Steven Grinspoon

Massachusetts General Hospital, Boston, Massachusetts, United States

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Publications (237)1632.18 Total impact

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    ABSTRACT: Telomere length (TL) and immune activation markers were measured in a cohort of HIV-infected (n=102) and age-matched non-HIV-infected (n=41) men. TL was significantly shorter in HIV-infected compared to non-HIV-infected subjects (P = 0.04). Univariate analysis revealed a strong inverse relationship of TL to sCD163, and thus, monocyte/macrophage activation, among the HIV group (ρ = -0.30, P = 0.003). In multivariate modeling among the whole group, HIV positive serostatus (P = 0.06) and sCD163 (P = 0.05) were independent predictors of TL controlling for age and smoking status. Our data demonstrate that increased immune activation relates to shorter TL in HIV.
    Journal of acquired immune deficiency syndromes (1999). 09/2014;
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    ABSTRACT: Objective Few studies have investigated irisin and FGF21 to elucidate the role of these hormones to regulate “beiging” in HIV-infected patients.Design50 HIV-infected subjects with the metabolic syndrome were previously recruited and randomized to receive lifestyle modification(LSM) and/or metformin over 12 months. In the current study, we assessed FGF21 and irisin at baseline and after intervention. In addition, we assessed circulating FGF21 and irisin in relationship to brown adipose tissue(BAT) gene expression in dorsocervical subcutaneous fat biopsies from 13 HIV-infected subjects.ResultsAt baseline, prior to intervention, HIV-infected subjects demonstrated increased log FGF21 (2.13±0.06 vs. 1.98±0.05 pg/mL, P=0.05) and log irisin (0.33±0.02 vs. 0.17±0.04 μg/mL, P=0.003) compared to healthy controls well-matched based on waist circumference. After 12 months, HIV-infected subjects randomized to LSM demonstrated a relative reduction in FGF21 compared to those not randomized to LSM (-10[-35,22]) vs. 40[0,94] %change, P=0.01). Changes in FGF21 were inversely associated with improved parameters of energy homeostasis, including increased REE (ρ=-0.34, P=0.046) and max VO2 (ρ=-0.38, P=0.02), and reduced RQ (ρ=0.40, P=0.02) among all HIV-infected subjects. Increased UCP-1 (r=0.75, P=0.003), DIO2 (r=0.58, P=0.04), and CideA(r=0.73, P=0.01) gene expression in dorsocervical fat was significantly associated with FGF21 in HIV-infected subjects.ConclusionHIV-infected subjects with metabolic complications demonstrate increases in FGF21 in relationship to BAT gene expression. Relative reductions in FGF21 in those receiving long-term LSM relate to overall improvements in energy expenditure parameters. In contrast, irisin levels are elevated in HIV-infected subjects, but are not influenced by LSM nor associated with BAT gene expression.This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 08/2014; · 3.40 Impact Factor
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    ABSTRACT: Among patients infected with human immunodeficiency virus (HIV), visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analog, specifically targets visceral fat reduction but its effects on liver fat are unknown.
    JAMA The Journal of the American Medical Association 07/2014; 312(4):380-9. · 29.98 Impact Factor
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    ABSTRACT: miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and "whitening" of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte-like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.
