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1.  Worse Cardiometabolic Health in African Immigrant Men than African American Men: Reconsideration of the Healthy Immigrant Effect 
Abstract
Background: The healthy immigrant effect is a phrase that has been used for decades to describe better cardiometabolic health in African immigrants than African Americans. The recent global increase in cardiometabolic diseases raises the possibility that immigrant health may be changing. Therefore, a new assessment of cardiometabolic health in African immigrants is warranted.
Methods: Glucose tolerance status, blood pressure, and visceral adipose tissue (VAT) volume were compared in 214 self-identified healthy men comprised of 138 African immigrants, 76 African Americans, mean age 36±9 years [mean±standard deviation (SD); range 20–64 years]. Insulin resistance was defined by the lowest quartile of the insulin sensitivity index (SI≤2.28 mU/L−1·min−1). The waist circumference (WC) which predicts insulin resistance was determined using receiver operating characteristic curves and the Youden index.
Results: Body mass index (BMI) and WC were lower in African immigrants than African Americans (BMI, 27.4±3.8 vs. 29.3±5.5 kg/m2, P<0.01; WC, 91±11 vs. 97±16 cm, P<0.01). However, blood pressure, fasting glucose, and 2-hr glucose were higher in the African immigrants (all P<0.01). In addition, African immigrants had a higher prevalence of previously undiagnosed diabetes (8% vs. 0%, P<0.01) and prediabetes (35% vs. 22%, P<0.01). After adjusting for WC, African immigrants had more visceral adipose tissue (VAT) than African Americans (P<0.01). Consequently, the WC that predicted insulin resistance was 92 cm in African immigrants but 102 cm in African Americans.
Conclusion: African immigrants were less obese than African Americans but had worse cardiometabolic health, specifically higher glucose levels, more hypertension, and greater visceral adiposity. Overall, the healthy immigrant effect may no longer be valid.
doi:10.1089/met.2014.0026
PMCID: PMC4117257  PMID: 24814168
2.  Mice with Altered Brain Lipoprotein Metabolism Display Maladaptive Responses to Environmental Challenges That May Predispose to Weight Gain 
Abstract
Background: Three-month-old neuron-specific lipoprotein lipase (LPL)-depleted mice (NEXLP−/−) mice are preobese and have normal body weight before developing obesity by 4.5 months. This series of experiments investigated responses to novel environment stimuli and acute sleep deprivation in preobese NEXLPL−/−) mice to test the hypothesis that neuron-specific LPL deletion alters normal adaptive metabolic responses to environmental challenges.
Methods: Three-month-old, age- and weight-matched, male NEXLPL−/−) (n=10) and wild-type (WT) (n=10) mice were housed in individual metabolic chambers with a 12-hr dark cycle. Food and water intake, locomotor activity, and calorimetry data were recorded in 12-min intervals. Novel environmental responses were elicited by first-time introduction to chambers at dark onset, followed by acclimation, baseline recording, and 6-hr of sleep deprivation on subsequent experimental days.
Results: NEXLPL−/−) mice displayed a 1.5-fold greater increase in activity in response to a novel environment than seen in WT controls (P=0.0308), and a two-fold greater increase in food intake following acute sleep deprivation (P=0.0117). NEXLPL−/−) mice averaged a 27% higher metabolic rate than WT mice throughout the experiments (P<0.0001). Body weight, composition, and temperature did not differ between murine groups throughout the experiments. Levels of free fatty acid, insulin, glucose, and triglycerides were similar between groups at the terminus.
Conclusions: A deficiency in neuronal LPL signaling disrupts normal responses to novel environmental exposure and acute sleep deprivation, a maladaptive response that may contribute to weight gain in genetically predisposed mice, and perhaps humans.
