Relationship of peak growth hormone to cardiovascular parameters, waist circumference, lipids and glucose in HIV-infected patients and healthy adults.

OBJECTIVE: Relative growth hormone (GH) deficiency is highly prevalent in patients with HIV. The purpose of this study was to investigate relationships of GH to metabolic and anthropometric parameters in HIV patients and non-HIV controls. DESIGN: Peak GH and metabolic parameters were assessed in a cross-sectional study of 191 HIV patients and 62 age and BMI-matched healthy controls. METHODS: Peak GH was assessed by GHRH/arginine stimulation testing. RESULTS: HIV patients demonstrated similar BMI, but increased waist circumference (WC) and reduced peak GH to GHRH/arginine compared with control subjects [median = 12.4 (interquartile range: 6.3-24.8) vs. 21.3 (8.8, 34.5) µg/l, P = 0.006, HIV vs. control]. Among HIV and non-HIV groups, peak GH was inversely associated with WC (rho = -0.44, P < 0.0001; rho = -0.63, P < 0.0001; HIV patients and controls, respectively), blood pressure (rho = -0.17, P = 0.02; rho = -0.36, P = 0.004), triglycerides (rho = -0.37, P < 0.0001; rho = -0.43, P = 0.001), glucose (rho = -0.34, P < 0.0001; rho = -0.30, P = 0.02), insulin (rho = -0.43, P < 0.0001; rho = -0.60, P < 0.0001) and CRP (rho= -0.29, P < 0.0001; rho = -0.59, P < 0.0001). Among HIV patients, the inverse association between peak GH and fasting glucose remained significant (ß = -0.006 mmol/l change in glucose per µg/l change in GH, P = 0.004) controlling for age, gender, race, BMI, WC, protease inhibitor (PI) and nucleoside reverse transcriptase inhibitors. Similarly, the inverse association between peak GH and triglycerides remained significant (ß = -0.01 mmol/l change in triglycerides per µg/l change in GH, P = 0.02) controlling for age, gender, race, BMI, WC, PI and lipid-lowering medications. HIV men with peak GH < 7.5 µg/l demonstrated higher BMI, WC, SBP, triglycerides, glucose and CRP. CONCLUSIONS: Reduced GH secretion is independently associated with dyslipidaemia and higher glucose, among HIV patients with abdominal fat accumulation.

Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation: a randomized controlled trial.

CONTEXT: Antiretroviral therapy can be associated with visceral adiposity and metabolic complications, increasing cardiovascular risk, and reduced growth hormone (GH) secretion may be a contributing factor. OBJECTIVE: To investigate the effects of low-dose physiological GH administration on body composition, glucose, and cardiovascular parameters in patients with human immunodeficiency virus (HIV) having abdominal fat accumulation and relative GH deficiency. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled trial of 56 patients with HIV, abdominal fat accumulation, and reduced GH secretion (peak GH <7.5 ng/mL) conducted at a US academic medical center between November 2003 and October 2007. INTERVENTION: Patients were randomly assigned to receive either subcutaneous GH or matching placebo titrated to the upper quartile of normal insulinlike growth factor 1 (IGF-1) range for 18 months. Starting dose was 2 microg/kg/d and increased to maximum dose of 6 microg/kg/d (average dose, 0.33 mg/d). MAIN OUTCOME MEASURES: Change in body composition assessed by computed tomographic scan and dual-energy x-ray absorptiometry. Secondary outcomes included glucose, IGF-1, blood pressure (BP), and lipids. Treatment effect was the difference in the change between GH and placebo groups, using all available data. RESULTS: Fifty-five patients (26 with GH and 29 with placebo) were included in the safety analyses and 52 patients (25 with GH and 27 with placebo) were included in the efficacy analyses. Visceral adipose tissue area (treatment effect [last-value-carried-forward analysis {n = 56}, -19 cm(2); 95% confidence interval {CI}, -37 to -0.3 cm(2)], -19 cm(2); 95% CI, -38 to -0.5 cm(2); P = .049); trunk fat (-0.8 kg; 95% CI, -1.5 to -0.04 kg; P = .04); diastolic BP (-7 mm Hg; 95% CI, -11 to -2 mm Hg; P = .006); and triglycerides (-7 mg/dL, P = .002) improved but 2-hour glucose levels on glucose tolerance testing increased in the GH group vs the placebo group (treatment effect, 22 mg/dL; 95% CI, 6-37 mg/dL; P = .009). The IGF-1 levels increased (treatment effect, 129 ng/mL; 95% CI, 95-164 ng/mL; P < .001). Adverse events were not increased for GH vs placebo (23%; 95% CI, 9%-44% vs 28%; 95% CI, 13%-47%; P = .70). CONCLUSIONS: In HIV-associated abdominal fat accumulation and relative GH deficiency, low-dose GH received for 18 months resulted in significantly reduced visceral fat and truncal obesity, triglycerides, and diastolic BP, but 2-hour glucose levels on glucose tolerance testing were increased. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00100698.