    The Journal of clinical investigation. 07/2014;
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    ABSTRACT: Mechanisms predisposing HIV-infected patients to increased cardiovascular disease (CVD) risk remain unclear. To determine the interrelationship between arterial inflammation and high-risk coronary plaque morphology in HIV-infected patients with subclinical coronary atherosclerosis. Forty-one HIV-infected patients on stable antiretroviral therapy without known CVD but with atherosclerotic plaque on coronary CT angiography were evaluated with F-FDG-PET. Patients were stratified into 2 groups based on relative degree of arterial inflammation [aortic target-to-background ratio (TBR)]. High-risk coronary atherosclerotic plaque morphology features were compared between groups. HIV-infected patients with higher and lower TBRs were similar with respect to traditional CVD risk parameters. Among HIV-infected patients with higher TBR, an increased percentage of patients demonstrated at least 1 low-attenuation coronary atherosclerotic plaque (40% vs. 10%, P = 0.02) and at least 1 coronary atherosclerotic plaque with both low attenuation and positive remodeling (35% vs. 10%, P = 0.04). Moreover, in the higher TBR group, both the number of low-attenuation plaques per patient (P = 0.02) and the number of vulnerability features in the most vulnerable plaque (P = 0.02) were increased. TBR grouping remained significantly related to the number of low-attenuation plaques/subject (β = 0.35, P = 0.004), controlling for age, gender, low-density lipoprotein, duration of HIV, and CD4. These data demonstrate a relationship between arterial inflammation on F-FDG-PET and high-risk coronary atherosclerotic plaque features among HIV-infected patients with subclinical coronary atherosclerosis. Further studies are needed to determine whether arterial inflammation and related high-risk coronary morphology increase the risk of clinical CVD events in the HIV population.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 06/2014; 66(2):164-71. · 4.65 Impact Factor
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    ABSTRACT: HIV is associated with atherosclerosis and low HDL. With inflammation, HDL becomes dysfunctional. We previously showed that pro-inflammatory HDL has high HDL redox activity (HRA). In this study, we: 1) compare HRA in HIV-infected versus non-HIV-infected subjects and 2) relate HRA to indices of macrophage activation and cardiovascular disease risk. 102 HIV-infected subjects and 41 matched non-HIV controls without clinical cardiovascular disease underwent coronary CT angiography (CTA) and testing for immune/inflammatory biomarkers. The effect of purified HDL from each study subject on the oxidation rate of dihydrorhodamine-123(DOR) was normalized to the DOR of pooled HDL from healthy subjects. The normalized ratio DORsubject/DORpooled (nHRA) was used as a measure of HRA, with higher HRA suggesting dysfunctional HDL. HRA was higher in HIV-infected versus non-HIV subjects (1.4±0.01 versus 1.3±0.01, p=0.03). In multivariate modeling for HRA among all subjects, HIV status remained positively related to HRA (p=0.02), even after controlling for traditional cardiovascular risk factors, comorbid conditions, and immune activation. Among HIV-infected subjects, HRA correlated inversely with HDL (rho=-0.32, p=0.002) and log adiponectin (r=-0.28, p=0.006) and correlated positively with log sCD163 (r=0.24, p=0.02) - a monocyte/macrophage activation marker - and with percent non-calcified coronary atherosclerotic plaque (r=0.29, p=0.03). sCD163 remained significantly associated with HRA in multivariate modeling among HIV-infected subjects (p=0.03). These data demonstrate increased HRA among HIV-infected subjects versus matched non-HIV subjects with comparable HDL levels. In HIV-infected subjects, HRA relates to macrophage activation and to non-calcified coronary atherosclerotic plaque, which may be rupture prone. Further studies are needed in HIV-infected patients to elucidate the interplay between immune activation, HDL function, and CVD risk.
    Antiviral therapy 02/2014; · 3.07 Impact Factor
  • Suman Srinivasa, Steven Grinspoon
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    ABSTRACT: In the absence of a cure, HIV-infected patients are being successfully treated with antiretroviral therapies (ART) and living longer. Indeed, an increasing number of HIV-infected patients are living beyond the age of 50, and in that regard, the use of ART has transformed HIV to a chronic medical condition. As more HIV-infected patients are virologically controlled and living longer, the trajectory of disease morbidity has shifted, however, primarily from opportunistic infections and immune dysfunction to metabolic complications. Evidence suggests that HIV-infected patients acquire significant metabolic risks, including lipodystrophic changes, subclinical atherosclerosis, and insulin resistance. The etiology of these metabolic complications specifically in HIV-infected patients is not entirely clear, but may be related to a complex interaction between long term consequences of infection and HIV itself, chronic use of antiretrovirals, and underlying inflammatory processes. Previous classes of ART, such as protease inhibitors and reverse transcriptase inhibitors, have been implicated in altering fat redistribution and lipid and glucose homeostasis. Advances in drug development have introduced newer ART with strategies to target novel mechanisms of action and improve patient adherence with multi-class drug combinations. In this review, we will focus on these newer classes of ART, including selected entry inhibitors, integrase inhibitors, and multi-class drug combinations, and two newer protease inhibitors, and the potential of these newer agents to cause metabolic complications in HIV-infected patients. Taken together, further reduction of morbidity in HIV-infected patients will require increasing awareness of the deleterious metabolic complications of ART with subsequent management to mitigate these risks.