doi:10.1089/met.2013.0141
PMCID: PMC4162444  PMID: 24730656
3.  Cardiovascular Effects of Incretin Therapy in Diabetes Care 
Abstract
Diabetes patients are at high risk for development of cardiovascular disease. The cardiovascular safety of antidiabetic medications is a concern. Incretin therapies, including glucagon-like peptide 1 receptor (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, have recently been introduced to clinical practice and are widely used. Data from phase 2 and 3 trials and retrospective analyses of clinical databases have shown favorable changes in cardiovascular risk factors and outcomes. However, only a few prospective trials have been designed with cardiovascular outcomes as a primary end point. From current data, alogliptin and saxagliptin do not change cardiovascular risk in type 2 diabetes mellitus (T2DM) patients. Vildagliptin does not alter myocardial function in T2DM patients with systolic dysfunction. However, the possibility of an increase in clinical heart failure and worsened outcomes in patients with existing heart failure is suggested by current data. Clinicians need to follow patients on DPP-4 inhibitors carefully for this possibility until more prospective randomized controlled data are available.
doi:10.1089/met.2014.0035
PMCID: PMC4162447  PMID: 24842063
4.  Use of HbA1c for Diagnoses of Diabetes and Prediabetes: Comparison with Diagnoses Based on Fasting and 2-Hr Glucose Values and Effects of Gender, Race, and Age 
Abstract
Background: Glycated hemoglobin (HbA1c) has been advocated for the diagnosis of diabetes and prediabetes. Its performance has been commonly assessed in corroboration with elevated fasting plasma glucose (FPG), but not the combination of FPG and 2-hr glucose values. This study assesses receiver operating characteristics (ROC) curves of HbA1c pertaining to the diagnoses of prediabetes and diabetes by FPG and/or 2-hr glucose, and the effects of age, gender, and race.
Methods: We assessed the utility of HbA1c for diagnosing diabetes and prediabetes among 5395 adults without known diabetes from the National Health and Nutrition Examination Survey (NHANES) 2005–2010.
Results: Current cutoffs of HbA1c for diabetes (6.5%) or prediabetes (5.7%) exhibited low sensitivity (0.249 and 0.354, respectively) and high specificity in identifying patients diagnosed using both FPG and 2-hr glucose, resulting in large false-negative rates (75.1% and 64.9%). Misdiagnosis rates increased with age and in non-Hispanic whites and Mexican Americans. When HbA1c was combined with FPG for diagnoses, the false-negative rate remained high for diabetes (45.7%), but was reduced for prediabetes (9.2%).
Conclusions: When assessed against diagnoses using both FPG and 2-hr glucose, HbA1c had low sensitivity and high specificity for identifying diabetes and prediabetes, which varied as a function of age and race. Regarding recently released American Diabetes Association (ADA) and joint European guidelines, it is important to consider that HbA1c values below 6.5% and 5.7% do not reliably exclude the presence of diabetes and prediabetes, respectively. Overall, the data argue for greater use of oral glucose tolerance tests (OGTTs) and both FPG and 2-hr glucose values for diagnosis of diabetes and prediabetes.
doi:10.1089/met.2013.0128
PMCID: PMC4088353  PMID: 24512556
5.  Neck Circumference Is a Predictor of Metabolic Syndrome and Obstructive Sleep Apnea in Short-Sleeping Obese Men and Women 
Abstract
Background: The constellation of metabolic syndrome, although controversial with regard to its clinical usefulness, is epidemiologically related to increased diabetes risk and cardiovascular mortality. Our goal was to investigate the associations among neck circumference (NC), obstructive sleep apnea syndromes (OSAS), and metabolic syndrome in obese men and women sleeping less than 6.5 hr per night.
Methods: This was a cross-sectional study of obese men and premenopausal obese women sleeping less than 6.5 hr per night. We enrolled 120 individuals (92 women), age 40.5±6.9 years and body mass index (BMI) 38.6±6.5 kg/m2. Metabolic syndrome severity was assessed by a score and OSAS was defined as a respiratory disturbance index (RDI) ≥5. Metabolic end endocrine parameters were measured, and sleep duration was determined by actigraphy and validated questionnaires.
Results: Metabolic syndrome was found in 41% and OSAS in 58% (28% had both). Subjects with metabolic syndrome were 3 years older and more often Caucasian; they had higher RDI scores, larger NC, more visceral fat, lower serum adiponectin, higher 24-hr urinary norepinephrine (NE) excretion, and lower growth hormone concentrations. A NC of ≥38 cm had a sensitivity of 54% and 58% and a specificity of 70% and 79% in predicting the presence of metabolic syndrome and OSAS, respectively. RDI, adiponectin, and NC accounted for approximately 30% of the variability in the metabolic syndrome score, as estimated by an age-, gender-, and race-corrected multivariate model (R2=0.376, P<0.001).
