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1.  Adiposity and Cardiovascular Risk Clustering in South Asians 
Abstract
Background
South Asians have increased risk for type-2 diabetes and cardiovascular disease, but the relationship between metabolic health and weight has not been described. This study establishes the prevalence of metabolic abnormalities in normal weight, overweight, and obese South Asians.
Methods
Participants were categorized by body mass index and waist circumference. Subjects with two or more cardiometabolic risk factors (blood pressure, glucose, insulin, triglycerides, high-density lipoprotein cholesterol, and C-reactive protein) were defined as metabolically abnormal.
Results
Forty-one percent of the sample (n=1015) was metabolically abnormal, and 12% of those were normal weight. Of metabolically healthy individuals, 58% were overweight or obese. At a normal level of adiposity, women were more likely to be metabolically unhealthy, whereas men were more likely to be unhealthy with increasing adiposity.
Conclusions
Similar to other ethnic groups, a significant number of normal weight South Asians can be metabolically unhealthy.
doi:10.1089/met.2013.0081
PMCID: PMC3882736  PMID: 24004335
2.  Hypoadiponectinemia As an Independent Predictor for the Progression of Carotid Atherosclerosis: A 5-Year Prospective Study 
Abstract
Background: Hypoadiponectinemia predicts the development of diabetes and hypertension, both being potent atherosclerotic risk factors. Whether adiponectin predicts the progression of early atherosclerosis remains unclear. In this 5-year prospective study, we examined the relationship between serum adiponectin and carotid intima media thickness (CIMT), a marker of subclinical atherosclerosis.
Methods: A total of 265 subjects from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study, with no known cardiovascular disease, underwent CIMT measurement at baseline and at 5 years.
Results: In all, 129 men and 136 women, aged 54.6±12.3 years, were studied. Median CIMT at baseline was 0.63 mm (interquartile range 0.52–0.73 mm) and increased to 0.67 mm (0.56–0.78 mm) after 5 years (P<0.001). CIMT increment correlated with baseline adiponectin, age, and smoking (all P<0.05) and baseline CIMT (P<0.001), but not with sex, fasting glucose, lipid profiles, hypertension, or diabetes. In multiple linear regression analysis, baseline serum adiponectin level was an independent predictor of CIMT increment β (standardized beta)=−0.17, P=0.015], after adjusting for age, smoking, baseline CIMT, hypertension, body mass index, fasting glucose, low-density lipoprotein cholesterol, and triglycerides.
Conclusion: Hypoadiponectinemia predicted CIMT progression, independent of known predictive factors such as age, smoking, hyperlipidemia, and hypertension.
doi:10.1089/met.2014.0024
PMCID: PMC4241893  PMID: 25211296
3.  Prevalence and Risk Factors of Elevated Blood Pressure, Overweight, and Dyslipidemia in Adolescent and Young Adults in Rural Nepal 
Abstract
Background
Chronic disease begins early in life, yet population data are sparse on potential causal factors in children and young adults in South Asia.
Methods
We assessed risk factors for chronic disease in two population cohorts, aged 9–23 years, in rural Nepal. Assessed variables included short height (less than −2 z), high body mass index (BMI) (z>0.42), waist circumference (WC) >90 cm (male) or 80 cm (female) or age-adjusted child cutoff], high blood pressure (>120/80 mmHg), fasting glucose (≥100 mg/dL), glycosylated hemoglobin (HbA1c) (>7%), blood lipids [triglyceride, high-density lipoprotein cholesterol (HDL-C), and total cholesterol], diet, smoking, alcohol, and socioeconomic status (SES) factors.
Results
The population was stunted (46%) and few were overweight (∼2%–4% with high BMI or WC). Twelve percent had high blood pressure. Plasma hypertriglyceridemia (≥150 mg/dL) affected ∼8.5%, and 78% had low HDL-C concentrations <40 mg/dL (male) or <50 mg/dL (female)], while few (≤3%) had elevated total cholesterol (≥180 mg/dL), glucose, and HbA1c. Females were at higher risk than males for high blood pressure [odds ratio (OR) 1.9; 95% confidence interval (CI) 1.6–2.3] and overweight (4.2; 3.0–5.8), but had lower risk of dyslipidemia (0.7; 0.6–0.9). Ethnic plains Madheshi were less likely to be overweight (0.3; 0.2–0.4), but had greater risk of dyslipidemia (1.4; 1.1–1.7) versus those of Hill origin. Some dietary factors were significantly associated with high blood pressure or dyslipidemia, but not overweight.
Conclusions
Dyslipidemia and high blood pressure are emerging health concerns among young adults in rural Nepal.
doi:10.1089/met.2013.0016
PMCID: PMC3817862  PMID: 23682595
4.  Lipoprotein Insulin Resistance Index: A Lipoprotein Particle–Derived Measure of Insulin Resistance 
Abstract
Background: Lipoprotein particle sizes and concentrations are characteristically altered in patients with insulin resistance (IR) or type 2 diabetes mellitus (T2DM). This study assessed the ability of an IR score, based on nuclear magnetic resonance (NMR)-derived lipoprotein information, to detect IR in otherwise healthy individuals.
Methods: Lipoprotein subclass and size information were evaluated for strength of association with IR, as measured by homeostasis model assessment of insulin resistance (HOMA-IR) in the Multi-Ethnic Study of Atherosclerosis (MESA). To increase the likelihood of identifying subjects with IR, six lipoprotein measures were combined into a single algorithm. The resulting assay [Lipoprotein Insulin Resistance Index (LP-IR)] was developed using HOMA-IR in 4972 nondiabetic subjects from MESA and verified independently using glucose disposal rates (GDRs) measured during hyperinsulinemic–euglycemic clamps in 56 insulin-sensitive, 46 insulin-resistant, and 46 untreated subjects with T2DM.
