Biomedical subjects

Steven Grinspoon

Publications and source records attributed to Steven Grinspoon.

54 records · Page 3Linked to original sources

PubMed2003

Psoas muscle attenuation measurement with computed tomography indicates intramuscular fat accumulation in patients with the HIV-lipodystrophy syndrome.

The human immunodeficiency virus (HIV)-lipodystrophy syndrome is characterized by abnormalities of lipid metabolism, glucose homeostasis, and fat distribution. Overaccumulation of intramuscular lipid may contribute to insulin resistance in this population. We examined 63 men: HIV positive with lipodystrophy (n = 22), HIV positive without lipodystrophy (n = 20), and age- and body mass index-matched HIV-negative controls (n = 21). Single-slice computed tomography was used to determine psoas muscle attenuation and visceral fat area. Plasma free fatty acids (FFA), lipid profile, and markers of glucose homeostasis were measured. Muscle attenuation was significantly decreased in subjects with lipodystrophy [median (interquartile range), 55.0 (51.0-58.3)] compared with subjects without lipodystrophy [57.0 (55.0-59.0); P = 0.05] and HIV-negative controls [59.5 (57.3-64.8); P < 0.01]. Among HIV-infected subjects, muscle attenuation correlated significantly with FFA (r = -0.38; P = 0.02), visceral fat (r = -0.49; P = 0.002), glucose (r = -0.38; P = 0.02) and insulin (r = -0.60; P = 0.0001) response to a 75-g oral glucose tolerance test. In forward stepwise regression analysis with psoas attenuation as the dependent variable, visceral fat (P = 0.02) and FFA (P < 0.05), but neither body mass index, subcutaneous fat, nor antiretroviral use, were strong independent predictors of muscle attenuation (r2 = 0.39 for model). Muscle attenuation (P = 0.02) and visceral fat (P = 0.02), but not BMI, subcutaneous fat, FFA, or antiretroviral use, were strong independent predictors of insulin response (area under the curve) to glucose challenge (r2 = 0.47 for model). These data demonstrate that decreased psoas muscle attenuation due to intramuscular fat accumulation may contribute significantly to hyperinsulinemia and insulin resistance in HIV-lipodystrophy patients. Further studies are needed to assess the mechanisms and consequences of intramuscular lipid accumulation in HIV-infected patients.

Absorptiometry, Photon↗

PubMed2003

Characterization of leptin pulse dynamics and relationship to fat mass, growth hormone, cortisol, and insulin.

To investigate the regulation of leptin secretion and pulsatility by fat mass, we performed overnight leptin sampling every 20 min for 12 h and compared leptin dynamics with total body and regional fat measurements in 20 healthy male subjects. Simultaneous growth hormone (GH), cortisol, and insulin levels were assessed to determine relatedness and synchronicity during overnight fasting. Deconvolution analyses were performed to determine simultaneous hormonal dynamics, synchronicity, and interrelatedness using cross-correlation and cross-approximate entropy (X-ApEn) analyses. Subjects demonstrated 4.7 +/- 0.4 leptin pulses/12 h. Leptin secretion correlated highly with total body fat (r = 0.78, P < 0.001) and regional fat depots. In contrast, leptin pulsatility did not correlate with total fat (r = 0.07, P = 0.785) or other measures of fat. There was synchronicity between GH and leptin (lag -39 minutes), cortisol and leptin (lag -211 min), and leptin and insulin, with leptin following insulin by 275 min. The mean random X-ApEn was significant between leptin and GH (0.854 +/- 0.030), cortisol (0.891 +/- 0.023), and insulin (0.868 +/- 0.034), demonstrating a high degree of regularity and pattern frequency. These data demonstrate differential regulation of leptin secretion and pulsatility in adipocytes and suggest that the leptin pulse generator is extrinsic to fat, whereas fat mass acts as an amplifier to modulate secretion and amplitude for a given pulsatility. We demonstrate synchronicity between leptin and GH, cortisol, and insulin. The directionality of the cross correlation suggests a temporal construct in which changes in leptin follow those of insulin but precede those of GH and cortisol during overnight fasting.