    European Journal of Endocrinology 02/2014; · 3.14 Impact Factor
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    ABSTRACT: To investigate the concordance/discordance of IGF-1 and peak stimulated GH in identifying subjects with reduced GH secretion and to determine the physiological significance of any discordance in obese subjects. 95 obese and 43 normal weight men and women underwent measurement of IGF-1 and GH stimulation testing with GH releasing hormone (GHRH)-arginine. Reduced IGF-1 and GH secretion were defined using pre-determined cut-points. Cardiovascular disease risk was determined by measuring carotid intima-media thickness (cIMT). In a second study, IGF-1 was measured in 52 obese men and women who underwent GH stimulation testing and overnight frequent blood sampling. The association of IGF-1 and peak stimulated GH with parameters of endogenous GH secretion was assessed. 60% of obese subjects had normal IGF-1 and peak stimulated GH while 8.4% of obese subjects had reduced IGF-1 and GH secretion. Discordance rate for IGF-1 and peak GH was 31.6%. Subjects with both low IGF-1 and low peak GH had the highest cIMT, while subjects with both normal IGF-1 and peak GH had the lowest cIMT. Subjects with reduction in either IGF-1 or peak GH, had intermediate cIMT (P=0.02). IGF-1 and peak stimulated GH were associated with maximum and mean overnight serum GH and GH AUC as well as maximum peak mass and median pulse mass. Peak stimulated GH, but not IGF-1, was also associated with nadir overnight serum GH concentration and basal GH secretion. Peak stimulated GH and IGF-1 demonstrate significant discordance in identification of subjects with reduced GH secretion in obesity. Subjects with reduction of either IGF-1 or peak GH had higher cIMT compared to subjects with both normal IGF-1 and peak GH. Subjects with reductions in both IGF-1 and peak GH had the highest cIMT. Peak GH, compared to IGF-1, has broader associations with various parameters of endogenous GH secretion which support its utility in identifying those with reduced GH secretion.
    Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 11/2013; · 2.35 Impact Factor
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    ABSTRACT: Context:Few studies have assessed the relationship between GH and mitochondrial function.Objective:The objective of this study was to determine the effects of improving IGF-1 using a GH releasing hormone (GHRH) analog, tesamorelin, on mitochondrial function assessed by phosphocreatine (PCr) recovery using (31)Phosphorous magnetic resonance spectroscopy in obese adults with reduced GH.Design:39 obese men and women with reduced GH secretion as determined by GHRH-arginine stimulation tests underwent MRS as part of a 12 months, double-blind, randomized, placebo-controlled trial comparing tesamorelin versus placebo. PCr recovery after sub-maximal exercise was assessed at baseline and at 12 months.Results:At baseline, there were no differences in age, gender, race/ethnicity, GH or PCr parameters between tesamorelin and placebo. After 12 months, tesamorelin treatment led to significantly greater increase in IGF-1 compared to placebo treatment (tesamorelin change: 102.9±31.8 vs. placebo: 22.8±8.9 μ g/l; P= 0.02). We demonstrated a significant positive relationship between increase in IGF-1 and improvements in PCr recovery represented as ViPCr (R=0.56; P=0.01). The association between IGF-1 and PCr recovery was even stronger amongst subjects treated with tesamorelin only (ViPCr: R=0.71; P=0.03). This association remained significant controlling for age, gender, race, ethnicity and parameters of body composition and insulin sensitivity (all P<0.05).Conclusions:Increases in IGF-1 from 12-months treatment with tesamorelin were significantly associated with improvements in PCr recovery parameters in obese men and women with reduced GH secretion, suggestive of improvements in mitochondrial function.