Results: LP-IR exhibited stronger associations with HOMA-IR (r=0.51) and GDR (r=−0.53) than each of the individual lipoprotein parameters as well as the triglycerides/high-density lipoprotein cholesterol (TGs/HDL-C) ratio (r=0.41 and −0.44, respectively). In MESA, associations between the LP-IR score and HOMA-IR were strong in men (r=0.51), women (r=0.52), European Americans (r=0.58), African Americans (r=0.48), Chinese Americans (r=0.49), and Hispanic Americans (r=0.45). When LP-IR was categorized by HOMA-IR and either body mass index (BMI) or fasting plasma glucose (FPG), subgroups were revealed whose LP-IR scores were high (≥50), despite having normal BMIs (<24 kg/m2) or FPG (<100 mg/dL).
Conclusions: LP-IR scores had strong associations with multiple measures, HOMA-IR, and GDR, the former being more reflective of hepatic and the latter of peripheral insulin sensitivity, and may represent a simple means to identify individuals with IR.
doi:10.1089/met.2014.0050
PMCID: PMC4175429  PMID: 24959989
5.  Heterogeneity in Subcutaneous Adipose Tissue Morphology and Metabolic Complications in Overweight and Obese Women 
Abstract
Objective
The aim of this study was to assess morphological features of intact adipose tissue (AT) ex vivo from both subcutaneous (s.c.) abdominal and gluteal areas using a novel approach of multiphoton autofluorescence microscopy (MPAM) combined with second harmonic generation microscopy (SHGM), and to assess the relationship between morphological features in the two AT sites and insulin resistance to peripheral glucose disposal.
Method
This study was a cross-sectional evaluation of AT morphology feature and peripheral insulin resistance.
Subjects
Fourteen overweight/obese premenopausal women underwent body composition studies, hyperinsulinemic–euglycemic clamps, and needle biopsy of both the s.c. abdominal and gluteal AT areas. MPAM combined with SHGM was used to measure adipocyte maximal diameter and collagen fiber bundle thickness within a sampled image volume after three-dimensional visualization.
Results
Higher body mass index (BMI) was associated with larger adipocyte diameter in s.c. abdominal, but not gluteal, AT. Higher adipocyte diameter was associated with higher pericellular collagen thickness. Adipocyte diameter in s.c. abdominal, but not gluteal, AT was associated positively with leptin and negatively with adiponectin plasma levels and peripheral glucose disposal rate. The latter correlation was no longer significant after adjustment for collagen thickness.
Conclusion
In overweight/obese premenopausal women, larger adipocyte diameter in s.c. abdominal, but not gluteal, AT associates with low plasma adiponectin and systemic insulin resistance, and suggests that increased collagen thickness (obesity-related scarring) could contribute to these findings.
doi:10.1089/met.2013.0024
PMCID: PMC3780308  PMID: 23621112
6.  Serum Uric Acid Predicts Both Current and Future Components of the Metabolic Syndrome 
Abstract
Background
Uric acid (UA) is known to be associated with excess adiposity and insulin resistance. Our aim was to investigate the relationship between UA and the factors associated with the metabolic syndrome and type 2 diabetes mellitus (T2DM), both initially and longitudinally.
Methods
Serum UA was assessed as a potential determinant of concurrent blood pressure, serum lipids, glucose regulation measured via an oral glucose tolerance test (OGTT), acute insulin response (AIR), and insulin action (M) measured with hyperinsulinemic–euglycemic clamps in 245 participants (72% Native American, 56% male). UA was also assessed as a predictor of the above variables in 60 participants with follow-up data available (median follow-up time=11.2 years [interquartile range (IQR)=8.1, 13.6 years]. The impact of UA on the risk of T2DM was determined as 36 of the 245 participants developed T2DM after the baseline visit.
Results
UA was negatively associated with both concurrent and future M, such that for every 1 mg/dL increase in serum UA, M decreased 7.6% (P<0.001) and future M decreased 6.3% (P=0.02). However, UA was not associated with AIR (P=0.7). UA concentrations were a predictor of T2DM [hazard risk ratio (HRR)=1.5; P=0.02]. UA was positively associated with both concurrent blood pressure and lipids and also predicted future increases in blood pressure and total cholesterol.
Conclusions
Not only did UA associate with concomitant insulin action, blood pressure, and lipids, it also predicted future declines in insulin action and T2DM. UA is a potential target for preventing decreases in insulin sensitivity and rises in blood pressure and cholesterol.
doi:10.1089/met.2012.0151
PMCID: PMC3661030  PMID: 23360433
7.  Coronary Artery Calcium Screening in Persons with Metabolic Syndrome and Diabetes: Implications for Prevention 
Abstract
Diabetes and metabolic syndrome are major risk factors for coronary heart disease (CHD). Many patients suffering CHD events are not adequately identified by traditional risk assessment, suggesting the need for early detection of subclinical CHD to identify those at highest risk. Coronary artery calcium (CAC) screening has added utility in categorizing patients with intermediate and high risk of CHD events, and a growing body of evidence suggests its use for CHD risk assessment in persons with metabolic syndrome and diabetes mellitus. These studies demonstrate the presence and extent of CAC to be greater in those with these conditions, compared to those without, and that CHD risk varies greatly according to the extent of CAC both in persons with and without metabolic syndrome and diabetes mellitus. More recently, guidelines regarding the use of CAC screening have been extended to those with diabetes mellitus, helping to further stratify those patients that may benefit from more intensive therapy. This review evaluates the role and possible benefits of CAC screening, with a focus on those with metabolic syndrome and diabetes mellitus for evaluating the risk for CHD.