Adipose Tissue↗

PubMed2003

Weight loss and wasting in patients infected with human immunodeficiency virus.

Weight loss and muscle wasting remain significant clinical problems, even in the era of potent antiretroviral therapy. In patients infected with human immunodeficiency virus (HIV), wasting, particularly loss of metabolically active lean tissue, has been associated with increased mortality, accelerated disease progression, loss of muscle protein mass, and impairment of strength and functional status. Factors that may contribute to wasting include inadequate intake, malabsorptive disorders, metabolic alterations, hypogonadism, and excessive cytokine production. Evidence now demonstrates that nutritional counseling and support, appetite stimulants, progressive resistance training, and anabolic hormones can reverse weight loss and increase lean body mass in HIV-infected patients. Despite a growing body of evidence on the importance of nutritional intervention to prevent wasting in adults, maintain growth velocity in children, and promote restoration of weight and lean body mass in stable, low-weight patients, no therapeutic guidelines currently exist for the management of weight loss and wasting in HIV-infected patients. Principles and guidelines for assessment and management of weight loss and wasting in patients with HIV/AIDS are presented.

Adult↗

PubMed2003

Prediction of coronary heart disease risk in HIV-infected patients with fat redistribution.

A metabolic syndrome has been described among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy; the syndrome is characterized by fat redistribution, insulin resistance, and dyslipidemia. We compared the 10-year coronary heart disease (CHD) risk estimates for 91 HIV-infected men and women with fat redistribution with the risk estimates for 273 age-, sex-, and body mass index (BMI)-matched subjects enrolled in the Framingham Offspring Study. Thirty HIV-infected patients without fat redistribution were also compared with 90 age- and BMI-matched control subjects. The 10-year CHD risk estimate was significantly elevated among HIV-infected patients with fat redistribution, particularly among men; however, when they were matched with control subjects by waist-to-hip ratio, the 10-year CHD risk estimate did not significantly differ between groups. HIV-infected patients without fat redistribution did not have a greater CHD risk estimate than did control subjects. In addition, the CHD risk estimate was greatest in HIV-infected patients who had primary lipoatrophy, compared with those who had either lipohypertrophy or mixed fat redistribution. Therefore, although CHD risk is increased in HIV-infected patients with fat redistribution, the pattern of fat distribution and sex are potential important components in determining the risk in this population.

Adult↗

PubMed2003

Reduced testosterone levels in human immunodeficiency virus-infected women with weight loss and low weight.

Risk factors for hypoandrogenemia among low-weight, human immunodeficiency virus (HIV)-infected patients are not known. Testosterone levels of 69 HIV-infected women with low weight and weight loss were compared with levels for 25 healthy, age- and body mass index-matched control subjects. HIV-infected subjects were of low weight, with a mean (+/- standard deviation) weight loss of -17.6% +/- 9.7% from preillness maximum, and 42% of HIV-infected subjects had a body mass index of <20 kg/m(2). Forty-nine percent of the HIV-infected population versus 8% of the control population exhibited low free testosterone levels (P<.001). Among HIV-infected women, when we controlled for chronic hepatitis status, age, and time of blood sampling, weight loss of >10% of maximum weight was a significant predictor of low free testosterone levels. Free testosterone levels did not differ by drug class or antiretroviral regimen. In conclusion, decreased androgen levels are common among HIV-infected women reporting significant weight loss, independent of exposure to antiretroviral medications.

Adolescent↗

PubMed2003

Mechanisms and strategies for insulin resistance in acquired immune deficiency syndrome.

Abnormalities of glucose regulation, including impaired glucose tolerance and insulin resistance, are often seen among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy. Insulin resistance in this population may result from antiviral medication directly impairing glucose uptake in the muscle, effects of HIV per se, or indirect effects, such as fat redistribution. Insulin resistance may increase the risk of coronary heart disease among this population of patients, in part by inhibiting normal thrombolysis. The optimal treatment for insulin resistance and impaired glucose intolerance in HIV-infected patients is not known, but preliminary studies have suggested that metformin, an insulin sensitizing agent, improves insulin sensitivity, blood pressure, and waist circumference. Initial studies of thiazolidinediones also suggest the potential utility of such agents to improve insulin sensitivity, decrease hepatic steatosis, and increase subcutaneous fat. Further studies are needed to determine the optimal treatment strategy for insulin resistance in this population.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Inhibition of lipolysis improves insulin sensitivity in protease inhibitor-treated HIV-infected men with fat redistribution.

