Wendy J. Brickman

Genetic and Environmental Contributions to Phenotypic Components of Metabolic Syndrome: A Population-based Twin Study

The increasing prevalence of metabolic syndrome (MS) poses a serious public‐health problem worldwide. Effective prevention and intervention require improved understanding of the factors that contribute to MS. We analyzed data on a large twin cohort to estimate genetic and environmental contributions to MS and to major MS components and their intercorrelations: waist circumference (WC), systolic (SBP) and diastolic blood pressure (DBP), fasting plasma glucose (FPG), triglycerides (TGs), and high‐density lipoprotein–cholesterol (HDL‐C). We applied structural equation modeling to determine genetic and environmental structure of MS and its major components, using 1,617 adult female twin pairs recruited from rural China. The heritability estimate for MS was 0.42 (95% confidence interval (CI): 0.00–0.83) in this sample with low MS prevalence (4.4%). For MS components, heritability estimates were statistically significant and ranged from 0.13 to 0.64 highest for WC, followed by TG, SBP, DBP, HDL‐C, and FPG. HDL‐C was mainly influenced by common environmental factors (0.62, 95% CI: 0.58–0.62), whereas the other five MS components were largely influenced by unique environmental factors (0.32–0.44). Bivariate Cholesky decomposition analysis indicated that the clinical clustering of MS components may be explained by shared genetic and/or environmental factors. Our study underscores the importance of examining MS components as intercorrelated traits, and to carefully consider environmental and genetic factors in studying MS etiology.

Acanthosis Nigricans Identifies Youth at High Risk for Metabolic Abnormalities

OBJECTIVE To determine the prevalence of abnormal glucose homeostasis and cardiovascular risk factors in youth with acanthosis nigricans (AN). STUDY DESIGN Youth (8-14 years) were recruited from community pediatric offices. Each subject underwent a questionnaire, a targeted physical examination, and an oral glucose tolerance test. RESULTS Subjects (n = 236) with AN of the neck (AN+) (60% Hispanic, 30% African American, 54% female, body mass index [BMI] z-score 2.3 kg/m(2)) and 51 youth without AN (65% Hispanic, 22% African American, 37% female, BMI z-score 2.1 kg/m(2)) completed the study. Twenty-nine percent of the AN+ group had abnormal glucose homeostasis, 27% had systolic blood pressure > 95th percentile, and 50% had high-density lipoprotein-cholesterol < or =5th percentile. Once corrected for sex, puberty, maternal education, and BMI z-score, AN remained significantly associated with insulin resistance and abnormal glucose homeostasis. For youth in the AN+ group, homeostasis model assessment of insulin resistance, female sex, and positive glutamic acid decarboxylase antibodies remained significantly and independently associated with impaired glucose tolerance. CONCLUSIONS Youth in the AN+ group had severe insulin resistance, and more than 1 in 4 already had abnormal glucose homeostasis. AN identified a high-risk population, for whom appropriate interventions have the potential to attenuate or even prevent the development of diabetes and further metabolic abnormalities.

Clinical status and cardiovascular risk profile of adults with a history of juvenile dermatomyositis

OBJECTIVE A pilot study of adults who had onset of juvenile dermatomyositis (JDM) in childhood, before current therapeutic approaches, to characterize JDM symptoms and subclinical cardiovascular disease. STUDY DESIGN Eight adults who had JDM assessed for disease activity and 8 healthy adults (cardiovascular disease controls) were tested for carotid intima media thickness and brachial arterial reactivity. Adults who had JDM and 16 age-, sex-, and body mass index-matched healthy metabolic controls were evaluated for body composition, blood pressure, fasting glucose, lipids, insulin resistance, leptin, adiponectin, proinflammatory oxidized high-density lipoprotein (HDL), and nail-fold capillary end row loops. RESULTS Adults with a history of JDM, median age 38 years (24-44 years) enrolled a median 29 years (9-38 years) after disease onset, had elevated disease activity scores, skin (7/8), muscle (4/8), and creatine phosphokinase (2/8). Compared with cardiovascular disease controls, adults who had JDM were younger, had lower body mass index and HDL cholesterol (P = .002), and increased intima media thickness (P = .015) and their brachial arterial reactivity suggested impairment of endothelial cell function. Compared with metabolic controls, adults who had JDM had higher systolic and diastolic blood pressure, P = .048, P = .002, respectively; lower adiponectin (P = .03); less upper arm fat (P = .008); HDL associated with end row loops loss (r = -0.838, P = .009); and increased proinflammatory oxidized HDL (P = .0037). CONCLUSION Adults who had JDM, 29 years after disease onset, had progressive disease and increased cardiovascular risk factors.

