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author:("Gupta, alk K")
1.  Prediabetes and Prehypertension in Healthy Adults Are Associated With Low Vitamin D Levels 
Diabetes Care  2011;34(3):658-660.
To determine whether modest elevations of fasting serum glucose (FSG) and resting blood pressure (BP) in healthy adults are associated with differential serum vitamin D concentrations.
Disease-free adults in the National Health and Nutrition Examination Survey 2001–2006 were assessed. Prediabetes (PreDM) and prehypertension (PreHTN) were diagnosed using American Diabetes Association and Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure criteria: FSG 100–125 mg/dL and systolic BP 120–139 mmHg and/or diastolic BP 80–89 mmHg. Logistic regression was used to assess the effects of low vitamin D levels on the odds for PreDM and PreHTN in asymptomatic adults (n = 1,711).
The odds ratio for comorbid PreDM and PreHTN in Caucasian men (n = 898) and women (n = 813) was 2.41 (P < 0.0001) with vitamin D levels ≤76.3 versus >76.3 nmol/L after adjusting for age, sex, and BMI.
This study strengthens the plausibility that low serum vitamin D levels elevate the risk for early-stage diabetes (PreDM) and hypertension (PreHTN).
PMCID: PMC3041202  PMID: 21282345
2.  Effects of Naltrexone Sustained- Release/Bupropion Sustained-Release Combination Therapy on Body Weight and Glycemic Parameters in Overweight and Obese Patients With Type 2 Diabetes 
Diabetes Care  2013;36(12):4022-4029.
To assess the efficacy and safety of 32 mg naltrexone sustained-release (SR)/360 mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetes drugs.
This was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardized lifestyle intervention and were randomized 2:1 to NB or placebo. Coprimary end points were percent weight change and achievement of ≥5% weight loss. Secondary end points included achievement of HbA1c <7% (53 mmol/mol), achievement of weight loss ≥10%, and change in HbA1c, waist circumference, fasting blood glucose, and lipids.
In the modified intent-to-treat population (54% female, 80% Caucasian, and mean age 54 years, weight 106 kg, BMI 37 kg/m2, and HbA1c 8.0% [64 mmol/mol]), NB resulted in significantly greater weight reduction (−5.0 vs. −1.8%; P < 0.001) and proportion of patients achieving ≥5% weight loss (44.5 vs. 18.9%, P < 0.001) compared with placebo. NB also resulted in significantly greater HbA1c reduction (−0.6 vs. −0.1% [6.6 vs. 1.1 mmol/mol]; P < 0.001), percent of patients achieving HbA1c <7% (53 mmol/mol) (44.1 vs. 26.3%; P < 0.001), and improvement in triglycerides and HDL cholesterol compared with placebo. NB was associated with higher incidence of nausea (42.3 vs. 7.1%), constipation (17.7 vs. 7.1%), and vomiting (18.3 vs. 3.6%). No difference was observed between groups in the incidence of depression, suicidal ideation, or hypoglycemia.
NB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.
PMCID: PMC3836105  PMID: 24144653
3.  Relationship of Anthropometric Indices to Abdominal and Total Body Fat in Youth: Sex and Race Differences 
Obesity (Silver Spring, Md.)  2014;22(5):1345-1350.
To determine the influence of sex and race on relationships between anthropometry (body mass index [BMI], waist circumference [WC], waist-to-height ratio [W/Ht]), and adiposity (fat mass [FM], abdominal subcutaneous [SAT] and visceral adipose tissue [VAT]) in African American and white youth.
Design and Methods
The sample included 382 youth 5–18 years of age. FM and abdominal adiposity were assessed using dual energy x-ray absorptiometry and magnetic resonance imaging. Regression was used to examine sex and race effects in the relationship between independent (BMI, WC, and W/Ht) and dependent (FM, SAT and VAT) variables.
BMI and WC were highly related to adiposity while W/Ht was moderately related. The association of BMI with FM and SAT was independent of sex and race, while the relationships of WC and W/Ht with FM and SAT were influenced by both sex and race. In contrast, the association between BMI and VAT was influenced by sex and race, while the relationships of WC and W/Ht with VAT were not.
WC and W/Ht have similar relationships with adiposity; however, WC presented stronger relationships. BMI is a predictor of overall adiposity but sex and race play a role in its relationship with VAT.
PMCID: PMC4008658  PMID: 24493150
abdominal adiposity; body composition; racial differences
4.  Role of Skeletal Muscle Mitochondrial Density on Exercise-Stimulated Lipid Oxidation 
Obesity (Silver Spring, Md.)  2011;20(7):1387-1393.