BACKGROUND: Fatty acid concentrations are increased in patients with HIV and fat redistribution and may contribute to insulin resistance in this population. OBJECTIVE: We determined the effects of acute inhibition of lipolysis on insulin sensitivity in HIV-infected patients with fat redistribution who were receiving a protease inhibitor. DESIGN: Seven HIV-infected men [age: 45 +/- 2 y; body mass index (in kg/m(2)): 28.8 +/- 1.9] with a fasting insulin concentration > or= 104 pmol/L (15 micro IU/mL), combined visceral adiposity and peripheral lipoatrophy, and receiving a protease inhibitor were studied. Tolbutamide-modified frequently sampled intravenous-glucose-tolerance tests (FSIGTTs) were performed after randomized double-blind administration of acipimox (500 mg at -90 and 0 min), a potent inhibitor of lipolysis, and placebo. The subjects completed 2 FSIGTTs separated by 3-7 d. RESULTS: At baseline, fasting insulin and fatty acid concentrations were 27.6 +/- 5.0 micro IU/mL and 0.83 +/- 0.08 mmol/L (normal range: 0.1-0.6 mmol/L), respectively. Fatty acid concentrations were significantly reduced after acipimox compared with placebo (fatty acid area under the curve: acipimox = 73 +/- 8 compared with placebo = 122 +/- 12 mmol x 270 min/L, P = 0.002). Acipimox treatment resulted in a significant increase in the insulin sensitivity index (acipimox = 1.63 +/- 0.5 compared with placebo = 0.88 +/- 0.3 x 10(-4) x min(-1) x micro IU/mL, P = 0.015). CONCLUSIONS: Acute inhibition of lipolysis and reduction in fatty acid concentrations are associated with improved insulin sensitivity in patients with HIV lipodystrophy and hyperinsulinemia. Further studies are needed to determine whether long-term antilipolytic strategies to reduce fatty acid concentrations may be useful in treating the metabolic disturbances associated with HIV lipodystrophy.

Adipose Tissue↗

PubMed2003

Regional body composition in adolescents with anorexia nervosa and changes with weight recovery.

BACKGROUND: Studies of regional fat distribution in adults with anorexia nervosa (AN) have shown decreased extremity fat at baseline and increased trunk fat with weight recovery, resulting in truncal adiposity. Little is known about fat distribution in adolescents with AN, especially with weight recovery. OBJECTIVE: We sought to determine whether regional fat distribution in adolescents with AN is comparable with that in healthy adolescents and whether weight recovery results in increased trunk fat and truncal adiposity. DESIGN: In 21 adolescent girls with AN and 21 control subjects matched for age and pubertal stage, we measured body-composition variables with dual-energy X-ray absorptiometry at baseline, 6 mo, and 12 mo. Weight recovery was defined as a > or = 10% increase in body mass index. RESULTS: At baseline, the girls with AN had a lower percentage of trunk fat than did the control subjects, whereas the percentage of extremity fat was not significantly different between the groups. Weight recovery in 13 subjects with AN resulted in an increased percentage of trunk fat and an increased ratio of trunk fat to extremity fat; however, this ratio did not exceed that of control subjects. CONCLUSIONS: In adolescents with AN, trunk fat rather than extremity fat is reduced. Weight recovery is associated with increased trunk fat and an increased ratio of trunk fat to extremity fat. In contrast with previous findings in adults, this most likely represents normalization of fat distribution rather than development of truncal adiposity.

Abdomen↗

PubMed2003

Effects of recombinant human insulin-like growth factor (IGF)-I and estrogen administration on IGF-I, IGF binding protein (IGFBP)-2, and IGFBP-3 in anorexia nervosa: a randomized-controlled study.