Conclusion: Greater NC is associated with OSAS and metabolic syndrome in short-sleeping obese men and premenopausal obese women. Addition of NC to the definition of metabolic syndrome should be considered and needs to be validated in future studies.
doi:10.1089/met.2013.0093
PMCID: PMC4094033  PMID: 24571423
6.  Metabolically Healthy Obesity and Its Associates in Mongolian Chinese Adults 
Abstract
Background: Not all obese individuals show cardiometabolic abnormalities. We examined metabolically healthy obesity (MHO) and its associates in 2530 Mongolian Chinese adults.
Methods: MHO was defined by waist circumference, low-density lipoprotein (LDL-C) cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), systolic blood pressure (SBP), diastolic blood pressure (DBP), and glucose.
Results: Only 3.0% of the participants had MHO, with 0.8% of men and 4.5% of women having this condition (P<0.001 for sex difference). Despite striking differences in obesity measures, MHO individuals had a comparable cardiometabolic profile to that for metabolically healthy, nonobese individuals (MHNO) and an improved cardiometabolic profile, i.e., lower levels of blood pressure, glucose, insulin, LDL-C, TGs, and higher levels of HDL-C compared to metabolically abnormal individuals (all P<0.01, except for insulin). MHO individuals had lower levels of high-sensitivity C-reactive protein and soluble intercellular adhesion molecule-1, compared to metabolically abnormal individuals, and had comparable levels of these markers to those in MHNO individuals. Furthermore, only 5.3% of MHO individuals had a family history of hypertension, comparable to 5.0% in MHNO individuals, and much lower than 15.9% in metabolically abnormal, nonobese individuals and 12.8% in metabolically abnormal, obese individuals (overall P<0.001).
Conclusions: We conclude that MHO is associated with a low inflammation state, and family history of hypertension may play a role in the MHO phenotype.
doi:10.1089/met.2013.0102
PMCID: PMC4275772  PMID: 24460218
7.  Metabolic Syndrome Prevalence and Associations in a Bariatric Surgery Cohort from the Longitudinal Assessment of Bariatric Surgery-2 Study 
Abstract
Background: Metabolic syndrome is associated with higher risk for cardiovascular disease, sleep apnea, and nonalcoholic steatohepatitis, all common conditions in patients referred for bariatric surgery, and it may predict early postoperative complications. The objective of this study was to determine the prevalence of metabolic syndrome, defined using updated National Cholesterol Education Program criteria, in adults undergoing bariatric surgery and compare the prevalence of baseline co-morbid conditions and select operative and 30-day postoperative outcomes by metabolic syndrome status.
Methods: Complete metabolic syndrome data were available for 2275 of 2458 participants enrolled in the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2), an observational cohort study designed to evaluate long-term safety and efficacy of bariatric surgery in obese adults.
Results: The prevalence of metabolic syndrome was 79.9%. Compared to those without metabolic syndrome, those with metabolic syndrome were significantly more likely to be men, to have a higher prevalence of diabetes and prior cardiac events, to have enlarged livers and higher median levels of liver enzymes, a history of sleep apnea, and a longer length of stay after surgery following laparoscopic Roux-en-Y gastric bypass (RYGB) and gastric sleeves but not open RYGB or laparoscopic adjustable gastric banding. Metabolic syndrome status was not significantly related to duration of surgery or rates of composite end points of intraoperative events and 30-day major adverse surgical outcomes.
Conclusions: Nearly four in five participants undergoing bariatric surgery presented with metabolic syndrome. Establishing a diagnosis of metabolic syndrome in bariatric surgery patients may identify a high-risk patient profile, but does not in itself confer a higher risk for short-term adverse postsurgery outcomes.
doi:10.1089/met.2013.0116
PMCID: PMC3942706  PMID: 24380645
8.  β-Cell Dysfunction Is Associated with Metabolic Syndrome Severity in Adults 
Abstract
Background: Metabolic syndrome is prevalent in adults characterized by increased visceral adiposity and insulin resistance (IR). However, the link between pancreatic β-cell function and metabolic syndrome severity in adults across the glucose spectrum is unknown. We hypothesized that poor β-cell function would independently predict a higher metabolic syndrome Z-score (i.e., severity).