    The Journal of clinical endocrinology and metabolism 10/2013; · 6.50 Impact Factor
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    ABSTRACT: This study sought to determine whether arterial inflammation measured by (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) improves prediction of cardiovascular disease (CVD) beyond traditional risk factors. It is unknown whether arterial (18)F-FDG uptake measured with routine PET imaging provides incremental value for predicting CVD events beyond Framingham risk score (FRS). We consecutively identified 513 individuals from 6,088 patients who underwent (18)F-FDG-PET and computed tomography (CT) imaging at Massachusetts General Hospital between 2005 and 2008 and who met additional inclusion criteria: ≥30 years of age, no prior CVD, and free of cancer. CVD events were independently adjudicated, while blinded to clinical data, using medical records to determine incident stroke, transient ischemic attack, acute coronary syndrome, revascularization, new-onset angina, peripheral arterial disease, heart failure, or CVD death. FDG uptake was measured in the ascending aorta (as target-to-background-ratio [TBR]), while blinded to clinical data. During follow-up (median 4.2 years), 44 participants developed CVD (2 per 100 person-years at risk). TBR strongly predicted subsequent CVD independent of traditional risk factors (hazard ratio: 4.71; 95% confidence interval [CI]: 1.98 to 11.2; p < 0.001) and (hazard ratio: 4.13; 95% CI: 1.59 to 10.76; p = 0.004) after further adjustment for coronary calcium score. Addition of arterial PET measurement to FRS scores improved the C-statistic (mean ± standard error 0.62 ± 0.03 vs. 0.66 ± 0.03). Further, incorporation of TBR into a model with FRS variables resulted in an integrated discrimination of 5% (95% CI: 0.36 to 9.87). Net reclassification improvements were 27.48% (95% CI: 16.27 to 39.92) and 22.3% (95% CI: 11.54 to 35.42) for the 10% and 6% intermediate-risk cut points, respectively. Moreover, TBR was inversely associated with the timing of CVD (beta -0.096; p < 0.0001). Arterial FDG uptake, measured from routinely obtained PET/CT images, substantially improved incident CVD prediction beyond FRS among individuals undergoing cancer surveillance and provided information on the potential timing of such events.
    JACC. Cardiovascular imaging 10/2013; · 14.29 Impact Factor
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    ABSTRACT: Background. Little is known about coronary plaque in HIV-infected women.Methods. Sixty HIV-infected and 30 non-HIV-infected women without symptoms or history of CVD were recruited to assess coronary plaque by coronary CT angiography and immune activation. Data from 102 HIV-infected men and 41 non-HIV-infected male controls were compared.Results. HIV-infected women demonstrated significantly higher percent of segments with noncalcified plaque (74±28 [75 (63,100)] vs. 23±39 [0 (0,56)]%, P=0.007) and number of segments with noncalcified plaque (0.92±1.48 [0 (0,2)] vs. 0.40±1.44 [0 (0,0)], P=0.04) vs. female control subjects. Immune activation parameters, including sCD163 (P= 0.006), CXCL10 (P=0.002), percentage of CD14+CD16+ monocytes (P=0.008) were higher in HIV-infected women vs. female control subjects, whereas no differences in general inflammatory markers were seen. Among HIV-infected women with noncalcified coronary plaque, sCD163 was significantly higher compared to HIV-infected women without noncalcified plaque (P=0.04). In multivariate modeling for sCD163 among male and female subjects, significant HIV (P<0.0001), age (P=0.002), and gender (P=0.0002) effects were seen.Conclusions. Young, asymptomatic, HIV-infected women, demonstrate increased noncalcified coronary plaque and increased immune activation, particularly monocyte activation. Independent effects of gender, HIV and aging on immune activation may contribute to CVD in this population.