doi:10.1089/met.2012.0165
PMCID: PMC3840472  PMID: 23438153
8.  Synthesis and Characterization of a Novel Inhibitor of C-Reactive Protein–Mediated Proinflammatory Effects 
Abstract
Background
Numerous studies have shown that high C-reactive protein (CRP) levels predict cardiovascular disease and augur a poor prognosis in patients with acute coronary syndromes. Much in vitro and in vivo data support of a role for CRP in atherogenesis. There is an urgent need to develop inhibitors that specifically block the biological effects of CRP in vivo. The one-bead–one-compound (OBOC) combinatorial library method has been used to discover ligands against several biological targets. In this study, we use a novel fluorescence-based screening method to screen an OBOC combinatorial library for the discovery of peptides against human CRP.
Methods
Human CRP was labeled with fluorescein isothiocyanate (FITC) and human serum albumin (HuSA) was labeled with phycoerythrin (PE) and used for screening. The OBOC library LWH-01 was synthesized on TentaGel resin beads using a standard solid-phase “split/mix” approach.
Results
By subtraction screening, eight peptides that bind specifically to CRP and not to HuSA were identified. In human aortic endothelial cells (HAECs) incubated with CRP, inhibitors CRPi-2, CRPi-3, and CRPi-6 significantly inhibited CRP-induced superoxide, cytokine release, and nuclear factor-κB (NFκB) activity. Molecular docking studies demonstrate that CRPi-2 interacts with the two Ca2+ ions in the single subunit of CRP. The binding of CRPi-2 is reminiscent of choline binding.
Conclusions
Future studies will examine the utility of this inhibitor in animal models and clinical trials.
doi:10.1089/met.2012.0123
PMCID: PMC3848264  PMID: 23445482
9.  Hydrogen Sulfide Upregulates Glutamate–Cysteine Ligase Catalytic Subunit, Glutamate–Cysteine Ligase Modifier Subunit, and Glutathione and Inhibits Interleukin-1β Secretion in Monocytes Exposed to High Glucose Levels 
Abstract
Glutathione (GSH) deficiency and interleukin-1β (IL-1β) upregulation are linked to the progression of vascular inflammation and atherosclerosis. The consumption of sulfide-rich vegetables is known to lower the risk of atherosclerosis. This study examined the hypothesis that hydrogen sulfide (H2S) upregulates the glutamate–cysteine ligase catalytic subunit (GCLC) and GSH and inhibits IL-1β in a monocyte cell model. U937 monocytes were supplemented with H2S (0–12.5 μM) for 2 hr and then exposed to a control or high glucose (HG, 25 mM) for 22 hr. Levels of GCLC and glutamate–cysteine ligase modifier subunit (GCLM) expression were determined by western blotting and GSH using high-performance liquid chromatography (HPLC), and IL-1β using enzyme-linked immunoassay (ELISA). H2S significantly (P<0.05) upregulated expression of GCLC and GCLM, and formation of GSH, and inhibited IL-1β secretion in controls and HG-treated monocytes. This is the first demonstration of H2S upregulation of GCLC and GSH and inhibition of IL-1β levels, which may be what mediates the beneficial effects of H2S-rich compounds in mitigating the pathogenesis of metabolic syndrome and atherosclerosis.
doi:10.1089/met.2014.0022
PMCID: PMC4050455  PMID: 24665821
10.  Ethnic and Gender Susceptibility to Metabolic Risk 
Abstract
Background: Aggregation of metabolic risk factors—i.e., elevated plasma triglyceride (TG), reduced high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, and raised plasma glucose—convey increased risk for atherosclerotic cardiovascular disease and type 2 diabetes.
Methods: This study was carried out to determine the association of waist girth, ethnicity, and gender with susceptibility for metabolic risk. Included were 1671 adult women (50.7% black) and 1339 men (46.5% black) enrolled in the Dallas Heart Study. Subjects were stratified into three categories by waist girth—low, intermediate, and high, corresponding to BMI ranges of <25 kg/m2, 25–29.9 kg/m2, and ≥30 kg/m2.
Results: Risk factor prevalence rose progressively through each waist-girth category. However, even among those with high waist-girth, prevalence of three or more risk factors was less than 50%. Several differences among the ethnic groups were noted; for example, Hispanic men had a higher prevalence of elevated TG compared to whites; black men, on the other hand, had a lower frequency of high TG. There were also fewer black men with low HDL-C than in the other groups. Black and Hispanic men had a higher prevalence of elevated glucose and updated homeostasis model assessment of insulin resistance (HOMA2-IR) than whites. More black men had elevated blood pressure than other groups. These differences were less pronounced among ethnic groups of women.