Reduced skeletal muscle mitochondrial density is proposed to lead to impaired muscle lipid oxidation and increased lipid accumulation in sedentary individuals. We assessed exercise-stimulated lipid oxidation by imposing a prolonged moderate-intensity exercise in men with variable skeletal muscle mitochondrial density as measured by citrate synthase (CS) activity. After a 2-day isoenergetic high-fat diet, lipid oxidation was measured before and during exercise (650 kcal at 50% VO2 max) in 20 healthy men with either high (HI-CS = 24 ± 1; mean ± s.e.) or low (LO-CS = 17 ± 1 nmol/min/mg protein) muscle CS activity. Vastus lateralis muscle biopsies were obtained before and immediately after exercise. Respiratory exchange data and blood samples were collected at rest and throughout the exercise. HI-CS subjects had higher VO2 max (50 ± 1 vs. 44 ± 2 ml/kg fat free mass/min; P = 0.01), lower fasting respiratory quotient (RQ) (0.81 ± 0.01 vs. 0.85 ± 0.01; P = 0.04) and higher ex vivo muscle palmitate oxidation (866 ± 168 vs. 482 ± 78 nmol/h/mg muscle; P = 0.05) compared to LO-CS individuals. However, whole-body exercise-stimulated lipid oxidation (20 ± 2 g vs. 19 ± 1 g; P = 0.65) and plasma glucose, lactate, insulin, and catecholamine responses were similar between the two groups. In conclusion, in response to the same energy demand during a moderate prolonged exercise bout, reliance on lipid oxidation was similar in individuals with high and low skeletal muscle mitochondrial density. This data suggests that decreased muscle mitochondrial density may not necessarily impair reliance on lipid oxidation over the course of the day since it was normal under a high-lipid oxidative demand condition. Twenty-four-hour lipid oxidation and its relationship with mitochondrial density need to be assessed.
PMCID: PMC4104481  PMID: 21681225
5.  Waist circumference measurement site does not affect relationships with visceral adiposity and cardiometabolic risk factors in children 
Pediatric obesity  2012;8(3):199-206.
Different waist circumference (WC) measurement sites are used in clinical and epidemiological settings.
To examine differences in WC measurement at four anatomic sites and how each WC measurement relates to visceral adipose tissue (VAT) and cardiometabolic risk factors in children.
371 white and African American children aged 5–18 years had WC measured at four sites: minimal waist, midpoint between the iliac crest and the lowest rib, superior border of the iliac crest, and the umbilicus. Abdominal VAT was measured using magnetic resonance imaging, and cardiometabolic risk factors were defined using NHLBI guidelines. Relationships between WC sites and VAT and risk factors were explored in each race-by-sex group.
All WC sites were highly correlated (r = 0.97 to 0.99). Differences in absolute mean WC values existed in all race-by-sex groups, and this affected the prevalence of high WC (≥90th percentile). Values were lowest for minimal waist and highest for umbilicus. Age-controlled partial correlations between WC and VAT were 0.81 to 0.89 (all p<0.001) and between WC and cardiometabolic risk factors were −0.24 to −0.41 and 0.19 to 0.52 (all p<0.05).
While the absolute values of WC at four anatomic locations differed, the relationships between WC values and both VAT and cardiometabolic risk factors were similar within all race-by-sex groups.
PMCID: PMC3582770  PMID: 23172858
6.  Maturity-Associated Variation in Total and Depot-Specific Body Fat in Children and Adolescents 
This study considered the association between sexual maturation and adiposity in children and adolescents, and examined the contribution of sexual maturation to ethnic differences in total and depot-specific body fat.
The sample included 382 White and African American 5–18-year-olds. Body mass index (BMI), waist circumference (WC) and sexual maturity status (breast/genital and pubic hair stage) were assessed in a clinical setting. Total body fat (TBF) was measured by dual-energy X-ray absorptiometry and abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) were measured by magnetic resonance imaging. Analysis of covariance adjusted for age was used to examine the association between sexual maturity status and adiposity, and linear regression adjusted for age was used to examine the influence of sexual maturation on ethnic differences in adiposity. Analysis of VAT also controlled for TBF. Significance was accepted at P<0.05.
Breast/genital stage was significantly associated with BMI, WC, TBF, and SAT in girls of both ethnic groups and in White boys. Breast stage was associated with VAT. Stage of pubic hair was significantly associated with TBF and VAT in White girls only. In girls, sexual maturation attenuated the ethnic effects on BMI and WC, but the ethnic effect in VAT persisted. In boys, sexual maturation did not attenuate ethnic differences on VAT and did not predict WC or SAT. Sexual maturity status independently explained variance in adiposity in girls only.