Effects of TNF-alpha neutralization on adipocytokines and skeletal muscle adiposity in the metabolic syndrome.

In a prior study, we have shown that tumor necrosis factor (TNF)-alpha neutralization improves inflammatory markers and total adiponectin in patients with the metabolic syndrome, without improving insulin sensitivity. In this study, we sought to extend our understanding of the effects of TNF-alpha neutralization in this human model of obesity by investigating the responses of high-molecular-weight (HMW) adiponectin, resistin, leptin, and muscle adiposity to etanercept in patients with the metabolic syndrome. Fifty-six men and women with the metabolic syndrome enrolled in a double-blind randomized placebo-controlled trial. Circulating concentrations of total and HMW adiponectin, resistin, and leptin were determined at baseline and after 4 wk of treatment with etanercept. Muscle adiposity was measured by computed tomography (CT). Although etanercept increased total adiponectin concentration, the HMW form, which is thought to mediate insulin sensitivity, was unchanged. Thus the ratio of HMW to total adiponectin decreased following etanercept treatment compared with placebo (-0.03 +/- 0.03 vs. 0.06 +/- 0.03, P = 0.02). Resistin tended to decrease in the etanercept-treated group compared with placebo (-0.6 +/- 0.7 vs. 1.2 +/- 0.7 ng/ml, P = 0.06), whereas leptin was not altered. Etanercept decreased muscle attenuation on CT [-0.61 +/- 0.64 Hounsfield units (HU) vs. 1.54 +/- 0.77 HU in placebo, P = 0.04], suggesting an increase in muscle adiposity. Together, these results demonstrate that neutralization of TNF-alpha in obese humans results in differential effects on critical adipokines and body composition indexes. These findings may help to explain the lack of effect on insulin sensitivity and extend our knowledge of the biological effects of TNF-alpha neutralization in obesity.

Effects of etanercept in patients with the metabolic syndrome.

BACKGROUND: Adipose-derived cytokines, including tumor necrosis factor alpha, may contribute to the inflammation that occurs in the metabolic syndrome. We investigated the effects of inhibition of tumor necrosis factor alpha with etanercept in patients with the metabolic syndrome. METHODS: Fifty-six subjects with the metabolic syndrome were randomized to administration of either etanercept or identical placebo, 50 mg subcutaneously once a week for 4 weeks. The C-reactive protein level was the primary end point. Effects on other inflammatory markers (including fibrinogen, interleukin 6, and adiponectin), insulin sensitivity, lipid levels, and body composition were also determined. RESULTS: Baseline characteristics were similar between the groups. Two subjects dropped out of each group, and etanercept was well tolerated throughout the study. The C-reactive protein levels decreased significantly in the treated compared with the placebo group (-2.4 +/- 0.4 vs 0.5 +/- 0.7 mg/L; P<.001). Adiponectin levels rose significantly in the etanercept group compared with the placebo group (0.8 +/- 0.4 vs -0.3 +/- 0.3 microg/mL; P = .03). Fibrinogen levels decreased (-68 +/- 16 vs -2 +/- 31 mg/dL [-2.0 +/- 0.47 vs -0.06 +/- 0.91 micromol/L]; P = .04) and interleukin 6 levels tended to decrease (-1.2 +/- 0.8 vs 0.5 +/- 0.5 ng/L; P = .07) in the etanercept-treated subjects compared with placebo, respectively. No changes occurred in body composition parameters or insulin sensitivity, but high-density lipoprotein levels tended to decrease in the etanercept group (-1 +/- 1 vs 2 +/- 1 mg/dL [-0.03 +/- 0.03 vs 0.05 +/- 0.03 mmol/L]; P = .06) compared with the placebo group. CONCLUSIONS: Etanercept reduces C-reactive protein levels and tends to improve other inflammatory cardiovascular risk indexes in patients with the metabolic syndrome. Etanercept may interrupt the inflammatory cascade that occurs with abdominal obesity. Further, longer-term studies are needed to determine the effects of tumor necrosis factor alpha inhibition on cardiovascular disease in patients with the metabolic syndrome.