Conclusion: Although ethnic and gender differences in risk factor prevalence may exist, it is notable that the majority of subjects, even when obese, did not have elevated risk factors. This finding points to the need to focus largely on subjects with metabolic risk factors when implementing therapeutic interventions.
doi:10.1089/met.2013.0113
PMCID: PMC3935470  PMID: 24325736
11.  Triglyceride-Based Screening Tests Fail to Recognize Cardiometabolic Disease in African Immigrant and African-American Men 
Abstract
Background
The prevalence of cardiometabolic disease in Africa now rivals that of Western nations. Therefore, screening programs that lead to effective prevention of cardiometabolic disease in Africans is imperative. Most screening tests for cardiometabolic disease use triglyceride (TG) levels as a criterion. However, the failure rate of TG-based screening tests in African Americans is high. In Africans, the efficacy of TG-based screening tests is unknown. Our goal was to determine the association between hypertriglyceridemia (TG ≥150 mg/dL) and cardiometabolic disease in African and African-American men.
Research Design and Methods
This was a cross-sectional study of 155 men (80 African immigrants, 75 African Americans) [age, 35±9 years, mean±standard deviation (SD), body mass index (BMI) 28.5±5.2 kg/m2] who self-identified as healthy. Lipid profiles were performed. Glucose tolerance and insulin resistance was determined by oral glucose tolerance tests (OGTT) and the insulin sensitivity index (SI), respectively. Cardiometabolic disease was defined by four possible subtypes—prediabetes, diabetes, insulin resistance, or metabolic triad [hyperinsulinemia, hyperapolipoprotein B, small low-density lipoprotein (LDL) particles].
Results
TG levels were higher in men with cardiometabolic disease than without (88±43 versus 61±26 mg/dL, P<0.01). However, <10% of men with cardiometabolic disease had TG ≥150 mg/dL. Even within each cardiometabolic disease subtype, the prevalence of TG ≥150 mg/dL was <10%. Furthermore, TG levels in the 5% of men identified by OGTT as diabetic were ≤100 mg/dL (mean 71±24, range 45–100 mg/dL).
Conclusions
Hypertriglyceridemia is a poor marker of cardiometabolic disease in men of African descent. Therefore TG-based screening tests fail to identify both African immigrants and African-American men with cardiometabolic disease. As a consequence, the opportunity for early intervention and prevention is lost.
doi:10.1089/met.2012.0114
PMCID: PMC3557430  PMID: 23215943
12.  The Ratio of Parathyroid Hormone to Vitamin D Is a Determinant of Cardiovascular Risk and Insulin Sensitivity in Adolescent Girls 
Abstract
Background
Vitamin D insufficiency and higher testosterone are common in obese girls and may adversely affect glucose homeostasis and cardiovascular risk. Data are conflicting regarding the impact of parathyroid hormone (PTH) on these factors. Our objective was to determine associations of 25-hydroxyvitamin D (25-OHD), PTH, and testosterone with measures of glucose homeostasis and cardiovascular risk in adolescent girls after controlling for regional adiposity, with the hypothesis that lower 25-OHD, a higher PTH or PTH/25-OHD ratio, and higher testosterone would be associated with lower insulin sensitivity and greater cardiovascular risk.
Methods
A total of 15 obese girls and 15 matched normal weight controls (12–18 years) underwent fasting measurements of 25-OHD, PTH, testosterone, sex hormone-binding globulin (SHBG), high-sensitivity C-reactive protein (hsCRP), oral glucose tolerance testing, and quantification of visceral (VAT) and subcutaneous (SAT) fat by magnetic resonance imaging (MRI).
Results
There were no associations of 25-OHD with measures of glucose homeostasis or hsCRP. In contrast, PTH and PTH/25-OHD were associated negatively with homeostasis model assessment of insulin resistance (HOMA-IR) and positively with quantitative insulin sensitivity check index (QUICKI) in obese girls but not controls. These associations remained significant after controlling for body mass index standard deviation score (BMI-SDS), but not for VAT. On regression modeling, PTH/25-OHD was positively associated with hsCRP after controlling for BMI-SDS or VAT. Free testosterone positively predicted the corrected insulin response.
Conclusions
In obese girls, PTH/25-OHD is positively associated with measures of insulin sensitivity and hsCRP. Further studies are needed to investigate the relationship between PTH and glucose homeostasis in obesity.
doi:10.1089/met.2012.0102
PMCID: PMC3593691  PMID: 23130887
13.  Serum Adiponectin in Relation to Race–Ethnicity and Vascular Risk Factors in the Northern Manhattan Study 
Abstract
Background
Population-based data on serum adiponectin levels, an adipocytokine secreted from adipose tissue, are lacking, particularly across race–ethnic groups. Studies have suggested an inverse association between adiponectin and vascular risk factors, but data are limited and inconsistent. We examined the cross-sectional association between adiponectin, vascular risk factors and race–ethnicity in the population-based Northern Manhattan Study (NOMAS).
Methods
Blood samples, anthropomorphics, and vascular risk factors were collected at baseline. Multivariable linear regression analysis was conducted with log-transformed adiponectin as the dependent variable.
Results
Adiponectin was measured among 2900 participants (age 69±10 years, body mass index (BMI) 28.0±5.6, 37% male, 21% white, 53% Hispanic, 24% black). The mean adiponectin was 11.4±6.2 μg/mL (median=9.8, range=2.1–53.3). After multivariable adjustment, adiponectin levels were greatest among whites, followed by Hispanics, and lowest among blacks. Lower adiponectin levels were observed in participants with the following characteristics: Male, former smoking, hypertension, diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), metabolic syndrome, moderate alcohol use, elevated waist circumference, BMI, estimated glomerular filtration rate (eGFR), triglycerides, low-density lipoprotein cholesterol (LDL-C), lower high-density lipoprotein cholesterol (HDL-C), and younger age. Obesity was a stronger risk factor for decreased adiponectin among blacks than among whites or Hispanics. The associations for several vascular risk factors, including hypertension, triglycerides, and low HDL-C, with low adiponectin were stronger among individuals who were not obese than among those who were obese.