Sexual maturity status is an important determinant of pediatric adiposity and attenuates ethnic differences in girls’ adiposity.
PMCID: PMC3947527  PMID: 23564417
7.  Television, Adiposity, and Cardiometabolic Risk in Children and Adolescents 
It is largely unknown how TV use relates to depot-specific adiposity or cardiometabolic risk in children.
To examine relationships between having a TV in the bedroom and TV viewing time with total fat mass, abdominal subcutaneous and visceral adiposity, and cardiometabolic risk in children and adolescents.
A cross-sectional study of 369 children and adolescents aged 5–18 years was conducted (2010–2011; analysis 2011–2012). Waist circumference; resting blood pressure; fasting triglycerides, high-density lipoprotein cholesterol [HDL-C] and glucose; fat mass by DXA; and abdominal subcutaneous and visceral adiposity by MRI were assessed. Cardiometabolic risk was defined as three or more risk factors including adverse levels of waist circumference, blood pressure, triglycerides, HDL-C, and glucose. Logistic regression analysis was used to compute ORs of high fat mass, subcutaneous and visceral adipose tissue mass (top age-adjusted quartile), and cardiometabolic risk, based on self-reported TV present in the bedroom and TV viewing time, controlling for age, gender, ethnicity, moderate-to-vigorous physical activity level, and unhealthy diet.
In multivariable models, presence of a TV in the bedroom and TV viewing time were associated with (p<0.05) higher odds of high waist circumference (OR= 1.9–2.1); fat mass (OR= 2.0–2.5); and subcutaneous adiposity (OR= 2.1–2.9), while viewing TV ≥5 hours/day was associated with high visceral adiposity (OR=2.0). Having a TV in the bedroom was associated with elevated cardiometabolic risk (OR=2.9) and high triglycerides (OR=2.0).
Having a bedroom TV and TV viewing time were related to high waist circumference, fat mass, and abdominal subcutaneous adiposity. TV viewing time was related to visceral adiposity, and bedroom TV was related to cardiometabolic risk in children, controlling for moderate-to-vigorous physical activity and an unhealthy diet.
This study is registered at NCT01595100.
PMCID: PMC3527837  PMID: 23253648
8.  BMI percentiles for the identification of abdominal obesity and metabolic risk in children and adolescents: Evidence in support of the CDC 95th percentile 
BMI percentiles have been routinely and historically used to identify elevated adiposity. This paper aimed to investigate the optimal Centers for Disease Control and Prevention (CDC) body mass index (BMI) percentile that predicts elevated visceral adipose tissue (VAT), fat mass and cardiometabolic risk in a biracial sample of children and adolescents.
Participants and Methods
This cross-sectional analysis included 369 white and African American children (5–18 y). BMI was calculated using height and weight and converted to BMI percentiles based on CDC growth charts. Receiver operating characteristic curve analysis identified the optimal (balance of sensitivity and specificity) BMI percentile to predict the upper quartile of age-adjusted VAT (measured by magnetic resonance imaging), age-adjusted fat mass (measured by dual energy x-ray absorptiometry) and elevated cardiometabolic risk (≥ 2 of high glucose, triglycerides and blood pressure and low high density lipoprotein cholesterol) for each race-by-sex group.
The optimal CDC BMI percentile to predict those in the top quartile of age-adjusted VAT, age-adjusted fat mass and elevated cardiometabolic risk were the 96th, the 96th and the 94th percentiles, respectively, for the sample as a whole. Sensitivity and specificity was satisfactory (> 0.70) for VAT and fat mass. Compared to age-adjusted VAT and age-adjusted fat mass, there was a lower overall accuracy of the optimal percentile in identifying those with elevated cardiometabolic risk.
The present findings support the utility of the 95th CDC BMI percentile as a useful threshold for the prediction of elevated levels of VAT, fat mass and cardiometabolic risk in children and adolescents.
The study is registered at as NCT01595100.
PMCID: PMC3566333  PMID: 23232587
body mass index; visceral adipose tissue; children; adolescents; Centers for Disease Control and Prevention; body fat
9.  Transcriptome and Proteome Data Reveal Candidate Genes for Pollinator Attraction in Sexually Deceptive Orchids 
PLoS ONE  2013;8(5):e64621.