Methods: Seventy (12 normal glucose tolerant, 37 prediabetic, 21 type 2 diabetic) obese adults [62.4±1.1 year; 34.6±0.6 kg/m2; data are mean±standard error of the mean (SEM)] participated in this cross-sectional study. A 2-hr 75-gram oral glucose tolerance test (OGTT) was administered, and insulin and glucose area under the curve was determined for calculations of insulin action. Fasting and glucose-stimulated insulin secretion was calculated using homeostasis model assessment of insulin secretion (HOMA-B) and the insulinogenic index (i.e., I0–30/Glc0–30 or I60–120/Glc60–120), respectively. Fasting and postprandial insulin sensitivity was assessed by HOMA-IR and the Matsuda Index, respectively. β-cell function was estimated using the disposition index via HOMA-B/HOMA-IR, I0–30/Glc0–30 or I60–120/Glc60–120×Matsuda Index, which represents basal, first-, and second-phase insulin release, respectively. Body composition (via computerized tomography and dual X-ray absorptiometry) and sex-specific metabolic syndrome Z-scores were calculated from waist circumference, blood pressure, fasting glucose, triglycerides, and high-density lipoproteins.
Results: Compared to those with normal glucose tolerance, visceral fat and IR were higher and β-cell function was lower in adults with glucose intolerance and type 2 diabetes mellitus. Elevated visceral fat and IR (HOMA-IR and Matsuda Index) correlated with elevated Z-scores (r=0.51, r=0.54, r=−0.49; all P<0.002, respectively). Basal, first-, and second-phase β-cell function correlated with low Z-scores (r=−0.59, r=−0.51, and r=−0.43, all P<0.001). Insulin secretion significantly predicted the Z-score independent of sex, body fat, blood lipids, blood pressure, IR, and glucose metabolism (P<0.005).
Conclusion: β-cell dysfunction is highly correlated with the severity of metabolic syndrome in adults. Future work is warranted to elucidate the mechanism by which cardiometabolic disturbances influence insulin secretion.
doi:10.1089/met.2013.0083
PMCID: PMC3942708  PMID: 24283920
9.  Mitochondrial Uncoupling Protein 2 Induces Cell Cycle Arrest and Necrotic Cell Death 
Abstract
Uncoupling protein 2 (UCP2) is a mitochondrial membrane protein that regulates energy metabolism and reactive oxygen species (ROS) production. We generated mouse carboxy- and amino-terminal green fluorescent protein (GFP)-tagged UCP2 constructs to investigate the effect of UCP2 expression on cell proliferation and viability. UCP2-transfected Hepa 1–6 cells did not show reduced cellular adenosine triphosphate (ATP) but showed increased levels of glutathione. Flow cytometry analysis indicated that transfected cells were less proliferative than nontransfected controls, with most cells blocked at the G1 phase. The effect of UCP2 on cell cycle arrest could not be reversed by providing exogenous ATP or oxidant supply, and was not affected by the chemical uncoupler carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP). However, this effect of UCP2 was augmented by treatment with genistein, a tyrosine kinase inhibitor, which by itself did not affect cell proliferation on control hepatocytes. Western blotting analysis revealed decreased expression levels of CDK6 but not CDK2 and D-type cyclins. Examination of cell viability in UCP2-transfected cells with Trypan Blue and Annexin-V staining revealed that UCP2 transfection led to significantly increased cell death. However, characteristics of apoptosis were absent in UCP2-transfected Hepa 1–6 cells, including lack of oligonucleosomal fragmentation (laddering) of chromosomal DNA, release of cytochrome c from mitochondria, and cleavage of caspase-3. In conclusion, our results indicate that UCP2 induces cell cycle arrest at G1 phase and causes nonapoptotic cell death, suggesting that UCP2 may act as a powerful influence on hepatic regeneration and cell death in the steatotic liver.
doi:10.1089/met.2013.0096
PMCID: PMC3996969  PMID: 24320727
10.  Serum Resistin Levels Are Associated with Adiposity and Insulin Sensitivity in Obese Hispanic Subjects 
Abstract
Background and Aims: Resistin is involved in the development of obesity and insulin resistance (IR) in mice and may play a similar role in humans through mechanisms that remain unresolved. The objective of this study was to characterize the relationship between resistin levels in obese subjects with and without IR among Hispanic subjects.