Conclusions
Adiponectin levels were lower among blacks and Hispanics and among those with various vascular risk factors, and greater with older age. The association between BMI and adiponectin varied across race–ethnic groups. Investigation of whether differences in body fat distribution may explain race–ethnic differences in adiponectin is needed.
doi:10.1089/met.2012.0065
PMCID: PMC3593695  PMID: 23127161
14.  Is the Metabolic Syndrome a “Small Baby” Syndrome?: The Bogalusa Heart Study 
Abstract
Background
Metabolic syndrome has been called a “small baby syndrome,” but other analyses suggest that postnatal growth is more important than birthweight, or that large babies are also at risk. The aim of this analysis was to examine whether there was a relationship between both low and high birthweight and metabolic syndrome, using multiple definitions of metabolic syndrome, and to determine whether this relationship varied by body size across the life course.
Methods
Data from the Bogalusa Heart Study, a study of cardiovascular disease in children and young adults, were linked to birth certificate data. Metabolic syndrome was defined by the National Cholesterol Education Program, the International Diabetes Foundation, and the World Health Organization (WHO) definition. Small-for-gestational-age (SGA) was defined as birthweight <10th percentile by sex for gestational age and large-for-gestational-age (LGA) as birthweight >90th percentile. Birthweight-for-gestational-age was also examined as a continuous predictor. Chi-squared tests and logistic regression were used to examine the relationship between birth size and metabolic syndrome.
Results
Higher birthweight-for-gestational-age was associated with a reduced risk of metabolic syndrome, especially by the WHO definition. After adjustment for body mass index (BMI), categorized birthweight was associated with metabolic syndrome, with the protective associations with LGA being stronger than the positive associations with SGA. Among the individual components of metabolic syndrome, higher waist circumference was associated with both SGA and LGA after BMI was controlled for. Effects of SGA and BMI at any age were largely independent rather than interactive.
Conclusions
SGA is associated with some, but not all, components of metabolic syndrome. The relationship between SGA and metabolic syndrome is partially confounded by later BMI.
doi:10.1089/met.2012.0031
PMCID: PMC3546360  PMID: 22831273
15.  Fat Distribution and Insulin Resistance in Young Adult Nonobese Asian Indian Women 
Abstract
Although Asian Indian (people of Indian subcontinent descent) men are shown to have higher total and truncal body fat as well as greater insulin resistance compared to white men matched for total body fat and age, data in women are not conclusive. The objective of this study was to compare total and regional fat distribution and insulin sensitivity between healthy young premenopausal Asian Indian and white women of similar body mass index (BMI). Twenty Asian Indian women (65% immigrants and 35% first generation living in Dallas) and 31 white women of similar age and BMI [age 24±3 vs. 25±4; BMI 22±4 vs. 23±5; mean±standard deviation (SD) in Asian Indian and white, respectively] without diabetes were evaluated with anthropometric measurements, underwater weighing for percentage of total body fat mass, magnetic resonance imaging of whole abdomen for measurement of abdominal subcutaneous and intraperitoneal fat mass, and euglycemic–hyperinsulinemic clamp study for measurement of insulin sensitivity. There were no differences in waist or hip circumference, total body subcutaneous abdominal or intraperitoneal fat mass, fasting plasma glucose, and insulin levels between Asian Indian women and white women. The peripheral glucose disposal rate (Rd) during hyperinsulinemic–euglycemic clamp was found to be almost identical in the two study groups (median value of 6.9 and 6.8 mg/min per kg of body weight, for Asian Indians and whites, respectively). For similar total or regional fat content, the glucose disposal rate was comparable in the two study groups. In conclusion, we demonstrate that young Asian Indian women do not have excess abdominal or intraperitoneal fat or insulin resistance for similar BMI compared to white women of European descent.
doi:10.1089/met.2012.0041
PMCID: PMC3503461  PMID: 22746275
16.  The Effect of Sleep Apnea and Insomnia on Blood Levels of Leptin, Insulin Resistance, IP-10, and Hydrogen Sulfide in Type 2 Diabetic Patients 
Abstract
Introduction
Sleep deficits associated with sleep apnea and insomnia increase the risk of vascular inflammation and insulin resistance. This study examined the hypothesis that inflammation markers are higher in those diabetic patients who experience sleep deficits compared with those without any history of a sleep disorder.
Methods
Fasting blood was obtained after written informed consent, and sleep disorder histories were obtained from type 2 diabetic patients (n=81) attending clinics of the Louisiana State University Health Sciences Center.
Results
There was a significant correlation between body weight and leptin, and leptin in turn was significantly correlated with 10-kDa interferon-γ–induced protein (IP-10) levels and insulin resistance in type 2 diabetic patients. Fasting blood levels of leptin, IP-10, and insulin resistance were significantly elevated in patients with sleep deficits compared with diabetics with normal sleep patterns. There were no differences in glycosylated hemoglobin (HbA1c) or fasting glucose in patients with sleep deficits compared with those with normal sleep patterns. Sleep deficits increase circulating levels of leptin, IP-10, and insulin resistance compared to levels seen in patients with diabetes who reported no difficulty with sleep. Patients with sleep apnea had significantly lower hydrogen sulfide (H2S) levels compared with patients with normal sleep patterns or patients with insomnia. Low levels of circulating H2S could contribute to higher vascular inflammation in patients with sleep apnea.