Sexually deceptive orchids of the genus Ophrys mimic the mating signals of their pollinator females to attract males as pollinators. This mode of pollination is highly specific and leads to strong reproductive isolation between species. This study aims to identify candidate genes responsible for pollinator attraction and reproductive isolation between three closely related species, O. exaltata, O. sphegodes and O. garganica. Floral traits such as odour, colour and morphology are necessary for successful pollinator attraction. In particular, different odour hydrocarbon profiles have been linked to differences in specific pollinator attraction among these species. Therefore, the identification of genes involved in these traits is important for understanding the molecular basis of pollinator attraction by sexually deceptive orchids.
We have created floral reference transcriptomes and proteomes for these three Ophrys species using a combination of next-generation sequencing (454 and Solexa), Sanger sequencing, and shotgun proteomics (tandem mass spectrometry). In total, 121 917 unique transcripts and 3531 proteins were identified. This represents the first orchid proteome and transcriptome from the orchid subfamily Orchidoideae. Proteome data revealed proteins corresponding to 2644 transcripts and 887 proteins not observed in the transcriptome. Candidate genes for hydrocarbon and anthocyanin biosynthesis were represented by 156 and 61 unique transcripts in 20 and 7 genes classes, respectively. Moreover, transcription factors putatively involved in the regulation of flower odour, colour and morphology were annotated, including Myb, MADS and TCP factors.
Our comprehensive data set generated by combining transcriptome and proteome technologies allowed identification of candidate genes for pollinator attraction and reproductive isolation among sexually deceptive orchids. This includes genes for hydrocarbon and anthocyanin biosynthesis and regulation, and the development of floral morphology. These data will serve as an invaluable resource for research in orchid floral biology, enabling studies into the molecular mechanisms of pollinator attraction and speciation.
PMCID: PMC3667177  PMID: 23734209
10.  Cardiovascular risk escalation with caloric excess: a prospective demonstration of the mechanics in healthy adults 
The link between weight gain and cardiovascular risk characterized with circadian blood pressure variability [CBPV] and endothelial function [EF] is unexplored.
To prospectively demonstrate weight gain in healthy adults, increases body fat [BF], enlarges waist circumference [WC], expands visceral adipose tissue [VAT], exacerbates systemic inflammation [sIF], worsens insulin resistance [IR] and enhances functional cardiovascular disease [CVD] risk.
Design, setting and participants
Healthy men [n=11] and women [n=3] provided initial and eight-week post-caloric excess anthropometric and fasting laboratory measures. Functional CVD risk assessments: CBPV and resting EF were also obtained with 7-day automatic ambulatory BP monitoring and increased test finger peripheral arterial tone [PAT] relative to control [reported as relative hyperemia index (RHI)], respectively.
After determining individualized mean energy requirements for weight maintenance over 7-days, each participant received a personalized over feeding prescription (1.4 times; 41% carbohydrate, 44% fat, and 15% protein) for 8-weeks.
mean (SEM). Participants increased body weight [BW; +7.4(0.1) kg]*, body mass index [BMI; +2.5(0.2) kg/m2]*, BF [+2.0(0.01)%]*, WC [+8.2(1.0) cm]*, and VAT [+0.2(0.03) L]* and intrahepatic lipid [IHL + 0.0004(0.002) L] :*all p < 0.01. Increased subcutaneous adipose cell size [+0.3(0.01) ρL; p = 0.02] accompanied significant sIF [hs-CRP + 0.4(0.09) mg/dL; p = 0.04; leptin 6.63 ng/ml; p = 0.0008] and IR [fasting plasma glucose; [FPG] +7.0(0.6) mg/dL;p = 0.01, fasting insulin; [FI] +5.7(1.4) uIU/ml; p = 0.001, HOMA-IR +1.6(0.5); p = 0.02]. Abn CBPV {systolic [+5.4(0.8); p = 0.002, diastolic [+1.7(0.1); p = 0.07 and pulse pressure [PP] [+3.5(0.4); p = 0.003 mm Hg} or elevated heart rate [HR] [+4.9(0.5) bpm; p = 0.003] ensued. Resting RHI declined by 0.47(0.004) from initial 2.24(0.09) to 1.77(0.1); p = 0.001, indicating endothelial dysfunction [ED].
Controlled caloric excess in healthy human adults over only 8-weeks significantly increased BF, VAT, sIF [hs-CRP], IR [FPG, FI, HOMA-IR] and functional CVD risk [measured as abnormal circadian blood pressure variability and impaired resting endothelial function].