Effects of physiological leptin administration on markers of inflammation, platelet activation, and platelet aggregation during caloric deprivation.

CONTEXT: Leptin is a nutritionally regulated adipocyte-derived cytokine. Previous studies in obese patients have demonstrated increased inflammatory markers and increased platelet aggregation in association with leptin. However, the effects of leptin administration on markers of inflammation and platelet aggregation in a human model of undernutrition have not previously been studied. OBJECTIVE: The objective of the study was to investigate markers of inflammation, platelet activation, and platelet aggregation in a model of caloric deprivation and increased leptin sensitivity. DESIGN: This study was a randomized, placebo-controlled study conducted between November 2002 and November 2003. SETTING: The study was conducted at an inpatient care setting at the General Clinical Research Center. PARTICIPANTS: Twenty healthy, young (18-35 yr old), normal-weight (body mass index, 20-26 kg/m2) women were recruited from local advertisements. No subjects withdrew due to adverse effects. INTERVENTION: The effects of physiological recombinant methionyl human leptin or identical placebo administration were investigated over a 4-d fast. MAIN OUTCOME MEASURES: The primary outcome measures for this study were C-reactive protein (CRP) and indices of platelet activity. RESULTS: Leptin administration prevented the fasting-induced decline in leptin (P < 0.05 vs. placebo at each time point). Leptin administration increased CRP (6.3 +/- 2.4 vs. 0.7 +/- 0.3 mg/liter; P = 0.04), circulating P-selectin (11.6 +/- 10.2 vs. -28.9 +/- 15.6 ng/ml; P = 0.04), and induction of platelet aggregation (5.8 +/- 2.6 vs. -2.7 +/- 2.9%, P = 0.04, percent maximum platelet aggregation) relative to placebo administration (change in leptin vs. change in placebo, respectively, for each variable). Leptin tended to increase serum amyloid A [0.1 +/- 0.2 vs. -0.3 +/- 0.1 log10 (ng/ml); P = 0.07], and the changes in serum amyloid A and CRP were highly correlated (r = 0.83; P < 0.0001). No changes in TNFalpha, IL-6, IL-10, plasminogen activator inhibitor-1, haptoglobin, intercellular adhesion molecule, or vascular cell adhesion molecule were seen between the groups. CONCLUSIONS: Our data provide evidence that physiological leptin administration stimulates inflammatory and platelet responses in humans during caloric deprivation.

Growth hormone (GH) responses to GH-releasing hormone-arginine testing in human immunodeficiency virus lipodystrophy.

Prior studies suggest reduced overnight GH secretion in association with excess visceral adiposity among patients with HIV lipodystrophy (LIPO, i.e. with fat redistribution). We now investigate GH responses to standardized GHRH-arginine in LIPO patients (n = 39) in comparison with body mass index- and age-matched control groups [HIV patients without fat distribution (NONLIPO, n = 17)] and healthy subjects (C, n = 16). IGF-I [242 +/- 17; 345 +/- 38; 291 +/- 27 ng/ml (P < 0.05 vs. NONLIPO)] was lowest in the LIPO group. Our data demonstrate failure rates of 18% for the LIPO group vs. 5.9% for the NONLIPO group and 0% for the C group, using a stringent criterion of 3.3 ng/ml for peak GH response to GHRH-arginine (P < 0.05 LIPO vs. C). Using less stringent cutoffs, the failure rate in the LIPO group rises to 38.5% at 7.5 ng/ml. Among the LIPO patients, the peak GH response to GHRH-arginine was significantly predicted by visceral adipose tissue (P = 0.008), free fatty acid (P = 0.04), and insulin level (P = 0.007) in regression modeling controlling for age, body mass index, sc fat area, and triglyceride level. These data demonstrate increased failure rates to standardized stimulation testing with GHRH-arginine in LIPO patients, in association with increased visceral adiposity. The effects of low-dose GH should be assessed in the large subset of LIPO patients with abnormal GH stimulation testing.

Effects of growth hormone-releasing hormone on bone turnover in human immunodeficiency virus-infected men with fat accumulation.