Conclusions
These results suggest that sleep apnea is associated with a decrease in circulating H2S and sleep disorders increase the risk of inflammation and insulin resistance, which can contribute to the increased risk of vascular disease in subjects with type 2 diabetes.
doi:10.1089/met.2012.0045
PMCID: PMC3503462  PMID: 22746298
17.  Opportunities for Using Lipoprotein Subclass Profile by Nuclear Magnetic Resonance Spectroscopy in Assessing Insulin Resistance and Diabetes Prediction 
Abstract
The incidence of type 2 diabetes mellitus (T2DM) has reached epidemic levels, and current trends indicate that its prevalence will continue to rise. The development of T2DM can be delayed by several years, and may even be prevented, by identifying individuals at risk for T2DM and treating them with lifestyle modification and/or pharmacological therapies. There are a number of methods available for assessing the insulin resistance (IR) that characterizes, and is the precursor to, T2DM. However, current clinical methods for assessing IR, based on measures of plasma glucose and/or insulin are either laborious and time-consuming or show a low specificity. IR manifests its earliest measurable abnormalities through changes in lipoproteins, and thus we propose that by examining lipoprotein subclass profile, it may be possible to alert physicians and patients to a heightened risk of developing diabetes. This will allow us to institute appropriate lifestyle changes and treatment potentially to delay the onset or possibly prevent the progression to diabetes.
doi:10.1089/met.2011.0148
PMCID: PMC3409454  PMID: 22533466
18.  Differences in Systemic Oxidative Stress Based on Race and the Metabolic Syndrome: The Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) Study 
Abstract
Background
Classification schema such as metabolic syndrome may underestimate cardiovascular disease (CVD) risk in African Americans, despite a higher burden of CVD in African Americans. Oxidative stress results from an imbalance of prooxidants and antioxidants and leads to endothelial dysfunction that promotes vascular inflammation and atherosclerosis. Aminothiol markers of oxidative stress are associated with CVD risk factors and metabolic syndrome; however, little is known about racial differences in levels of oxidative stress. We sought to investigate whether oxidative stress would be higher in African Americans compared to whites independently of traditional risk factor burden.
Methods
We assessed oxidative stress in a biracial, community-based cohort. In 620 subjects (59% female, 52% African American) in the Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) study, we measured plasma levels of glutathione, an intracellular antioxidant, and its redox potential as a ratio of reduced and oxidized glutathione (Eh glutathione).
Results
African Americans had lower glutathione levels (P<0.001) compared to whites. There was a trend toward more oxidized Eh glutathione (P=0.07) in African Americans; however, this did not reach statistical significance. After adjustment for demographics and CVD risk factors, African-American race remained a significant correlate of lower glutathione levels (P<0.001) and a more oxidized Eh glutathione (P=0.04). After further adjustment for high-sensitivity C-reactive protein (hsCRP), glutathione remained significantly lower in African Americans (P=0.001). African Americans with or without metabolic syndrome had lower glutathione levels compared to whites with or without metabolic syndrome, respectively (both P≤0.001), and African Americans without metabolic syndrome had a more oxidized Eh glutathione compared to whites without metabolic syndrome (P=0.003).
Conclusions
African Americans have higher levels of oxidative stress than whites, even after adjustment for differences in CVD risk factors and inflammation. Racial differences in oxidative stress may play a key role in understanding observed racial disparities in CVD.
doi:10.1089/met.2011.0117
PMCID: PMC3449394  PMID: 22385338
19.  Regulation of Small Ubiquitin-Like Modifier-1, Nuclear Receptor Coreceptor, Histone Deacetylase 3, and Peroxisome Proliferator-Activated Receptor-γ in Human Adipose Tissue 
Abstract
Background
This study investigated the regulation of peroxisome proliferator-activated receptor-γ (PPARγ), the histone deacetylase 3 (HDAC3)–nuclear receptor coreceptor (NCoR) complex (a corepressor of transcription used by PPARγ), and small ubiquitin-like modifier-1 (SUMO-1) (a posttranslational modifier of PPARγ) in human adipose tissue and both adipocyte and macrophage cell lines. The objective was to determine whether there were alterations in the human adipose tissue gene expression levels of PPARγ, HDAC3, NCoR, and SUMO-1 associated either with obesity or with treatment of impaired glucose tolerance (IGT) subjects with insulin-sensitizing medications.
Methods
We obtained subcutaneous adipose tissue biopsies from 86 subjects with a wide range of body mass index (BMI) and insulin sensitivity (SI). Additionally, adipose tissue biopsies were obtained from a randomized subgroup of IGT subjects before and after 10 weeks of treatment with either pioglitazone or metformin.
Results
The adipose mRNA levels of PPARγ, NCoR, HDAC3, and SUMO-1 correlated strongly with each other (P<0.0001); however, SUMO-1, NCoR, and HDAC3 gene expression were not significantly associated with BMI or SI. Pioglitazone increased SUMO-1 expression by 23% (P<0.002) in adipose tissue and an adipocyte cell line (P<0.05), but not in macrophages. Small interfering RNA (siRNA)-mediated knockdown of SUMO-1 decreased PPARγ, HDAC3, and NCoR in THP-1 cells and increased tumor necrosis factor-α (TNF-α) induction in response to lipopolysaccharide (LPS).