PMCID: PMC3598491  PMID: 23347533
Fasting plasma glucose; Healthy adults; Visceral adipose tissue; Ectopic adipose tissue; Fat cell size; Insulin resistance; Systemic inflammation; Dyslipidemia; Predisease conditions; Circadian blood pressure variability; Relative hyperemia index; Endothelial dysfunction
11.  Elevated C-Reactive Protein in Children from Risky Neighborhoods: Evidence for a Stress Pathway Linking Neighborhoods and Inflammation in Children 
PLoS ONE  2012;7(9):e45419.
Childhood socioeconomic status is linked to adult cardiovascular disease and disease risk. One proposed pathway involves inflammation due to exposure to a stress-inducing neighborhood environment. Whether CRP, a marker of systemic inflammation, is associated with stressful neighborhood conditions among children is unknown.
Methods and Results
The sample included 385 children 5–18 years of age from 255 households and 101 census tracts. Multilevel logistic regression analyses compared children and adolescents with CRP levels >3 mg/L to those with levels ≤3 mg/L across neighborhood environments. Among children living in neighborhoods (census tracts) in the upper tertile of poverty or crime, 18.6% had elevated CRP levels, in contrast to 7.9% of children living in neighborhoods with lower levels of poverty and crime. Children from neighborhoods with the highest levels of either crime or poverty had 2.7 (95% CI: 1.2–6.2) times the odds of having elevated CRP levels when compared to children from other neighborhoods, independent of adiposity, demographic and behavioral differences.
Children living in neighborhoods with high levels of poverty or crime had elevated CRP levels compared to children from other neighborhoods. This result is consistent with a psychosocial pathway favoring early development of cardiovascular risk that involves chronic stress from exposure to socially- and physically-disordered neighborhoods characteristic of poverty.
PMCID: PMC3458094  PMID: 23049799
12.  Identification of white campion (Silene latifolia) guaiacol O-methyltransferase involved in the biosynthesis of veratrole, a key volatile for pollinator attraction 
BMC Plant Biology  2012;12:158.
Silene latifolia and its pollinator, the noctuid moth Hadena bicruris, represent an open nursery pollination system wherein floral volatiles, especially veratrole (1, 2-dimethoxybenzene), lilac aldehydes, and phenylacetaldehyde are of key importance for floral signaling. Despite the important role of floral scent in ensuring reproductive success in S. latifolia, the molecular basis of scent biosynthesis in this species has not yet been investigated.
We isolated two full-length cDNAs from S. latifolia that show similarity to rose orcinol O-methyltransferase. Biochemical analysis showed that both S. latifolia guaiacol O-methyltransferase1 (SlGOMT1) &S. latifolia guaiacol O-methyltransferase2 (SlGOMT2) encode proteins that catalyze the methylation of guaiacol to form veratrole. A large Km value difference between SlGOMT1 (~10 μM) and SlGOMT2 (~501 μM) resulted that SlGOMT1 is 31-fold more catalytically efficient than SlGOMT2. qRT-PCR expression analysis showed that the SlGOMT genes are specifically expressed in flowers and male S. latifolia flowers had 3- to 4-folds higher level of GOMT gene transcripts than female flower tissues. Two related cDNAs, S. dioica O-methyltransferase1 (SdOMT1) and S. dioica O-methyltransferase2 (SdOMT2), were also obtained from the sister species Silene dioica, but the proteins they encode did not methylate guaiacol, consistent with the lack of veratrole emission in the flowers of this species. Our evolutionary analysis uncovered that SlGOMT1 and SlGOMT2 genes evolved under positive selection, whereas SdOMT1 and SdOMT2 genes show no evidence for selection.
Altogether, we report the identification and functional characterization of the gene, SlGOMT1 that efficiently catalyzes veratrole formation, whereas another copy of this gene with only one amino acid difference, SlGOMT2 was found to be less efficient for veratrole synthesis in S. latifolia.
PMCID: PMC3492160  PMID: 22937972
Floral scent; VOC; 1, 2-dimethoxybenzene; Pollination; Hadena bicruris
13.  Endothelial Dysfunction: An Early Cardiovascular Risk Marker in Asymptomatic Obese Individuals with Prediabetes 
To elucidate if endothelial dysfunction is an early CV risk marker in obese men and women with prediabetes.
Study Design
Cross-sectional study.
Place and Duration of Study
Clinical Research Unit, Pennington Biomedical Research Center, Baton Rouge, LA. United States.