Acanthosis Nigricans: A Common Finding in Overweight Youth

Abstract:  We evaluated the prevalence of acanthosis nigricans among urban youth. Youth (7–17 years) at nine pediatric practices completed surveys on demographics and family history of diabetes and had weight and height measured. Acanthosis nigricans was scored and digital photography of the neck performed. A total of 618 youth were included in the analysis: mean age 11.5 years; 51% female; 61% African American, 27% Hispanic, 12% Caucasian, and 32% with body mass index ≥95th percentile. Acanthosis was found in 19%, 23%, and 4% of the African American, Hispanic, and Caucasian youth, respectively, and in 62% of youth with a body mass index ≥98th percentile. Using multiple logistic regression, we found increasing body mass index z‐score, presence of maternal gestational diabetes, female gender, and not being Caucasian each were independently associated with acanthosis nigricans. Acanthosis was common among overweight youth and was associated with risk factors for glucose homeostasis abnormalities. Acanthosis nigricans can be a trigger to counsel families on its causes and consequences; and thus motivate them to make healthy lifestyle changes that can decrease the risk of developing cardiovascular disease or diabetes.

Short sleep duration is associated with insulin resistance independent of adiposity in Chinese adult twins

OBJECTIVE To investigate the association between sleep duration and insulin resistance in rural Chinese adults and examine whether any such associations are independent of adiposity. METHODS This is a cross-sectional analysis of 854 men and 640 women aged 20 to 70 years from the Anqing Twin Cohort. The following measures were obtained for each subject: Body mass index (BMI) and percentage of trunk fat (%TF), fasting plasma glucose, homeostatic model assessment of insulin resistance index (HOMA-IR), self-reported sleep duration and measures of snoring and sleep disturbance from the Pittsburgh Sleep Quality Indices (PSQI) questionnaire were modified for a Chinese population. Multivariate linear regressions were applied to examine the association of sleep duration with HOMA-IR, with and without adjustment for adiposity variables, along with other relevant covariates. RESULTS In this sample of relatively lean rural Chinese adults, short sleep duration was associated with HOMA-IR in women but not in men. In women, short (≤ 7 h/night) sleep duration was associated with a higher HOMA-IR (p=0.003) compared with normal sleep duration (>7 to ≤ 8 h/night) after adjustment for all the covariates except adiposity. Further adjustment for BMI or %TF attenuated the sleep-HOMA-IR association, but the association remained significant upon adjustment for BMI (p=0.013); and upon adjustment for %TF (p=0.026). Long sleep duration (> 8 h/night) was not significantly associated with HOMA-IR. CONCLUSION In this rural Chinese cohort, short sleep duration is independently associated with increased insulin resistance among women only, even after adjusting for adiposity and other potential confounders.

Association of plasma leptin concentrations with adiposity measurements in rural Chinese adolescents.

CONTEXT There is evidence that leptin is involved in the etiology of obesity-related cardiovascular disease in adults. This raises the question of whether leptin levels in adolescence are indicative of adiposity-related cardiovascular risk. OBJECTIVE This study investigated gender-specific patterns of plasma leptin during adolescence, assessed which adiposity measurements are most strongly associated with plasma leptin, and estimated to what degree leptin-adiposity associations are influenced by genetic factors. METHODS Plasma leptin concentrations were determined using a sandwich immunoassay. Associations between plasma leptin and several adiposity measurements were examined using generalized estimating equations. Genetic contribution to leptin-adiposity association was estimated by Cholesky decomposition models using twin design. RESULTS Plasma leptin levels were higher in females than males at all Tanner stages. In females, body mass index, waist circumference, fat mass index (FMI), and percentage body fat (%BF) had similar associations with leptin levels. In males, %BF and FMI were more strongly associated with leptin levels than body mass index and waist circumference. In both males and females, percentage trunk fat had the weakest association with leptin among the five adiposity measures. Shared genetic factors account for more than 80% of the phenotypic correlation between %BF and leptin. CONCLUSIONS We found gender differences in leptin levels and leptin-adiposity associations. In both genders, leptin levels were strongly associated with %BF and FMI, particularly in males. Shared genetic factors contributed largely to the phenotypic correlation between leptin and %BF. Our findings underscored the importance of further investigation of leptin as a biomarker of adiposity in adolescents.

Complementary and Alternative Medicine Use in Children with Type 1 Diabetes: A Pilot Survey of Parents

OBJECTIVE The aim of this study was to examine the prevalence and characteristics of complementary and alternative medicine (CAM) use among children with diabetes. DESIGN Anonymous surveys were completed by guardians of children with diabetes attending an urban diabetes clinic over three months. The survey included demographics, parent and child CAM use (excluding vitamins), and perceived opinions of health providers about CAM use. The representativeness of the surveyed sample was evaluated and analyses examined associations with child CAM use. RESULTS Children in the analysis (N = 86, 33% response rate) were similar to the potential population for age, gender, insurance type, and age at diabetes diagnosis. Children analyzed were mean 10.9 years of age (SD 3.9), 56% male, 71% Caucasian, 83% privately insured, and 90% spoke English at home. Parents were 22% foreign born and 45% college graduates; 19% of children and 45% of parents had tried CAM. There were 30 CAM use occurrences among 16 children; 60% were CAM activities (ie, faith healing, chiropractic treatments, relaxation techniques) and 40% were CAM supplements (ie, herbs, nutritional supplements, herbal teas). Child CAM use was more common if a parent had used CAM (33% vs 6%; P = .002) and among children with foreign-born parents (37% vs 13%; P = .04). CAM was used to decrease diabetes complications and improve overall health. Parents were comfortable discussing CAM with the diabetes team and their childs primary care provider. CONCLUSIONS Children with diabetes were using CAM as an adjunctive therapy for diabetes. The diabetes healthcare team needs an increased awareness about CAM.