Conclusions
These results suggest that the coordinate regulation of SUMO-1, PPARγ1/2, HDAC3, and NCoR may be more tightly controlled in macrophages than in adipocytes in human adipose and that these modulators of PPARγ activity may be particularly important in the negative regulation of macrophage-mediated adipose inflammation by pioglitazone.
doi:10.1089/met.2011.0121
PMCID: PMC3449396  PMID: 22651256
20.  Effect of Endoplasmic Reticulum Stress on Inflammation and Adiponectin Regulation in Human Adipocytes 
Abstract
The endoplasmic reticulum (ER) of adipocytes plays a major role in the assembly and secretion of adipokines. The levels of serum adiponectin, secreted by adipocytes, are decreased in insulin resistance, diabetes, and obesity. The role of ER stress in downregulating adiponectin levels has been demonstrated in mouse models of obesity. Studies examining human adipose tissue have indicated that there is an increase in the ER stress transcript HSPA5 with increased body mass index (BMI). However, it is not established whether ER stress results in changes in adiponectin levels or multimerization in human adipocytes. We examined whether the induction of ER stress using tunicamycin, thapsigargin, or palmitate alters the messenger RNA (mRNA) and protein expression of adiponectin and the mRNA expression of chaperones ERP44 and ERO1 in adult-derived human adipocyte stem (ADHAS) cells. ER stress was measured using key indicators of ER stress–HSPA5, ERN1, CHOP, and GADD34, as well as changes in eIF2α phosphorylation. Because ER stress is suggested to be the proximal cause of inflammation in adipocytes, we further examined the change in inflammatory status by quantitating the change in Iκβ-α protein following the induction of ER stress. Our studies indicate that: (1) ER stress markers were increased to a higher degree using tunicamycin or thapsigargin compared to palmitate; (2) ER stress significantly decreased adiponectin mRNA in response to tunicamycin and thapsigargin, but palmitate did not decrease adiponectin mRNA levels. In all three instances, the induction of ER stress was accompanied by a decrease in adiponectin protein as well as adiponectin multimerization. All three inducers of ER stress increased tumor necrosis factor-α (TNF-α) mRNA and decreased Iκβ-α protein in adipocytes. The data suggest that ER stress modifies adiponectin secretion and induces inflammation in ADHAS cells.
doi:10.1089/met.2012.0002
PMCID: PMC3449395  PMID: 22545589
21.  Mediterranean Dietary Pattern Adherence: Associations with Prediabetes, Metabolic Syndrome, and Related Microinflammation 
Abstract
Background
The adherence to the Mediterranean Diet (Med Diet) seems to reduce the incidence of metabolic syndrome. The present study aimed to explore whether the adherence to the overall Med Diet pattern and to specific Med Diet items is associated with the presence of metabolic syndrome, impaired fasting glucose (IFG), insulin resistance (IR), and microinflammation in subjects free of diabetes and cardiovascular diseases.
Measurements
Each patient underwent clinical assessment. Adherence to the Med Diet was measured by a previously validated 14-item questionnaire. Metabolic syndrome was defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria; IR was defined by homeostasis model assessment of insulin resistance (HOMA-IR); inflammation was assessed through a high-sensitivity C-reactive protein (hsCRP) assay.
Results
A total of 120 subjects (64.2% women, mean age 59.8±10.2 years) were enrolled at this study. Subjects with lower Med Diet pattern adherence exhibited higher occurrence of metabolic syndrome and all its components and higher HOMA-IR and hsCRP values (P for all <0.0001). Subjects with metabolic syndrome were less likely to consume olive oil (P=0.002) and vegetables (P=0.023). By multivariable analyses, the overall Med Diet score was found to be strongly and inversely associated with the presence of metabolic syndrome [B=−0.066; 95% confidence interval (CI) −0.105 to −0.028; P=0.001], IFG (B=−0.076; 95% CI −0.114 to −0.038; p<0.0001), high HOMA-IR (B=−0.071; 95% CI −0.108 to −0.034; P<0.0001) and high hsCRP (B=−0.082; 95% CI −0.125 to −0.045; P<0.0001). None of specific Med Diet items independently predicted metabolic syndrome, IFG, and high HOMA-IR. Instead, the consumption of white meat over red meat (B=−0.324; 95% CI −0.467 to −0.178; P<0.0001) was found to be inversely associated with increased hsCRP.
Conclusions
The inverse associations between adherence to Med Diet and the prevalence of metabolic syndrome and prediabetes may be due more to the effects of the entire dietary pattern rather than to individual food components. Metabolic syndrome–related microinflammation may further be linked to specific Med Diet components.
doi:10.1089/met.2012.0168
PMCID: PMC3696914  PMID: 23451814
22.  The Triglyceride Paradox in People of African Descent 
Abstract
Even though insulin resistance, cardiovascular disease (CVD), and type 2 diabetes (T2D) are associated with hypertriglyceridemia, blacks with these conditions usually have normal triglyceride (TG) levels. This is often called a lipid paradox. More precisely, it is a “TG paradox.” The pathways that lead to hypertriglyceridemia have been intensively explored. Yet, the pathways that allow TG levels to be normal in the presence of insulin resistance have received little attention and this is problematic. Tests designed for the early detection of insulin-resistant conditions often use elevated TG levels as a diagnostic criterion. However, insulin resistance, CVD, and T2D are not usually associated with hypertriglyceridemia in people of African descent; therefore, the widespread use of TG levels to predict these conditions needs re-evaluation. This review focuses on black–white differences in: (1) the lipid profile across North America, Europe, and Africa; (2) the efficacy of TG-based screening tests, specifically the metabolic syndrome and its two abbreviated versions, the hypertriglycerdemic waist and TG/high-density lipoprotein cholesterol (HDL-C) ratio; and (3) the mechanisms that allow TG to be normal even in the presence of insulin resistance. Overall, a broader understanding of how TG physiology varies by race could lead to better diagnostic tests and improved health outcomes.
doi:10.1089/met.2011.0108
PMCID: PMC3311911  PMID: 22224930
23.  Electrocardiographic Abnormalities Associated with the Metabolic Syndrome and Its Components: The Multi-Ethnic Study of Atherosclerosis 
Abstract
Background
The association between metabolic syndrome and electrocardiographic (ECG) abnormalities is not well established.