Overweight and obese status denotes an increasing adipose tissue burden which spills over into ectopic locations, including the visceral compartment, muscle and liver. Associated co-morbidities enhance cardiovascular (CV) risk. Endothelium which is the largest receptor-effector end-organ in our bodies, while responding to numerous physical and chemical stimuli maintains vascular homeostasis. Endothelial dysfunction (ED) is the initial perturbation, which precedes fatty streak known to initiate atherosclerosis: insidious process which often culminates as sudden catastrophic CV adverse event. Asymptomatic men and women; [n=42] coming in after an overnight fast had demographic, anthropometric, clinical chemistry and resting endothelial function [EF: increased test finger peripheral arterial tone (PAT) relative to control; expressed as relative hyperemia index (RHI)] assessments.
Adults with desirable weight [n=12] and overweight [n=8] state, had normal fasting plasma glucose [Mean(SD)]: FPG [91.1(4.5), 94.8(5.8) mg/dL], insulin [INS, 2.3(4.4), 3.1(4.8) μU/ml], insulin sensitivity by homeostasis model assessment [HOMA-IR, 0.62(1.2), 0.80(1.2)] and desirable resting clinic blood pressure [SBP/DBP, 118(12)/74(5), 118(13)/76(8) mmHg]. Obese adults [n=22] had prediabetes [FPG, 106.5(3.5) mg/dL], hyperinsulinemia [INS 18.0(5.2) μU/ml], insulin resistance [HOMA-IR 4.59(2.3)], prehypertension [PreHTN; SBP/DBP 127(13)/81(7) mmHg] and endothelial dysfunction [ED; reduced RHI 1.7(0.3) vs. 2.4(0.3); all p<0.05]. Age-adjusted RHI correlated with BMI [r=−0.53; p<0.001]; however, BMI-adjusted RHI was not correlated with age [r=−0.01; p=0.89].
Endothelial dysfunction reflective of cardiometabolic changes in obese adults can be an early risk marker for catastrophic CV events.
PMCID: PMC3419538  PMID: 22905340
Fasting plasma glucose; healthy adults; reverse cholesterol transport pathway; insulin resistance; body weight; relative hyperemia index
14.  Dysglycemia induces abnormal circadian blood pressure variability 
Prediabetes (PreDM) in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV).
Systemic inflammation and glycemia influence circadian blood pressure variability.
Dahl salt-sensitive (S) rats (n = 19) after weaning were fed either an American (AD) or a standard (SD) diet. The AD (high-glycemic-index, high-fat) simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat) mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG), adipokines (leptin and adiponectin), and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α)] were measured. Rats were surgically implanted with C40 transmitters and blood pressure (BP-both systolic; SBP and diastolic; DBP) and heart rate (HR) were recorded by telemetry every 5 minutes during both sleep (day) and active (night) periods. Pulse pressure (PP) was calculated (PP = SBP-DBP).
[mean(SEM)]: The AD fed group displayed significant increase in body weight (after 90 days; p < 0.01). Fasting glucose, adipokine (leptin and adiponectin) concentrations significantly increased (at 90 and 172 days; all p < 0.05), along with a trend for increased concentrations of systemic pro-inflammatory cytokines (MCP-1 and TNF-α) on day 90. The AD fed group, with significantly higher FG, also exhibited significantly elevated circadian (24-hour) overall mean SBP, DBP, PP and HR (all p < 0.05).
These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms (adipose tissue dysfunction induced local and systemic inflammation, insulin resistance and alteration of adipose tissue precursors for the renin-aldosterone-angiotensin system) which generate abnormal CBPV.
PMCID: PMC3247849  PMID: 22108527
caloric excess; adipose tissue dysfunction; insulin resistance; renin-aldosterone-angiotensin system; circadian blood pressure variability; adipokines; leptin; adiponectin; pro-inflammatory cytokines; MCP-1; TNF-α; early CVD risk
15.  Effect of Pioglitazone on Energy Intake and Ghrelin in Diabetic Patients 
Diabetes Care  2010;33(4):742-744.
To measure ghrelin and energy intake in the laboratory after pioglitazone treatment.
This was a parallel, three-arm study with 51 obese diabetic subjects randomized to either 1) pioglitazone plus a portion-controlled diet (Pio+PC), 2) pioglitazone plus American Diabetes Association (ADA) dietary advice (Pio+ADA), or 3) metformin plus ADA advice (Met+ADA). Energy intake and the suppressive response of a meal on ghrelin were measured at weeks 0 and 16. Mixed models tested if changes from week 0 to 16 differed by group.
The Pio+ADA group had a significantly larger increase (P < 0.05) in energy intake ([adjusted means ± SE] 207 ± 53 kcal) compared with the Pio+PC (50 ± 46 kcal) and Met+ADA (52 ± 49 kcal) groups. Change in restraint and disinhibition (variables associated with eating behavior) mediated weight change. Ghrelin suppression increased in the Pio+ADA group, which gained weight.