Material and Methods: A cross-sectional study was performed on 117 nondiabetic Hispanic subjects of both genders that were allocated into three study groups: A control group (n=47) of otherwise healthy individuals in metabolic balance, a group with obesity (OB) (n=36), and a group with obesity and IR (OB-IR) (n=34). Anthropometric and clinical characterization was carried out, and resistin levels were determined by enzyme-linked immunosorbent assay (ELISA).
Results: We found that resistin levels were higher in OB and OB-IR groups when compared to the control group (1331.79±142.15 pg/mL, 1266.28±165.97 pg/mL vs. 959.21±171.43 pg/mL; P<0.05), an effect that was not confounded by age (control, 34.04±10.00 years; OB, 37.30±10.78 years; and OB-IR, 35.67±10.15 years). In addition, we observed a significant correlation (P<0.001) between resistin levels and higher adiposity and insulin sensitivity (IS) in our cohort.
Conclusions: Our results suggest that higher resistin levels are associated with higher adiposity and lower IS among obese Hispanic subjects.
doi:10.1089/met.2013.0118
PMCID: PMC3997139  PMID: 24266722
11.  Metabolic Syndrome As an Underlying Disease Entity and Its Relationship to Subclinical Atherosclerosis in Andean Hispanics 
Abstract
Background: The question of whether the metabolic syndrome truly reflects a single disease entity with a common underlying pathology remains unclear. In this study, we assess whether metabolic syndrome represents an underlying disease construct in a large population-based sample of Andean Hispanic adults and examine its relationship to subclinical atherosclerosis.
Methods: The study sample was comprised of 2513 participants. Confirmatory factor analysis (CFA) was used to identify a metabolic syndrome latent factor using waist circumference, systolic and diastolic blood pressure, high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), and glucose levels as indicators. The relationship with subclinical atherosclerosis, measured by carotid intima media thickness (cIMT), was assessed using structural equation modeling.
Results: Results supported the proposed structure of the metabolic syndrome latent factor evidenced by adequate fit indexes. HDL-C did not significantly load on the metabolic syndrome latent factor (standardized factor loading=0.01, P=0.88). The metabolic syndrome latent factor was significantly associated with cIMT in women (B=0.007, P<0.001) and men (B=0.008, P<0.001) after controlling for age, low-density lipoprotein cholesterol and smoking.
Conclusions: Our findings suggest that metabolic syndrome components, such as waist circumference, blood pressure, TGs, and glucose levels, but not HDL-C, share a common underlying pathophysiology that may contribute to the progression of atherosclerosis in Andean Hispanics. Its longitudinal association with cardiovascular disease should be the focus of future research.
doi:10.1089/met.2013.0092
PMCID: PMC4361393  PMID: 24206171
12.  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
13.  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
14.  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
15.  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
16.  The “Metabolic Winter” Hypothesis: A Cause of the Current Epidemics of Obesity and Cardiometabolic Disease 
Abstract
The concept of the “Calorie” originated in the 1800s in an environment with limited food availability, primarily as a means to define economic equivalencies in the energy density of food substrates. Soon thereafter, the energy densities of the major macronutrients—fat, protein, and carbohydrates—were defined. However, within a few decades of its inception, the “Calorie” became a commercial tool for industries to promote specific food products, regardless of health benefit. Modern technology has altered our living conditions and has changed our relationship with food from one of survival to palatability. Advances in agriculture, food manufacturing, and processing have ensured that calorie scarcity is less prevalent than calorie excess in the modern world. Yet, many still approach dietary macronutrients in a reductionist manner and assume that isocalorie foodstuffs are isometabolic. Herein, we discuss a novel way to view the major food macronutrients and human diet in this era of excessive caloric consumption, along with a novel relationship among calorie scarcity, mild cold stress, and sleep that may explain the increasing prevalence of nutritionally related diseases.
doi:10.1089/met.2014.0027
PMCID: PMC4209489  PMID: 24918620
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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