Methods
ECG tracings of 6,765 men and women aged 45–84 years, free of clinical cardiovascular disease, from the Multi-Ethnic Study of Atherosclerosis were obtained (2000–2002) and classified as normal or having major or minor abnormalities. We evaluated the associations of metabolic syndrome and its components with ECG abnormalities, adjusting for age, ethnicity, and gender and testing for effect modification by ethnicity and gender.
Results
The associations of metabolic syndrome, hypertension, and high triglycerides with ECG abnormalities varied significantly by gender. In males, metabolic syndrome and hypertension were significantly associated with major ECG abnormality [1.69 (1.33–2.13), and 2.22 (1.72–2.86), respectively] after adjusting for ethnicity and gender. Hypertension was also associated significantly with minor ECG abnormality in males after adjusting for age and ethnicity. In females, metabolic syndrome and hypertension were significantly associated with major [1.84 (1.44–2.37), and 1.68 (1.27–2.22), respectively] and minor [1.38 (1.19–1.59), and 1.53 (1.32–1.79), respectively] ECG abnormalities after adjusting for age and ethnicity. High triglycerides were only significantly associated with major ECG abnormality in females after adjusting for age and ethnicity. After adjusting for age, ethnicity, and gender, central obesity and high fasting blood glucose were significantly associated with major and minor ECG abnormalities, whereas low high-density lipoprotein cholesterol was significantly associated with major ECG abnormality only.
Conclusions
Metabolic syndrome and its components are associated with major and/or minor ECG abnormalities. The relationship of metabolic syndrome, hypertension, and high triglycerides with ECG abnormalities varied according to gender.
doi:10.1089/met.2011.0090
PMCID: PMC3339381  PMID: 22053762
24.  Hyperleptinemia and Hypoadiponectinemia in Extreme Pediatric Obesity 
Abstract
Background
Adiponectin and leptin, adipokines associated with metabolic syndrome, type 2 diabetes, and cardiovascular disease, have not been well characterized in extreme pediatric obesity. Therefore, levels were compared in youth that were extremely obese (EO) to normal weight (NW), overweight (OW), and obese (OB) youth.
Methods
Leptin, adiponectin, body mass index (BMI), blood pressure, fasting glucose, insulin, and lipids were obtained in 277 children and adolescents (age 13.4±2.6 years; 152 boys). Participants were classified into four BMI groups (NW, OW, OB, EO). Variables were compared across groups using analysis of covariance (ANCOVA) adjusted for gender, age, and race.
Results
Risk factors generally worsened across BMI groups. EO had significantly higher levels of leptin than OB (P<0.0001), OW (P<0.0001), and NW (P<0.0001). Leptin was higher in OB compared to OW (P<0.005) and NW (P<0.0001) and higher in OW compared to NW (P<0.0001). Adiponectin levels in EO did not significantly differ from OB or OW but were significantly lower than NW (P<0.0001). Adiponectin was not significantly different among the OB, OW, and NW groups.
Conclusions
Leptin was markedly elevated in EO children and adolescents, suggesting that this subset of obese youth may be at particularly high risk of future weight gain and potentially reduced response to weight-loss interventions.
doi:10.1089/met.2011.0086
PMCID: PMC3339383  PMID: 22217186
25.  General Versus Central Adiposity and Relationship to Pediatric Metabolic Risk 
Abstract
Background
The influence of moderate-to-vigorous physical activity (MVPA) and general versus central adiposity on pediatric metabolic risk is not well described.
Methods
Secondary analyses on pediatric participants from the National Health and Nutrition Examination Survey, 2003–2006 (n=2,155). MVPA (min/day) and adherence to MVPA recommendations were assessed objectively by accelerometers. Body mass index (BMI) z-score and waist circumference (WC) were measured by standard protocols. The main dependent variables included an overall metabolic risk score and clinical tests related to metabolic risk. A series of linear regression analyses were used to examine BMI z-score versus WC as a mediator of the relationship between MVPA and the metabolic risk score or the individual components, controlling for sociodemographic covariates. All analyses with BMI z-score as an independent variable controlled for WC and vice versa. The product-of-coefficients method was used to test for mediation.
Results
MVPA adherence was inversely associated and WC was positively associated with the metabolic risk score (all P<0.05). MVPA was inversely associated with systolic blood pressure and positively associated with high-density lipoprotein cholesterol (HDL-C) (all P<0.05). WC was inversely associated with HDL-C and positively associated with C-reactive protein (CRP), glycohemoglobin, fasting triglycerides, and fasting insulin (all P<0.05). WC mediated the relationship between MVPA and CRP or HDL-C (both P<0.05).
Conclusions
MVPA correlated with pediatric metabolic risk and this relationship was mediated by central adiposity for CRP and HDL-C. This finding suggests the need for programs to screen for and improve children's MVPA and WC.
doi:10.1089/met.2011.0064
PMCID: PMC3339386  PMID: 22149935

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