Administration of recombinant human (rh) IGF-I has been shown to have positive effects on bone density in anorexia nervosa, but the effects of rhIGF-I and estrogen on IGF binding protein (IGFBP)-2 and IGFBP-3 in anorexia nervosa are not known. Sixty-five osteopenic women with anorexia nervosa were randomized to rhIGF-I (30 micro g/kg sc twice daily) alone (n = 15), daily ethinyl estradiol (Ovcon 35) with rhIGF-I (n = 15), estradiol and placebo (n = 15), or placebo (n = 14) for 9 months. Subjects were 25.6 +/- 0.8 yr of age, low weight (body mass index 16.6 +/- 0.2 kg/m(2)) and osteopenic (T scores -2.06 +/- 0.09 for spine and -1.76 +/- 0.13 for hip). IGFBP-3 correlated with total hip bone density (r = 0.47, P = 0.0002) and was a significant predictor of hip bone density (P = 0.010) independent of IGF-I and body mass index in a multivariate regression model. During therapy, IGFBP-2 increased by 48 +/- 19 ng/ml in response to rhIGF-I and decreased by -38 +/- 22 ng/ml in response to placebo (P = 0.011). IGFBP-3 decreased (-895 +/- 120 ng/ml) in response to rhIGF-I but showed a minimal change (-53 +/- 99 ng/ml) in response to placebo (P < 0.0001). In contrast, no significant effect of estrogen was seen on IGF-I, IGFBP-2 or IGFBP-3. Among patients receiving rhIGF-I, the change in IGFBP-2 was inversely associated with the change in total hip bone density (R = -0.47, P = 0.013). In conclusion, our data suggest that chronic rhIGF-I administration increases IGF-I and IGFBP-2 and decreases IGFBP-3 in women with anorexia nervosa. IGFBP-2 and IGFBP-3 may be important determinants of bone density in this population.

Adolescent↗

PubMed2003

Serum osteoprotegerin in adolescent girls with anorexia nervosa.

Low bone mineral density (BMD) in adolescents with anorexia nervosa (AN) is associated with a low bone turnover state. Osteoprotegerin (OPG), a cytokine that acts as a decoy receptor for receptor activator of nuclear factor-kappaB ligand, decreases bone resorption by inhibiting differentiation of osteoclast precursors and activation of mature osteoclasts, and by stimulating osteoclast apoptosis. We compared OPG levels in 43 adolescent girls with AN with 38 controls and examined bone density, bone turnover, and hormonal parameters. Girls with AN had lower fat mass, lean body mass, lumbar BMD z-scores, and lumbar bone mineral apparent density than controls. OPG levels were higher in girls with AN than in controls (44.5 +/- 22.5 pg/ml vs. 34.5 +/- 12.7 pg/ml, P = 0.02). Osteocalcin, deoxypyridinoline, estradiol, free testosterone, IGF-I, and leptin were lower in AN than in healthy adolescents. OPG values correlated negatively with body mass index (r = -0.27, P = 0.02), percent fat mass (r = -0.35, P = 0.0002), leptin (r = -0.28, P = 0.02), lumbar BMD z-scores (r = -0.25, P = 0.03), and lumbar bone mineral apparent density (r = -0.26, P = 0.03). In conclusion, adolescent girls with AN have higher serum OPG values than controls. OPG values correlate negatively with markers of nutritional status and lumbar bone density z-scores and may be a compensatory response to the bone loss seen in this population.

Adolescent↗

PubMed2002

Reduced intravertebral bone marrow fat in HIV-infected men.