A portion-controlled diet attenuated the increase in energy intake after pioglitazone. Ghrelin responded to weight change not pioglitazone exposure.
PMCID: PMC2845018  PMID: 20067964
16.  Pioglitazone, but not metformin, reduces liver fat in Type-2 diabetes mellitus independent of weight changes⋆ 
Pioglitazone (Pio) treatment induces weight gain in Type 2 diabetes mellitus (T2DM), which could worsen hepatic lipid accumulation, and alter adiponectin and high-sensitivity C-reactive protein (hs-CRP).
To compare changes in hepatic lipid, serum adiponectin and hs-CRP in diabetics treated with Pio (with and without weight gain) against metformin (Met) treatment, which produces weight loss.
Fifty-one men and women with T2DM, naive to thiazolidinediones, entered a 16-week, open-label, parallel arm study, where participants were randomized to one of three groups: (1) Pio plus the American Diabetes Association diet (Pio+ADA); (2) Pio plus a portion control weight loss diet (Pio+PC), or (3) metformin plus ADA diet (Met+ADA).
Hepatic lipid was assessed with abdominal computed tomography (CT) and the serum adiponectin and hs-CRP by enzyme-linked immunosorbent assay at baseline and study end.
Forty-eight subjects completed the study. The Pio+ADA group gained (mean±S.E.M.) 2.15±1.09 kg, while Pio+PC and Met+ADA group lost −2.59±1.25 and −3.21±0.7 kg, respectively. Pio-treated groups (Pio+ADA and Pio+PC) significantly decreased hepatic fat as indicated by increased liver density on CTscan [10.1±2.4: 11.4±1.0 Hounsfield units (HU)], compared with Met+ADA group (−2.4±3.1 HU). The Pio groups demonstrated significantly increased serum adiponectin, (8.6±1.5; 7.4±1.6 μg/ml) independent of weight change, compared to Met+ADA (−0.14±0.6 μgm/ml) group which lost weight. Serum hs-CRP decreased in groups showing weight loss (Pio+PC, −3.1±1.7 mg/l; Met+ADA, −1.5±1.2 mg/l) compared to Pio+ADA (1.8±3.0 mg/l) group that gained weight.
Pio treatment in T2DM significantly reduced hepatic lipid and increased adiponectin independent of weight change, while decreasing hs-CRP with weight loss.
PMCID: PMC2891296  PMID: 19577936
ALT; NAFLD; NASH; Metformin; Cardiovascular disease; Adiponectin; hs-CRP; Diabetes; Obesity; Adipose tissue
17.  Abnormalities in circadian blood pressure variability and endothelial function: pragmatic markers for adverse cardiometabolic profiles in asymptomatic obese adults 
Cardiovascular disease (CVD) risk, although perceived to be high, is often difficult to demonstrate in disease free (healthy) obese adults.
Changes in circadian blood pressure variability (CBPV) and endothelial function (EF) may be early correlates of cardiometabolic disorders.
Asymptomatic men and women in 3 groups: normal weight (n = 10), overweight (n = 10) and obese (n = 15) were evaluated. Blood pressure and heart rate were recorded over 7 days: every 30 minutes during the day and every 60 minutes during the night, by automatic ambulatory monitoring. Resting EF was assessed in a fasting state between 8-10 AM by brachial ultrasound. Anthropometric and cardiometabolic indicators were measured and correlations with CBPV and EF were investigated.
The 3 groups had (Mean(SD)) BMI: 22.6(1.6), 27(3) and 34(5) kg/m2, respectively, weight: 64(16), 79(14), 95(16) kg and waist circumference: 79(9), 93(10), 107(13) cm. None in normal-weight or overweight groups had abnormal CBPV, while 8 of 15 obese adults had one or more CBPV abnormities (p < 0.05). Obese adults with CBPV abnormalities had elevated hs-CRP (15.3(9.3) mg/L), fibrinogen (593(97) mg/dl), fasting serum glucose (102(16) mg/dL), and cardiac risk ratios (Total-C/HDL-C: 5.2(1.9), LDL-C/HDL-C: 3.1(1.4)). Adults in the 3 respective groups who did not have CBPV abnormalities had flow-mediated brachial artery dilatation (FMD) of 0.22(0.06); 0.20(0.04), 0.23(0.02) mm over resting diameter. Obese participants with CBPV abnormalities (Mesor-hypotension, circadian hyper amplitude tension, elevated pulse pressure), had attenuated FMD at 78, 52, and 56% of resting reference diameter (means 0.18(0.07), 0.12(0.08), and 0.13(0.05) mm; p < 0.05), respectively.