    The Journal of Infectious Diseases 09/2013; · 5.85 Impact Factor
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    ABSTRACT: As women with human immunodeficiency virus (HIV) are living longer, more are entering perimenopause. Prior studies suggest that HIV-infected women are more likely to have hot flashes than non-HIV-infected women. However, little is known regarding hot flash severity and hot flash-related interference with daily function, mood, and quality of life in this population. Perimenopausal HIV-infected and non-HIV-infected women matched by age, race, and menstrual patterns completed the Menopause Rating Scale (to assess hot flash severity) and the Hot Flash Related Daily Interference Scale (HFRDIS). Menopause Rating Scale and HFRDIS scores and subscores were compared between the groups. Thirty-three HIV-infected women and 33 non-HIV-infected women who were similar in age (median [interquartile range], 47 [45-48] vs 47 [46-49] y), race (64% vs 52% nonwhite, P = 0.32), and menstrual patterns (number of periods in the past year; 5 [4-9] vs 6 [4-10], P = 0.53) were studied. Perimenopausal HIV-infected women reported greater hot flash severity (HIV vs non-HIV: 2 [1-3] vs 1 [0-3], P = 0.03) and hot flash-related interference (HFRDIS total score, 37 [10-60] vs 6 [0-20], P = 0.001). Perimenopausal HIV-infected women experience greater hot flash severity and related interference compared with non-HIV-infected perimenopausal women. Increased distress secondary to hot flashes may reduce quality of life and negatively impact important health-promoting behaviors, including adherence to antiretroviral therapy, in HIV-infected women.
    Menopause (New York, N.Y.) 07/2013; · 3.08 Impact Factor
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    ABSTRACT: What is already known about this subject Obesity-related insulin resistance is highly prevalent in children and adolescents, and contributes to an increased lifetime risk of type 2 diabetes mellitus and cardiovascular disease. Intensive exercise training may improve insulin sensitivity. What this study adds Three monitored exercise training sessions per week for 8 weeks can improve fitness-related insulin sensitivity in obese, insulin resistant children. Insulin sensitivity and skeletal muscle oxidative phosphorylation may be dissociable in this population. Improvements in fitness may be accompanied by a rise in intramyocellular lipid content and an associated increase in resting energy expenditure. Obesity is associated with poor fitness and adverse metabolic consequences in children. To investigate how exercise and lifestyle modification may improve fitness and insulin sensitivity in this population. Randomized controlled trial, 21 obese (body mass index ≥ 95% percentile) subjects, ages 10 to 17 years. Subjects were given standardized healthful lifestyle advice for 8 weeks. In addition, they were randomized to an in-home supervised exercise intervention (n = 10) or control group (n = 11). Fasting laboratory studies (insulin, glucose, lipid profile) and assessments of fitness, body composition, skeletal muscle oxidative phosphorylation and intramyocellular lipid content (IMCL), were performed at baseline and study completion. Subjects were 13.0 ± 1.9 (standard deviation) years old, 72% female and 44% non-white. Exercise improved fitness (P = 0.03) and power (P = 0.01), and increased IMCL (P = 0.02). HOMA-IR decreased among all subjects in response to lifestyle modification advice (P = 0.01), regardless of exercise training assignment. In univariate analysis in all subjects, change in cardiovascular fitness was associated with change in HOMA-IR. In exploratory analyses, increased IMCL was associated with greater resting energy expenditure (r = 0.78, P = 0.005) and a decrease in fasting respiratory quotient (r = -0.70, P = 0.02) (n = 11). Change in fitness was found to be related to change in insulin resistance in response to lifestyle modification and exercise in obese children. IMCL increased with exercise in these obese children, which may reflect greater muscle lipid oxidative capacity.
    Pediatric Obesity 06/2013; · 2.28 Impact Factor
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    ABSTRACT: BACKGROUND: HIV-infected patients are at increased risk of coronary artery disease (CAD). We evaluated the cost-effectiveness of cardiac screening for HIV-positive men at intermediate or greater CAD risk. DESIGN: We developed a lifetime microsimulation model of CAD incidence and progression in HIV-infected men. METHODS: Input parameters were derived from two HIV cohort studies and the literature. We compared no CAD screening with stress testing and coronary computed tomography angiography (CCTA)-based strategies. Patients with test results indicating 3-vessel/left main CAD underwent invasive coronary angiography (ICA) and received coronary artery bypass graft surgery. In the stress testing + medication and CCTA + medication strategies, patients with 1-2-vessel CAD results received lifetime medical treatment without further diagnostics whereas in the stress testing + intervention and CCTA + intervention strategies, patients with these results underwent ICA and received percutaneous coronary intervention. RESULTS: Compared to no screening, the stress testing + medication, stress testing + intervention, CCTA + medication, and CCTA + intervention strategies resulted in 14, 11, 19, and 14 quality-adjusted life days per patient and incremental cost-effectiveness ratios of 49,261, 57,817, 34,887 and 56,518 Euros per quality-adjusted life year (QALY), respectively. Screening only at higher CAD risk thresholds was more cost-effective. Repeated screening was clinically beneficial compared to one-time screening, but only stress testing + medication every 5 years remained cost-effective. At a willingness-to-pay threshold of 83,000 €/QALY (∼100,000 US$/QALY), implementing any CAD screening was cost-effective with a probability of 75-95%. CONCLUSIONS: Screening HIV-positive men for CAD would be clinically beneficial and comes at a cost-effectiveness ratio comparable to other accepted interventions in HIV care.