OBJECTIVE: To measure intravertebral bone marrow fat in HIV-infected men. DESIGN: A cross-sectional study of HIV-positive men, subcategorized by lipodystrophy and antiretroviral status, and healthy age- and body mass index (BMI)-matched HIV-negative controls. SETTING: A tertiary care academic medical institution. PATIENTS: Fifteen HIV-infected men and nine age- and BMI-matched healthy control subjects were recruited for bone density, intravertebral bone marrow fat, and body composition measurements. METHODS: Magnetic resonance spectroscopy was used to measure intravertebral marrow fat. Quantitative computed tomography was used to quantify visceral and subcutaneous fat. Dual energy X-ray absorptiometry was used to determine lumbar spine bone density. Statistical comparisons were performed according to HIV, lipodystrophy, and protease inhibitor (PI) exposure status. RESULTS: Intravertebral marrow fat was reduced in HIV-infected men (N = 15) compared with healthy HIV-negative controls (N = 9) (28.5 +/- 8.0 versus 37.3 +/- 12.5%, P = 0.04). Intravertebral bone marrow fat was most severely reduced in HIV-infected men with lipodystrophy compared with healthy HIV-negative controls (25.6 +/- 8.8% versus 37.3 +/- 12.5%, P = 0.04). Furthermore, nelfinavir (P = 0.02) was associated with decreased intravertebral marrow fat and indinavir (P < 0.05) was associated with increased intravertebral marrow fat in HIV-infected subjects. CONCLUSION: We demonstrated reduced intravertebral marrow fat in HIV-infected men using magnetic resonance spectroscopy. Notably, reduced marrow fat occurred in the setting of reduced bone density and may be affected by specific PI and lipodystrophy status. Further studies are necessary to determine the relationship between marrow fat and osteopenia and the effect of antiretroviral therapy on marrow fat in this population.

Absorptiometry, Photon↗

PubMed2002

Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge in human immunodeficiency virus-infected subjects with fat redistribution.

Fat redistribution, defined by both increased abdominal visceral fat and/or decreased abdominal, extremity, and facial subcutaneous fat, is increasingly recognized among human immunodeficiency virus (HIV)-infected patients treated with combination antiretroviral therapy. Fat redistribution in this population is associated with insulin resistance and dyslipidemia and is often referred to as the HIV lipodystrophy syndrome (LIPO). Fatty acids are known to modulate insulin resistance in other disease states, but a comprehensive evaluation of fatty acids has not been undertaken among HIV-infected patients with fat redistribution. In this study, we investigated fatty acid concentrations in 64 HIV-infected individuals (45 men and 19 women) with evidence of fat redistribution (LIPO) in comparison to 30 HIV-infected individuals (20 men and 10 women) without evidence of fat redistribution (NONLIPO) and 32 HIV-negative healthy control subjects (C) (21 males and 11 females) of similar age and body mass index (BMI). Glucose, insulin, and free fatty acid (FFA) levels were measured in response to a 75-g oral glucose tolerance test (OGTT) in the LIPO, NONLIPO, and C subjects. In addition, fasting lipids were obtained, and body composition was determined by anthropometric measurements and dual-energy x-ray absorptiometry (DXA). Fasting FFA concentrations were significantly increased in the LIPO group as compared with NONLIPO and C subjects (0.74 +/- 0.03 v 0.60 +/- 0.04 [mean +/- SEM] mmol/L, P =.002, LIPO v NONLIPO; 0.74 +/- 0.03 v 0.59 +/- 0.03 mmol/L, P =.001, LIPO v C). In contrast, fasting FFA concentrations were not increased in the NONLIPO group (0.60 +/- 0.04 v 0.59 +/- 0.03, P =.909, NONLIPO v C). Similarly, fasting triglycerides and 120-minute OGTT FFA were significantly increased in the LIPO group as compared with the NONLIPO and C group. FFA decreased in HIV-infected LIPO, NONLIPO, and C subjects in response to OGTT, but the 120-minute FFA concentrations remained significantly elevated in LIPO patients compared with NONLIPO and C subjects. In a multivariate regression model of LIPO patients, fasting FFA (P =.027) was a strong independent predictor of insulin area under the curve (AUC), controlling for age, BMI, gender, and body composition (r(2) for model =.31). No differences were observed in FFA concentrations in the LIPO group in an analysis based on current protease inhibitor (PI) use. These data suggest that FFA concentrations are increased in HIV-infected patients with fat redistribution. Increased fasting concentrations of fatty acids are associated with abnormal insulin responses to standard glucose challenge in HIV-infected patients with fat redistribution. Further studies are necessary to determine the mechanism of increased fatty acid concentrations and the role played by increased FFA in mediating insulin resistance in this population.

Absorptiometry, Photon↗

PubMed2002

Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy.