A novel double mutation in the luteinizing hormone receptor in a kindred with familial Leydig cell hypoplasia and male pseudohermaphroditism.

We report a novel mutant of the luteinizing hormone receptor (LHR) in a case of familial Leydig cell hypoplasia and pseudohermaphrotidism. The proband was homozygous for two missense mutations, T1121C and C1175T, causing substitutions I374T and T392I. The molecular effects of the mutations were investigated by heterologous expression of the WT LHR, the double mutant LHR, or receptors with either the I374T or the T392I mutation, and measuring hormone binding and cAMP signaling. All mutant LHRs exhibited severe defects, including loss of ligand binding and cAMP production. Immunoblots showed little difference in protein levels between the WT and mutant receptors.

Adiposity is inversely related to insulin sensitivity in relatively lean Chinese adolescents: a population-based twin study

BACKGROUND Adolescence is a critical period for rising adiposity and falling insulin sensitivity (IS), but the independent relation between adiposity and IS remains understudied. OBJECTIVE The objective was to examine which adiposity measures are most strongly associated with IS in nondiabetic adolescents, whether sex-difference exists, and to what degree genetic or environmental factors affect the adiposity-IS relation. DESIGN The study included 1613 rural Chinese adolescents (888 males) aged 13-20 y from a population-based twin cohort. We used graphic plots and linear mixed models to examine the relation of anthropometric and dual-energy X-ray absorptiometry-based measures of adiposity with IS [QUantitative Insulin-sensitivity ChecK Index (QUICKI), fasting serum insulin (FSI), homeostasis model assessment of insulin resistance (HOMA-IR)] and structural equation models to estimate genetic/environmental influences on these associations. RESULTS In graphic analyses, participants in the highest quintile (quintile 5) of waist circumference (WC) and percentage body fat (%BF) had the lowest QUICKI and the highest FSI and HOMA-IR values for all age-sex groups. In regression models adjusted for age, Tanner stage, zygosity, and physical activity, all adiposity measures showed inverse associations with IS in both sexes, but WC explained the largest fraction of variance in IS measures (10-14%). Of the phenotypic correlations between adiposity measures and IS (-0.28 to -0.38), 74-85% were attributed to shared genetic factors and 15-26% to common unique environmental factors in both sexes. CONCLUSIONS In these relatively lean Chinese adolescents, WC and %BF (quintile 5) are the adiposity measures most consistently and strongly associated with decreased IS in both sexes. To a large degree, shared genetic factors contribute to this association.

Prediabetes is not all about obesity: association between plasma leptin and prediabetes in lean rural Chinese adults

OBJECTIVE This study investigated the associations of plasma leptin levels with insulin resistance (IR) and prediabetes in relatively lean, rural Chinese men and women. DESIGN AND METHODS This study included 574 subjects aged 21-45 years from a community-based twin cohort. Plasma leptin concentrations were measured by sandwich immunoassays using flowmetric xMAP technology. Prediabetes was defined based on fasting plasma glucose and 75-g oral glucose tolerance test. Multivariate linear and logistic regression analyses were used to investigate gender-specific associations of leptin with IR measures and prediabetes, adjusting for intra-twin correlation, measures of adiposity, and other pertinent covariates. RESULTS The body mass index is 22.3+/-2.7 kg/m(2) in men and 22.5+/-2.7 kg/m(2) in women. Leptin levels were positively associated with IR. Individuals with higher tertiles of leptin also had increased risk of prediabetes with odds ratios (OR) of 2.6 (95% confidence interval (CI): 1.4-5.1) and 4.3 (95% CI: 2.1-8.7) in men; OR of 1.1 (95% CI: 0.6-2.1) and 3.1 (95% CI 1.5-6.2) in women for second and third tertile respectively. These associations were attenuated after further adjusting for adiposity measurements only in men. The leptin-prediabetes associations disappeared after adjusting for the homeostatic model assessment of IR in both genders. CONCLUSION In this sample of relatively lean rural Chinese adults, plasma leptin levels were associated with IR and prediabetes in a dose-response fashion, which were not totally explained by adiposity. Our data emphasize that prediabetes is not all about obesity, and leptin may be an additional biomarker for screening individuals at high risk for prediabetes in this population.