    European journal of preventive cardiology. 03/2013;
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    ABSTRACT: OBJECTIVE:: Among HIV-infected patients, high rates of MI and sudden cardiac death have been observed. Exploring potential underlying mechanisms, we used multidetector spiral coronary computed tomography angiography (coronary CTA) to compare atherosclerotic plaque morphology in HIV-infected subjects and non-HIVinfected controls. METHODS:: Coronary atherosclerotic plaques visualized by CTA in HIV-infected (101) and non-HIV-infected (41) men without clinically apparent heart disease matched on cardiovascular risk factors were analyzed for 3 vulnerability features: low attenuation, positive remodeling, and spotty calcification. RESULTS:: 95% of HIV-infected subjects were receiving ART (median duration 7.9 years) and had well-controlled disease (median CD4 473 cells/mm3, median HIV RNA <50 copies/ml). Age and traditional cardiovascular risk factors were similar in HIV-infected subjects and controls. Among the HIV-infected (versus control) group, there was a higher prevalence of subjects with at least one: 1) low attenuation plaque (22.8% versus 7.3%, p = 0.02), 2) positively remodeled plaque (49.5% versus 31.7%, p = 0.05) and 3) high-risk 3-feature plaque (7.9% versus 0%, p = 0.02). Moreover, subjects in the HIV-infected (versus control) group demonstrated a higher number of low attenuation plaques (p = 0.01) and positively remodeled plaques (p = 0.03) per subject. CONCLUSIONS:: Our data demonstrate an increased prevalence of vulnerable plaque features among relatively young HIV-infected patients. Differences in coronary atherosclerotic plaque morphology - namely, increased vulnerable plaque among HIVinfected subjects - are here for the first time reported and may contribute to increased rates of MI and sudden cardiac death in this population.
    AIDS (London, England) 01/2013; · 4.91 Impact Factor
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    ABSTRACT: Background/Objective: HIV lipodystrophy - characterized by peripheral lipoatrophy, with or without central fat accumulation - confers increased metabolic risk. However, the functional activity of HIV lipodystrophic tissue in relation to metabolic risk has yet to be fully explored in vivo through the use of non-invasive imaging techniques. This study assesses the relationship between FDG uptake in various fat depots and metabolic/immune parameters among subjects with HIV lipodystrophy.Design/Methods: Lipodystrophic men on anti-retroviral therapy (ART) underwent whole-body (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scans and detailed metabolic/immune phenotyping. RESULTS: FDG uptake in the subcutaneous adipose tissue (SAT) of the extremities (mean standardized uptake value, or SUV, of the arm and leg SAT) was found to correlate with the degree of peripheral lipoatrophy (r = 0.7, p = 0.01). Extremity SAT FDG uptake was positively associated with HOMA-IR (r (=) 0.6, p = 0.02) and fasting hyperinsulinemia (r (=) 0.7, p 0.01), while fat percentage of extremities was not. Further, extremity SAT FDG uptake was significantly associated with CD4 count (r (=) 0.6, p = 0.05). In multivariate modeling for HOMA-IR, extremity SAT FDG uptake remained significant after controlling for BMI and TNF-α (R(2) for model = 0.71, p = 0.02; SUV in the extremity SAT β-estimate 12.3, p = 0.009). CONCLUSIONS: In HIV lipodystrophic patients, extremity SAT FDG uptake is increased in association with reduced extremity fat and may contribute to insulin resistance. Noninvasive assessments of in situ inflammation using FDG-PET may usefully complement histological and gene expression analyses of metabolic dysregulation in peripheral fat among HIV+ patients.