GHRH is a potentially appealing strategy to simultaneously improve fat distribution and increase bone turnover in HIV-infected patients. We investigated the effects of GHRH (1 mg sc twice a day over 12 wk) in 31 HIV-infected men with abdominal fat accumulation (age 46 +/- 1 yr, body mass index 26.2 +/- 0.6 kg/m2) in a randomized, double-blind, placebo-controlled study. We previously reported significant effects of GHRH on IGF-I and truncal fat. In this study, we assessed whether GHRH increased markers of bone turnover. At baseline, 32% of our subjects (n = 10) demonstrated a bone density Z score less than -1.0 sd and greater than or equal to -2.5 sd, and 3% (n = 1) demonstrated a Z score of less than -2.5 sd. IGF-I correlated with N-terminal telopeptide (NTx) (r = 0.49, P = 0.005) and tended to correlate with C-terminal telopeptide (CTx) (r = 0.35, P = 0.06) at baseline. Of the bone resorption markers, CTx increased significantly (0.16 +/- 0.07 vs. -0.03 +/- 0.03 ng/ml, GHRH vs. placebo, P = 0.02), and NTx tended to increase in response to GHRH (2.8 +/- 1.4 vs. -0.5 +/- 1.0 nm bone collagen equivalent, GHRH vs. placebo, P = 0.07). Of the bone formation markers, N-terminal propeptide of type 1 procollagen increased (14.6 +/- 9 vs. -6.8 +/- 3.1 microg/liter, GHRH vs. placebo, P = 0.03) and osteocalcin tended to increase (8.4 +/- 3.0 vs. 2.0 +/- 1.6 ng/ml, GHRH vs. placebo, P = 0.06) in response to GHRH. The calciotropic hormones, calcium and phosphorus, did not change significantly. The change in IGF-I correlated with the change in NTx (r = 0.45, P = 0.02), CTx (r = 0.38, P = 0.05), and osteocalcin (r = 0.55, P = 0.002). GHRH improves fat distribution and bone metabolism in men with HIV-related fat accumulation. Long-term studies are needed to determine whether the stimulatory effects of GHRH on bone turnover will translate into increased bone density in this population.

Endocrine and metabolic effects of physiologic r-metHuLeptin administration during acute caloric deprivation in normal-weight women.

Leptin is a nutritionally regulated hormone that may modulate neuroendocrine function during caloric deficit. We hypothesized that administration of low-dose leptin would prevent changes in neuroendocrine function resulting from short-term caloric restriction. We administered physiologic doses of r-metHuLeptin [(0.05 mg/kg sc daily or identical placebo in divided doses (0800, 1400, 2000, and 0200 h)] to 17 healthy, normal-weight, reproductive-aged women during a 4-d fast. Leptin levels were lower in the placebo-treated group during fasting (3.3 +/- 0.2 vs. 9.6 +/- 1.0 ng/ml, P < 0.001, placebo vs. leptin-treated at end of study). Fat mass decreased more in the leptin than the placebo-treated group (-0.6 +/- 0.1 vs. -0.2 +/- 0.1 kg, P = 0.03). Both overnight LH area (38.9 +/- 21.5 vs. 1.2 +/- 11.1 microIU/ml.min, P = 0.05) and LH peak width increased (15.8 +/- 7.1 vs. -2.3 +/- 6.7 min, P = 0.06) and LH pulsatility decreased (-2.0 +/- 0.9 vs. 1.0 +/- 0.8 peaks/12 h, P = 0.03) more in the leptin vs. placebo group. LH pulse regularity was higher in the leptin-treated group (P = 0.02). Twenty-four-hour mean TSH decreased more in the placebo than the leptin-treated group, respectively (-1.06 +/- 0.27 vs. -0.32 +/- 0.18 microIU/ml, P = 0.03). No differences in 24-h mean GH, cortisol, IGF binding protein-1, and IGF-I were observed between the groups. Hunger was inversely related to leptin levels in the subjects randomized to leptin (r = -0.76, P = 0.03) but not placebo (r = -0.18, P = 0.70) at the end of the study. Diminished hunger was seen among subjects achieving the highest leptin levels. Our data provide new evidence of the important role of physiologic leptin regulation in the neuroendocrine response to acute caloric deprivation.

Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial.