Asymptomatic obese adults with abnormal CBPV and EF exhibit unfavorable cardiometabolic profiles.
PMCID: PMC2955642  PMID: 20868493
18.  Prediabetes and prehypertension in disease free obese adults correlate with an exacerbated systemic proinflammatory milieu 
Obesity is a pro-inflammatory state frequently associated with widespread metabolic alterations that include insulin resistance and deregulation of blood pressure (BP). This cascade of events in some measure explains the susceptibility of obese adults for co-morbid conditions like diabetes mellitus and hypertension.
We hypothesized that an elevated systemic proinflammatory burden correlates with dysglycemia and deregulated blood pressure.
We analyzed the screening anthropometric and laboratory measures from healthy disease free obese adults (n = 35; women (W) 27, men (M) 8) in a weight loss study.
Healthy obese normoglycemic (fasting serum glucose: FSG <100 mg/dL) women and men compared with healthy obese with prediabetes (FSG 100-125 mg/dL) had no significant differences for age (Mean ± SD: 52 ± 12 vs. 56 ± 9 y), weight (95 ± 11 vs. 99 ± 13 kg), or waist circumference (108 ± 10 vs. 108 ± 11 cm). Normoglycemic group (n = 24; W = 19, M = 5) had normal FSG 92 ± 4 mg/dL, HbA1c 5.4 ± 0.3%, BP 118/75 mm Hg, but had elevated high sensitivity C-reactive protein (hs CRP) 3.7 ± 3 mg/L and fibrinogen 472 ± 76 mg/dL. The group with prediabetes (n = 11; W = 8, M = 3) with significantly higher FSG (106 ± 3 mg/dL; p < 0.0001), HbA1c (5.9 ± 0.5%; p < 0.002), had prehypertension (BP: 127/80 mm Hg) and significantly higher hs CRP (16.9 ± 9 mg/; p < 0.0001) and fibrinogen (599 ± 95 mg/dL; p < 0.0002).
In otherwise healthy disease free obese adults, a higher degree of systemic inflammation is associated with prediabetes and prehypertension.
PMCID: PMC2920244  PMID: 20659335
19.  Clinical Outcomes by Race in Hypertensive Patients with and without the Metabolic Syndrome in ALLHAT 
Archives of internal medicine  2008;168(2):207-217.
Antihypertensive drugs with favorable metabolic effects on glucose and lipid levels are advocated for first-line therapy in hypertensive patients with metabolic/cardiometabolic syndrome (MetS). We compared outcomes by race in black and nonblack hypertensive individuals with and without MetS treated with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), an α-blocker (doxazosin mesylate), or an angiotensin-converting enzyme inhibitor (lisinopril).
A post hoc subgroup analysis from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled hypertension treatment trial in 42 418 participants. We defined MetS as hypertension plus at least 2 of the following: fasting serum glucose level of at least 100 mg/dL, body mass index (calculated as weight in kilograms divided by height in meters squared) of at least 30 kg/m2, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men (or less than 50 mg/dL in women).
Significantly higher rates of heart failure were consistent across all treatment comparisons in those with MetS. Relative risks (RRs) were 1.50 (95% confidence interval [CI], 1.18–1.90), 1.49 (95% CI, 1.17–1.90), and 1.88 (95% CI, 1.42–2.47) in black participants and 1.25 (95% CI, 1.06–1.47), 1.20 (95% CI, 1.01–1.41), and 1.82 (95% CI, 1.51–2.19) in nonblack participants for amlodipine, lisinopril, and doxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril-chlorthalidone (RR, 1.24 [95% CI, 1.09–1.40] and 1.10 [95% CI, 1.02–1.19], respectively) and doxazosin-chlorthalidone comparisons (RR, 1.37 [95% CI, 1.19–1.58] and 1.18 [95% CI, 1.08– 1.30], respectively), in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [95% CI, 1.07–1.76] for the lisinopril-chlorthalidone comparison; RR, 1.49 [95% CI, 1.09–2.03] for the doxazosin-chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 1 [95% CI, 1.13– 2.55]) with lisinopril compared with chlorthalidone.
The ALLHAT findings fail to do not support the preference of for calcium channel blockers, α-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the MetS, despite their more favorable metabolic profiles. This was particularly true for black participants.
PMCID: PMC2805022  PMID: 18227370

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