Human immunodeficiency virus (HIV) lipodystrophy is associated with fat redistribution, dyslipidemia, and insulin resistance; however, the mechanism of insulin resistance remains unknown. We hypothesized that HIV-infected subjects with fat redistribution have increased rates of lipolysis and increased circulating free fatty acid (FFA) levels that contribute to insulin resistance. Anthrompometric and body composition data were obtained and a standard 75-g oral glucose tolerance test (OGTT) was performed on day 1 of the study. Stable isotope infusions of glycerol and palmitate were completed following an overnight fast to assess rates of lipolysis and FFA flux in HIV-infected men (n = 19) with and without fat redistribution and healthy controls (n = 8) on day 2. Total FFA levels after standard glucose challenge were increased among HIV-infected subjects and positively associated with abdominal visceral adipose tissue area. In contrast, fasting total FFA levels were inversely associated with subcutaneous fat area. Rates of basal lipolysis were significantly increased among HIV-infected subjects (rate of appearance [Ra] glycerol, 4.1 +/- 0.2 v 3.3 +/- 0.2 micromol/kg/min in controls; P =.02). Among HIV-infected subjects, use of stavudine (P =.006) and the rate of lipolysis (ie, Ra glycerol, P =.02) were strong positive predictors of insulin resistance as measured by insulin response to glucose challenge, controlling for effects of age, body mass index (BMI), waist-to-hip ratio (WHR), and protease inhibitor (PI) exposure. These data demonstrate increased rates of lipolysis and increased total FFA levels in HIV-infected subjects and suggest that increased lipolysis may contribute to insulin resistance in this patient population.

Adipose Tissue↗

PubMed2002

Body-composition measurements as predictors of glucose and insulin abnormalities in HIV-positive men.

BACKGROUND: Fat redistribution and metabolic abnormalities are seen increasingly in HIV-positive patients. However, the degree to which abnormalities in fat distribution predict glucose and insulin concentrations in these patients remains unknown. OBJECTIVE: We determined how well measurements of fat distribution derived from anthropometry, dual-energy X-ray absorptiometry, and computed tomography predicted hyperinsulinemia in HIV-positive men. DESIGN: Body-composition data were analyzed in 41 HIV-positive men (21 with fat redistribution and 20 without) and 20 HIV-negative control subjects matched for age and body mass index (BMI). Multivariate modeling was performed to determine the effects of body composition on fasting insulin and insulin area under the curve (AUC) during standard glucose tolerance testing. RESULTS: WHR was superior to other body-composition measures in predicting fasting hyperinsulinemia and was a strong predictor of insulin AUC in HIV-positive men. Fasting insulin increased by 77.4 pmol/L for each 0.1-unit change in WHR (95% CI: 18.6, 136.1; P = 0.011), overall r(2) = 0.415 in a model also including age, BMI, and protease inhibitor use. Measures of intraabdominal and subcutaneous fat did not predict fasting hyperinsulinemia but were independent predictors of insulin AUC in multivariate modeling. The ratio of visceral to subcutaneous abdominal fat predicted the largest degree of variance in insulin AUC. CONCLUSIONS: Fat redistribution contributes to hyperinsulinemia in HIV-positive men, independent of BMI and protease inhibitor use. WHR is an integrated index of body-composition changes and strongly predicts both fasting hyperinsulinemia and insulin AUC in HIV-positive men.

Adipose Tissue↗

PubMed2002

Role of cytokines and testosterone in regulating lean body mass and resting energy expenditure in HIV-infected men.

Although catastrophic weight loss is no longer common in HIV-infected men, we hypothesized that a more gradual process of cachexia [loss of lean body mass (LBM) without severe weight loss, often accompanied by elevated resting energy expenditure (REE)] is still common and is driven by excessive production of the catabolic cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). We performed a longitudinal analysis of an ongoing cohort study of nutritional status in 172 men with HIV infection. LBM loss of >1 kg occurred in 35% of the cohort, and LBM loss of >5% occurred in 12.2% over 8 mo of observation, but classical wasting (loss of approximately 10% of weight) was rare (2%). Both TNF-alpha (-150 g LBM. ng(-1) x ml(-1), P < 0.02) and IL-1 beta production (-130 g LBM x ng(-1) x ml(-1), P < 0.01) by peripheral blood mononuclear cells predicted loss of LBM. A rise in REE of >200 kcal/day was found in 17.7% of the subjects regardless of weight change. IL-1 beta (+9 kcal/day per ng/ml, P < 0.002) and TNF-alpha (+10 kcal/day per ng/ml, P < 0.02) production predicted Delta REE. Serum free testosterone was inversely associated with TNF-alpha production and was not an independent predictor of either Delta LBM or Delta REE after adjustment for cytokine production. Even though weight loss was rare in this cohort of patients treated with highly active antiretroviral therapy, loss of LBM was common and was driven by catabolic cytokines and not by inadequate dietary intake or hypogonadism.