CONTEXT: Reduced growth hormone (GH) concentrations are observed in men with human immunodeficiency virus (HIV) lipodystrophy. OBJECTIVE: To investigate the effects of growth hormone-releasing hormone (GHRH), a GH secretagogue, in treatment of HIV lipodystrophy. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial conducted at a research center in the United States between October 2002 and June 2003 and enrolling 31 HIV-infected men aged 18 to 60 years with evidence of lipodystrophy. INTERVENTIONS: Participants were assigned to receive GHRH (1 mg subcutaneously twice daily) or placebo for 12 weeks. MAIN OUTCOME MEASURES: The primary outcome was change in concentrations of insulin-like growth factor 1 (IGF-1) to detect overall change in GH levels in response to GHRH. Secondary end points included body composition by dual-energy x-ray absorptiometry and computed tomography, lipodystrophy ratings, and levels of glucose, insulin, and lipids. RESULTS: Mean (SD) IGF-1 concentrations increased significantly in the GHRH group vs the placebo group (104 [110] ng/mL vs 6 [44] ng/mL, P =.004). Lean body mass significantly increased in the GHRH group vs the placebo group (0.9 [1.3] kg vs -0.3 [1.7] kg, P =.04), trunk fat significantly decreased (-0.4 [0.7] kg vs 0.2 [0.6] kg, P =.03), and the ratio of trunk to lower extremity fat improved significantly (-0.22 [0.32] vs 0.14 [0.29], P =.005). Abdominal visceral fat was reduced (-19.2 [36.6] cm2 vs 2.3 [24.3] cm2, P =.07) and the ratio of abdominal visceral fat to abdominal subcutaneous fat improved significantly more in the GHRH group (-0.19 [0.28] vs 0.07 [0.27], P =.02). Both physician and patient rating of lipodystrophy in the arms, legs, and abdomen also improved significantly. Levels of glucose, insulin, and lipids did not change significantly. CONCLUSIONS: GHRH was well tolerated and effectively increased levels of IGF-1 in HIV-infected men with lipodystrophy. Total and regional body composition improved in response to GHRH, with increased lean mass and reduced truncal and visceral fat. Use of GHRH may potentially be a beneficial treatment strategy for this population.

Nocturnal ghrelin pulsatility and response to growth hormone secretagogues in healthy men.

The physiological importance of endogenous ghrelin in the regulation of growth hormone (GH) secretion is still unknown. To investigate the regulation of ghrelin secretion and pulsatility, we performed overnight ghrelin and GH sampling every 20 min for 12 h in eight healthy male subjects [age 37 +/- 5 (SD) years old, body mass index 27.2 +/- 2.9 kg/m2]. Simultaneous GH and ghrelin levels were assessed to determine the relatedness and synchronicity between these two hormones in the fasted state during the overnight period of maximal endogenous GH secretion. Pulsatility analyses were performed to determine simultaneous hormonal dynamics and investigate the relationship between GH and ghrelin by use of cross-approximate entropy (X-ApEn) analyses. Subjects demonstrated 3.0 +/- 2.1 ghrelin pulses/12 h and 3.3 +/- 0.9 GH pulses/12 h. The mean normalized ghrelin entropy (ApEn) was 0.93 +/- 0.09, indicating regularity in ghrelin hormone secretion. The mean normalized X-ApEn was significant between ghrelin and GH (0.89 +/- 0.12), demonstrating regularity in cosecretion. In addition, we investigated the ghrelin response to standard GH secretagogues [GH-releasing hormone (GHRH) alone and combined GHRH-arginine] in separate testing sequences separated by 1 wk. Our data demonstrate that, in contrast to GHRH alone, which had little effect on ghrelin, combined GHRH and arginine significantly stimulated ghrelin with a maximal peak at 120 min, representing a change of 66 +/- 14 pg/ml (P = 0.001 by repeated-measures ANOVA and P = 0.02 for GHRH vs. combined GHRH-arginine by MANOVA). We demonstrate relatedness between ghrelin and GH pulsatility, suggesting either that ghrelin participates in the pulsatile regulation of GH or that the two hormones are simultaneously coregulated, e.g., by somatostatin or other stimuli. Furthermore, the differential effects of GHRH alone vs. GHRH-arginine suggest that inhibition of somatostatin tone may increase ghrelin. These data provide further evidence of the physiological regulation of ghrelin in relationship to GH.

Relation of leptin pulse dynamics to fat distribution in HIV-infected patients.