    Antiviral therapy 10/2012; · 3.07 Impact Factor
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    ABSTRACT: HIV-1 elite controllers (EC) spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary CT angiography (CTA) in: 1) EC, 2) non EC, chronically HIV-1 infected, ART-treated patients with undetectable viral load ("chronic HIV"), and 3) HIV-negative controls. Prevalence of atherosclerosis (78% vs. 42%, P < 0.05) and markers of immune activation were increased in EC compared to HIV-negative controls. sCD163, a monocyte activation marker, was increased in EC compared to chronic HIV-1 (P < 0.05) and compared to HIV-negative controls (P < 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among EC.
    AIDS (London, England) 10/2012; · 4.91 Impact Factor
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    ABSTRACT: Context:Obesity is associated with reduced GH secretion and increased cardiovascular disease risk.Objective:We performed this study to determine the effects of augmenting endogenous GH secretion on body composition and cardiovascular disease risk indices in obese subjects with reduced GH secretion.Design, Patients and Methods:A randomized, double-blind, placebo-controlled study was performed involving 60 abdominally obese subjects with reduced GH secretion. Subjects received tesamorelin, a GHRH(1-44) analog, 2 mg once daily, or placebo for 12 months. Abdominal visceral adipose tissue (VAT) was assessed by abdominal computed tomography scan, and carotid intima-media thickness (cIMT) was assessed by ultrasound. Treatment effect was determined by longitudinal linear mixed-effects modeling.Results:VAT [-16 ± 9 vs.19 ± 9 cm(2), tesamorelin vs. placebo; treatment effect (95% confidence interval): -35 (-58, -12) cm(2); P = 0.003], cIMT (-0.03 ± 0.01 vs. 0.01 ± 0.01 mm; -0.04 (-0.07, -0.01) mm; P = 0.02), log C-reactive protein (-0.17 ± 0.04 vs. -0.03 ± 0.05 mg/liter; -0.15 (-0.30, -0.01) mg/liter, P = 0.04), and triglycerides (-26 ± 16 vs. 12 ± 8 mg/dl; -37 (-67, -7) mg/dl; P = 0.02) improved significantly in the tesamorelin group vs. placebo. No significant effects on abdominal sc adipose tissue (-6 ± 6 vs. 3 ± 11 cm(2); -10 (-32, +13) cm(2); P = 0.40) were seen. IGF-I increased (86 ± 21 vs. -6 ± 8 μg/liter; 92 (+52, +132) μg/liter; P < 0.0001). No changes in fasting, 2-h glucose, or glycated hemoglobin were seen. There were no serious adverse events or differences in adverse events between the groups.Conclusion:Among obese subjects with relative reductions in GH, tesamorelin selectively reduces VAT without significant effects on sc adipose tissue and improves triglycerides, C-reactive protein, and cIMT, without aggravating glucose.
    The Journal of clinical endocrinology and metabolism 09/2012; · 6.50 Impact Factor
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    ABSTRACT: What is already known about this subject Circulating concentrations of branched-chain amino acids (BCAAs) can affect carbohydrate metabolism in skeletal muscle, and therefore may alter insulin sensitivity. BCAAs are elevated in adults with diet-induced obesity, and are associated with their future risk of type 2 diabetes even after accounting for baseline clinical risk factors. What this study adds Increased concentrations of BCAAs are already present in young obese children and their metabolomic profiles are consistent with increased BCAA catabolism. Elevations in BCAAs in children are positively associated with insulin resistance measured 18 months later, independent of their initial body mass index. BACKGROUND: Branched-chain amino acid (BCAA) concentrations are elevated in response to overnutrition, and can affect both insulin sensitivity and secretion. Alterations in their metabolism may therefore play a role in the early pathogenesis of type 2 diabetes in overweight children. OBJECTIVE: To determine whether paediatric obesity is associated with elevations in fasting circulating concentrations of BCAAs (isoleucine, leucine and valine), and whether these elevations predict future insulin resistance. METHODS: Sixty-nine healthy subjects, ages 8-18 years, were enrolled as a cross-sectional cohort. A subset of subjects who were pre- or early-pubertal, ages 8-13 years, were enrolled in a prospective longitudinal cohort for 18 months (n = 17 with complete data). RESULTS: Elevations in the concentrations of BCAAs were significantly associated with body mass index (BMI) Z-score (Spearman's Rho 0.27, P = 0.03) in the cross-sectional cohort. In the subset of subjects that followed longitudinally, baseline BCAA concentrations were positively associated with homeostasis model assessment for insulin resistance measured 18 months later after controlling for baseline clinical factors including BMI Z-score, sex and pubertal stage (P = 0.046). CONCLUSIONS: Elevations in the concentrations of circulating BCAAs are significantly associated with obesity in children and adolescents, and may independently predict future insulin resistance.
