndrome was observed in inactive adolescents (males, 11.4%; females, 7.2%) and adolescents with low cardiorespiratory fitness levels (males, 13.9%; females, 8.6%). A significant relationship existed between metabolic syndrome and low cardiorespiratory fitness (OR, 3.0 [1.13-7.94]).</p> <p>Conclusion</p> <p>The prevalence of metabolic syndrome is high among adolescents who are inactive and those with low cardiorespiratory fitness. Prevention strategies for metabolic syndrome should concentrate on enhancing fitness levels early in life.</p

Effect of genetic testing for risk of type 2 diabetes mellitus on health behaviors and outcomes: study rationale, development and design

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes is a prevalent chronic condition globally that results in extensive morbidity, decreased quality of life, and increased health services utilization. Lifestyle changes can prevent the development of diabetes, but require patient engagement. Genetic risk testing might represent a new tool to increase patients' motivation for lifestyle changes. Here we describe the rationale, development, and design of a randomized controlled trial (RCT) assessing the clinical and personal utility of incorporating type 2 diabetes genetic risk testing into comprehensive diabetes risk assessments performed in a primary care setting.</p> <p>Methods/Design</p> <p>Patients are recruited in the laboratory waiting areas of two primary care clinics and enrolled into one of three study arms. Those interested in genetic risk testing are randomized to receive <it>either </it>a standard risk assessment (SRA) for type 2 diabetes incorporating conventional risk factors plus upfront disclosure of the results of genetic risk testing ("SRA+G" arm), <it>or </it>the SRA alone ("SRA" arm). Participants not interested in genetic risk testing will not receive the test, but will receive SRA (forming a third, "no-test" arm). Risk counseling is provided by clinic staff (not study staff external to the clinic). Fasting plasma glucose, insulin levels, body mass index (BMI), and waist circumference are measured at baseline and 12 months, as are patients' self-reported behavioral and emotional responses to diabetes risk information. Primary outcomes are changes in insulin resistance and BMI after 12 months; secondary outcomes include changes in diet patterns, physical activity, waist circumference, and perceived risk of developing diabetes.</p> <p>Discussion</p> <p>The utility, feasibility, and efficacy of providing patients with genetic risk information for common chronic diseases in primary care remain unknown. The study described here will help to establish whether providing type 2 diabetes genetic risk information in a primary care setting can help improve patients' clinical outcomes, risk perceptions, and/or their engagement in healthy behavior change. In addition, study design features such as the use of existing clinic personnel for risk counseling could inform the future development and implementation of care models for the use of individual genetic risk information in primary care.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00849563">NCT00849563</a></p

Association between Changes in Muscle Quality with Exercise Training and Changes in Cardiorespiratory Fitness Measures in Individuals with Type 2 Diabetes Mellitus: Results from the HART-D Study

Introduction: Type 2 diabetes mellitus (T2DM) is associated with a reduction in muscle quality. However, there is inadequate empirical evidence to determine whether changes in muscle quality following exercise are associated with improvement in cardiorespiratory fitness (CRF) in individuals with T2DM. The objective of this study was to investigate the association between change in muscle quality following a 9-month intervention of aerobic training (AT), resistance training (RT) or a combination of both (ATRT) and cardiorespiratory fitness (CRF) in individuals with T2DM. Material and Methods A total of 196 participants were randomly assigned to a control, AT, RT, or combined ATRT for a 9-months intervention. The exposure variable was change in muscle quality [(Post: leg muscle strength/leg muscle mass)-[(Pre: leg muscle strength/leg muscle mass)]. Dependent variables were change in CRF measures including absolute and relative VO2peak, and treadmill time to exhaustion (TTE) and estimated metabolic equivalent task (METs). Results Continuous change in muscle quality was independently associated with change in absolute (β = 0.015; p = 0.019) and relative (β = 0.200; p = 0.005) VO2peak, and TTE (β = 0.170; p = 0.043), but not with estimated METs (p > 0.05). A significant trend was observed across tertiles of change in muscle quality for changes in absolute (β = 0.050; p = 0.005) and relative (β = 0.624; p = 0.002) VO2peak following 9 months of exercise training. No such association was observed for change in TTE and estimated METs (p > 0.05). Discussion: The results from this ancillary study suggest that change in muscle quality following exercise training is associated with a greater improvement in CRF in individuals with T2DM. Given the effect RT has on increasing muscle quality, especially as part of a recommended training program (ATRT), individuals with T2DM should incorporate RT into their AT regimens to optimize CRF improvement