BACKGROUND: HIV-infected patients are affected by changes in fat distribution, ie, significant losses of subcutaneous fat in association with metabolic abnormalities. OBJECTIVE: The objective was to investigate the relation between leptin secretion and subcutaneous fat loss in HIV-infected patients. DESIGN: We investigated leptin pulse dynamics, measured every 20 min overnight from 2000 to 0800 in 41 HIV-infected patients with a mean (+/-SEM) age of 42.7 +/- 1.1 y and body mass index (in kg/m(2)) of 24.7 +/- 0.4 and in 20 healthy control subjects (age: 42.8 +/- 1.8 y; body mass index: 24.6 +/- 0.5). Leptin pulse variables were compared with total body fat, abdominal subcutaneous fat, and abdominal visceral fat in univariate and multivariate regression analyses. RESULTS: The number of leptin pulses was not significantly different between the HIV-infected and control subjects. Subcutaneous fat correlated significantly with mean leptin secretion (r = 0.72, P <0.0001), leptin pulse amplitude (r = 0.62, P <0.0001), and leptin nadir (r = 0.62, P <0.0001) in the HIV-infected patients. In stepwise regression modeling, subcutaneous fat (P <0.0001), but not visceral fat, was significantly associated with leptin secretion (overall R(2) for the model = 0.57, P <0.0001) in the HIV-infected patients. For each 1-cm(2) decrease in abdominal subcutaneous fat area, leptin decreased by 0.044 ng/mL when visceral fat was controlled for. Subcutaneous fat was also significantly related to leptin in the control subjects. CONCLUSIONS: This is the first study to investigate the relation between fat distribution and leptin pulse dynamics in HIV-infected patients. There was a significant reduction in leptin secretion with subcutaneous fat loss in this population.

Acute regulation of adiponectin by free fatty acids.

Little is known about the acute regulation of adiponectin in humans. In animal studies, adiponectin increases the clearance of free fatty acids (FFA) from the circulation by increasing skeletal uptake and oxidation of lipid, thereby regulating the FFA concentration. However, it is unknown if FFA regulate adiponectin. The aim of the present study was to investigate the effect of an acute reduction in free fatty acids on adiponectin concentration in healthy subjects. Ten normal male subjects were admitted for 2 inpatient visits and randomized to receive either acipimox (500 mg orally at 2 am and again at 6 am) or placebo on the first visit and vice versa on the second visit. Adiponectin, FFA, insulin and glucose were measured at 7:45 am. FFA concentrations were significantly lower after acipimox than placebo administration (0.08 +/- 0.02 mEq/L v 0.35 +/- 0.53 mEq/L, P <.05). Adiponectin concentrations were also significantly lower after acipimox than placebo administration (7.4 +/- 1.2 microg/mL v 10.3 +/- 1.7 microg/mL, P <.05). The change in FFA between acipimox and placebo correlated significantly with the change in adiponectin (r = 0.66, P <.05), eg, the larger the reduction in FFA in response to acipimox, the larger the reduction in adiponectin. These results suggest that acute lowering of FFA is associated with decreased adiponectin concentrations.

Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy.

Human immunodeficiency virus (HIV)-lipodystrophy is a syndrome characterized by changes in fat distribution and insulin resistance. Prior studies suggest markedly reduced growth hormone (GH) levels in association with excess visceral adiposity among patients with HIV-lipodystrophy. We investigated mechanisms of altered GH secretion in a population of 13 male HIV-infected patients with evidence of fat redistribution, compared with 10 HIV-nonlipodystrophic patients and 11 male healthy controls similar in age and body mass index (BMI). Although similar in BMI, the lipodystrophic group was characterized by increased visceral adiposity, free fatty acids (FFA), and insulin and reduced extremity fat. We investigated ghrelin and the effects of acute lowering of FFA by acipimox on GH responses to growth hormone-releasing hormone (GHRH). We also investigated somatostatin tone, comparing GH response to combined GHRH and arginine vs. GHRH alone with a subtraction algorithm. Our data demonstrate an equivalent number of GH pulses (4.1 +/- 0.6, 4.7 +/- 0.8, and 4.5 +/- 0.3 pulses/12 h in the HIV-lipodystrophic, HIV-nonlipodystrophic, and healthy control groups, respectively, P > 0.05) but markedly reduced GH secretion pulse area (1.14 +/- 0.27 vs. 4.67 +/- 1.24 ng.ml(-1).min, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 1.14 +/- 0.27 vs. 3.18 +/- 0.92 ng.ml(-1).min, P < 0.05 HIV-lipodystrophic vs. control), GH pulse area, and GH pulse width in the HIV-lipodystrophy patients compared with the control groups. Reduced ghrelin (418 +/- 46 vs. 514 +/- 37 pg/ml, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 418 +/- 46 vs. 546 +/- 45 pg/ml, P < 0.05, HIV-lipodystrophic vs. control), impaired GH response to GHRH by excess FFA, and increased somatostatin tone contribute to reduced GH secretion in patients with HIV-lipodystrophy. These data provide novel insight into the metabolic regulation of GH secretion in subjects with HIV-lipodystrophy.

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.