Quantitative linkage of physiology and gene expression through empirical model construction: an investigation of diabetes

A methodology for the construction of predictive empirical models of physiological characteristics from microarray data is presented. The method, applied here to the study of the development of diabetes and insulin resistance, can be further expanded to other cases and to also include a variety of other data, such as protein expression, or metabolic flux data. The importance of several of the genes identified by the modeling methodology can be verified by comparison with results from prior literature. This implies potentially significant roles in diabetes for several of the uncharacterized genes discovered during the modeling procedure.Singapore-MIT Alliance (SMA

Sex Disparities in the Treatment and Control of Cardiovascular Risk Factors in Type 2 Diabetes

OBJECTIVE—To assess whether sex differences exist in the effective control and medication treatment intensity of cardiovascular disease (CVD) risk factors

Total and High-Molecular-Weight Adiponectin and Risk of Incident Diabetes in Older People

OBJECTIVE To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults. RESEARCH DESIGN AND METHODS Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals. RESULTS Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39–0.63]) and HMW adiponectin (0.42 [0.32–0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables. CONCLUSIONS In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation

Adiponectin and cancer: a systematic review

Recent studies have demonstrated that obesity is a significant risk factor for the development of several malignancies, but the mechanisms underlying this relationship remain to be fully elucidated. Adiponectin, an adipocyte secreted endogenous insulin sensitizer, appears to play an important role not only in glucose and lipid metabolism but also in the development and progression of several obesity-related malignancies. In this review, we present recent findings on the association of adiponectin with several malignancies as well as recent data on underlying molecular mechanisms that provide novel insights into the association between obesity and cancer risk. We also identify important research questions that remain unanswered

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood

Association between serum keptin concentrations and insulin resistance: A population-based study from China

BACKGROUND Insulin resistance contributes to the cardio-metabolic risk. The effect of leptin in obese and overweight population on insulin resistance was seldom reported. METHODS A total of 1234 subjects (572 men and 662 women) aged ≥18 y was sampled by the procedure. Adiposity measures included BMI, waist circumference, hip circumference, WHR, upper arm circumference, triceps skinfold and body fat percentage. Serum leptin concentrations were measured by an ELISA method. The homeostasis model (HOMA-IR) was applied to estimate insulin resistance. RESULTS In men, BMI was the variable which was most strongly correlated with leptin, whereas triceps skinfold was most sensitive for women. More importantly, serum leptin levels among insulin resistant subjects were almost double compared to the subjects who had normal insulin sensitivity at the same level of adiposity in both men and women, after controlling for potential confounders. In addition, HOMA-IR increased significantly across leptin quintiles after adjustment for age, BMI, total energy intake, physical activity and smoking status in both men and women (p for trend <0.0001). CONCLUSIONS There was a significant association between HOMA-IR and serum leptin concentrations in Chinese men and women, independently of adiposity levels. This may suggest that serum leptin concentration is an important predictor of insulin resistance and other metabolic risks irrespective of obesity levels. Furthermore, leptin levels may be used to identify the cardio-metabolic risk in obese and overweight population.Hui Zuo, Zumin Shi, Baojun Yuan, Yue Dai, Gaolin Wu, Akhtar Hussai

Measuring Adiposity in Patients: The Utility of Body Mass Index (BMI), Percent Body Fat, and Leptin

Background: Obesity is a serious disease that is associated with an increased risk of diabetes, hypertension, heart disease, stroke, and cancer, among other diseases. The United States Centers for Disease Control and Prevention (CDC) estimates a 20 % obesity rate in the 50 states, with 12 states having rates of over 30%. Currently, the body mass index (BMI) is most commonly used to determine adiposity. However, BMI presents as an inaccurate obesity classification method that underestimates the epidemic and contributes to failed treatment. In this study, we examine the effectiveness of precise biomarkers and duel-energy x-ray absorptiometry (DXA) to help diagnose and treat obesity. Methodology/Principal Findings: A cross-sectional study of adults with BMI, DXA, fasting leptin and insulin results wer