Adult↗

PubMed2002

Abnormal bone mineral accrual in adolescent girls with anorexia nervosa.

Anorexia nervosa (AN) is increasingly common in adolescent girls and occurs at a time of peak bone mass formation. Osteopenia is common in adolescent girls with AN, and in a cross-sectional study, we have reported low bone formation markers in such girls. To determine the impact of chronic undernutrition on bone mineral accrual in contrast to healthy controls, we prospectively measured bone mineral density (BMD) and body composition by dual energy x-ray absorptiometry, bone metabolism markers, and nutritional and hormonal status at baseline, 6 months, and 12 months in 19 adolescent girls with AN (mean +/- SEM, 15.4 +/- 0.4 yr) and 19 controls of comparable chronological and skeletal age. Overall, nutritional status in subjects with AN improved (mean percentage increase in body mass index from baseline, 9.2 +/- 1.9% and 15.2 +/- 2.6% at 6 and 12 months, respectively), with 11 subjects having recovered weight at 12 months. However, lumbar BMD at 12 months (AN, 0.88 +/- 0.02 g/cm(2), vs. control, 0.98 +/- 0.03 g/cm(2); P = 0.008) remained significantly reduced in AN compared with controls, even in recovered subjects. This was due to significant increases in lumbar BMD in controls vs. no change in AN subjects over the year (0.003 +/- 0.001 g/cm(2).month vs. 0.000 +/- 0.001 g/cm(2).month, respectively; P = 0.04). The most significant determinant of change in lumbar BMD at 12 months was change in lean body mass in both AN (r = 0.62; P = 0.008) and control (r = 0.80; P = 0.0006) groups. There were significant increases in surrogate markers of bone turnover in subjects with AN compared with controls as assessed by osteocalcin (AN, 0.9 +/- 0.4 micro g/liter.month, vs. control, -1.1 +/- 0.4 micro g/liter.month; P = 0.0007), bone-specific alkaline phosphatase (AN, 0.6 +/- 0.5 U/liter.month, vs. control, -1.5 +/- 0.4 U/liter.month; P = 0.002), deoxypyridinoline [AN, 0.1 +/- 0.1 nmol/mmol creatinine (cr).month, vs. control, -0.4 +/- 0.1 nmol/mmol cr.month; P = 0.005], and N-telopeptide (AN, 4 +/- 4 nmol BCE/mmol cr/month, vs. control, -9 +/- 4 nmol BCE/mmol cr/month; P = 0.01). Changes in IGF-I levels over the year were highly correlated with changes in bone turnover over the same period in AN (osteocalcin, r = 0.77; P = 0.001; deoxypyridinoline, r = 0.66; P = 0.01). A rise in N-telopeptide over the year was correlated with an increase in all bone mineral measures, including lumbar bone mineral content (r = 0.58; P = 0.03) and BMD (r = 0.53; P = 0.05) and total bone mineral content (r = 0.69; P = 0.006) and BMD (r = 0.69; P = 0.006) in the AN group. Therefore, despite recovery over 1 yr, poor bone mineral accrual persists in adolescent girls with AN in contrast to rapid bone accrual in healthy girls. Normalization of bone turnover markers occurs in association with nutritional recovery and an increase in the nutritionally dependent bone trophic factor IGF-I. A rise in bone turnover markers may be an early indicator of increase in BMD in recovering girls with AN.

Adipose Tissue↗

PubMed2002

Sustained benefits of metformin therapy on markers of cardiovascular risk in human immunodeficiency virus-infected patients with fat redistribution and insulin resistance.