    Pediatric Obesity 09/2012; · 2.28 Impact Factor
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    ABSTRACT: Patients with thyrotropin-secreting pituitary adenomas may present with mass effect, hypopituitarism, and/or hyperthyroidism. The spectrum of pathologic and clinical features of patients whose tumors demonstrate β-thyrotropin immunoreactivity (β-TSH IR) has not been characterized. To characterize the phenotype of patients with pituitary adenomas with positive β-TSH IR, we conducted a retrospective analysis of patient records of all adult patients (n = 1,223) undergoing pituitary surgery in our institution over one decade (1999-2009). The search identified 166 adults with tumors which had β-TSH IR. These patients were individually matched to 166 patients whose tumors revealed no β-TSH IR. Clinical, pathological, imaging and biochemical data were extracted. 332 patients, aged 51.4 ± 15.1 years [150 women (45 %) and 182 men (55 %)], with pituitary adenomas (mean tumor diameter ± SD: 22.7 ± 9.0 mm) were studied. The degree of β-TSH IR was associated with the presence of central hyperthyroidism (p < 0.0001) or goiter (p = 0.0217). Patients whose tumors expressed more extensive β-TSH IR were less likely to develop pituitary apoplexy than those without β-TSH IR (p = 0.0428). In addition, the degree of β-TSH IR correlated with the presence of immunoreactivity for β-FSH (p < 0.0001), β-LH (p < 0.0001), alpha subunit (p < 0.0001), and GH (p = 0.0036). Conclusions: Pituitary adenomas expressing β-TSH IR were more likely to demonstrate immunoreactivity for β-FSH, β-LH, GH or alpha subunit. Patients with such tumors were more likely to exhibit hyperthyroidism and goiter, but less likely to develop pituitary apoplexy than patients without β-TSH IR. These findings suggest that β-TSH IR is associated with specific phenotypic features in patients with pituitary adenomas.
    Pituitary 08/2012; · 2.67 Impact Factor

Publication Stats

9k Citations
1,632.18 Total Impact Points

Institutions

  • 1994–2014
    • Massachusetts General Hospital
      • • Division of Infectious Diseases
      • • Division of Endocrinology
      • • Neuroendocrine Unit
      Boston, Massachusetts, United States
  • 1970–2012
    • Harvard Medical School
      • Department of Radiology
      Boston, Massachusetts, United States
  • 2011
    • Chestnut Hill College
      Boston, Massachusetts, United States
  • 2010
    • McGill University
      • Department of Medicine
      Montréal, Quebec, Canada
  • 2005–2010
    • McGill University Health Centre
      Montréal, Quebec, Canada
    • U.S. Food and Drug Administration
      Washington, Washington, D.C., United States
    • Indiana University-Purdue University Indianapolis
      • Division of Infectious Diseases
      Indianapolis, IN, United States
  • 2009
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2008
    • Columbia University
      • Department of Epidemiology
      New York City, NY, United States
  • 2007
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
  • 2004–2007
    • Brigham and Women's Hospital
      Boston, Massachusetts, United States
    • Boston Children's Hospital
      • Department of Radiology
      Boston, MA, United States
  • 2003–2007
    • University of California, San Francisco
      San Francisco, California, United States
  • 2002–2003
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
    • University of Massachusetts Medical School
      • Department of Pediatrics
      Worcester, MA, United States