The purpose of this study was to evaluate the metabolic and cardiovascular benefits of continued metformin therapy for HIV-infected patients with lipodystrophy. Eligible subjects who participated in the 3-month randomized study received an additional 6-month open label metformin treatment extension. Nineteen of the 25 potential subjects were eligible to receive open label metformin based on preestablished safety and efficacy criteria. Insulin and glucose response to oral glucose challenge, cardiovascular disease risk markers (e.g. tissue plasminogen activator), weight, and anthropometric measurements were the primary outcome measures. Continued treatment with metformin resulted in further significant reductions in tissue plasminogen activator antigen levels (P = 0.02) and body mass index (P = 0.03). Reductions in insulin levels were sustained during the 6-month treatment extension. In addition, waist circumference decreased significantly in subjects continuing metformin treatment (P = 0.01). Metformin was well tolerated and no one discontinued treatment due to side effects. These data demonstrate a sustained benefit of metformin treatment to reduce hyperinsulinemia and certain markers of cardiovascular disease risk in patients with HIV infection and lipodystrophy.

Adipose Tissue↗

PubMed2002

Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa.

Over 90% of women with anorexia nervosa demonstrate osteopenia, and almost 40% demonstrate osteoporosis at one or more skeletal sites. In addition to estrogen deficiency causing an increase in bone resorption, nutritional effects on the GH-IGI-I axis may contribute to the severe bone loss in this population by decreasing bone formation. We tested the hypothesis that recombinant human IGF-I (rhIGF-I) would increase bone density in women with anorexia nervosa and furthermore assessed the effects of combined rhIGF-I and oral contraceptive administration (OCP) in this population. Sixty osteopenic women with Diagnosis and Statistical Manual of Mental Disorders IV Revised confirmed anorexia nervosa [age (25.2 +/- 0.7 yr, range 18-38 yr), body mass index (17.8 +/- 0.3 kg/m(2) ), spinal bone mineral density T score (-2.1 +/- 0.1 SD) were randomized to one of four treatment groups [rhIGF-I (30 microg/kg sc twice daily) and a daily oral contraceptive (Ovcon 35, 35 microg ethinyl estradiol and 0.4 mg norethindrone], rhIGF-I alone (30 microg/kg sc twice daily), oral contraceptive alone, or neither treatment for 9 months. All subjects received calcium 1500 mg/d and a standard multivitamin containing 400 IU of vitamin D. Administration of rhIGF-I was placebo controlled and blinded to subjects. The rhIGF-I was titrated to maintain IGF-I levels within the age-adjusted normal range for each patient and was well tolerated. The effects of rhIGF-I and OCP were analyzed simultaneously among all subjects in a factorial analysis and in an analysis of the four individual treatment groups. Anteroposterior spinal bone density increased significantly in response to rhIGF-I (1.1% +/- 0.5% vs. -0.6% +/- 0.8%, P = 0.05, all rhIGF-I vs. all placebo treated, respectively, by analysis of covariance). In contrast, OCP did not result in increased bone density (0.8% +/- 0.6% vs. -0.4% +/- 0.8%, P = 0.21, all OCP vs. all non-OCP treated, respectively, by analysis of covariance). However, bone density increased to the greatest extent in the combined treatment group (rhIGF-I and OCP), compared with control patients receiving no active therapy (1.8% +/- 0.8% vs. 0.3% +/- 0.6% vs. -0.2% +/- 0.8% vs. -1.0% +/- 1.3%, rhIGF-I and OCP vs. rhIGF-I alone vs. OCP alone vs. no active therapy, P < 0.05 for rhIGF-I and OCP vs. no active therapy). These data demonstrate that osteopenic women with anorexia nervosa treated with rhIGF-I showed more beneficial changes in bone density, compared with patients not treated with rhIGF-I. Antiresorptive therapy with OCP is not sufficient to improve bone density in undernourished patients, but such therapy may augment the effects of rhIGF-I in a combined treatment strategy. Further long-term studies are needed to investigate the effects of rhIGF-I and combined anabolic/antiresorptive strategies on bone in women with anorexia nervosa.

Adult↗