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Objective: The aim of the study was to determine circulating levels of fatty acid binding protein 4 (FABP-4) in a cohort of HIV-1-infected patients treated with combination antiretroviral therapy (cART) and to investigate the relationships between FABP-4 levels and insulin resistance, dyslipidaemia, lipodystrophy and levels of proinflammatory adipocytokines in these patients., Methods: A total of 282 HIV-1-infected patients treated with stable cART for at least 1 year (132 with lipodystrophy and 150 without) and 185 uninfected controls (UCs) were included in the study. Anthropometric parameters were determined. Plasma levels of FABP-4, soluble tumour necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2), interleukin-18 (IL-18), IL-6, adiponectin and leptin were also analysed. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). Subcutaneous adipose tissue mRNA expression of proinflammatory cytokines was assessed in 38 patients (25 with lipodystrophy and 13 without) by real-time polymerase chain reaction (PCR)., Results: The plasma FABP-4 concentration was significantly higher in patients with lipodystrophy than in those without (P=0.012). FABP-4 concentration was positively correlated with body mass index (BMI), HOMA-IR, and the concentrations of insulin, total cholesterol, triglycerides, sTNF-R1, leptin and IL-18, but showed a negative correlation with high-density lipoprotein (HDL) cholesterol and adiponectin concentrations. After adjusting for age, sex and BMI, the odds ratio (OR) for risk of lipodystrophy was found to be significantly increased for those with the highest levels of FABP-4 [OR 0.838, 95% confidence interval (CI) 0.435-1.616 for medium FABP-4 vs. OR 2.281, 95% CI 1.163-4.475 for high FABP-4]. In a stepwise regression model, FABP-4 was independently associated with HOMA-IR after controlling for clinical and inflammatory parameters (P=0.004). Moreover, a positive relationship was observed in patients with lipodystrophy between subcutaneous adipose tissue CD68 expression and FABP-4 plasma levels (r=0.525; P=0.031)., Conclusions: cART-treated HIV-1-infected patients with lipodystrophy have a systemic overproduction of FABP-4, which is closely linked to insulin resistance and inflammatory markers in subcutaneous adipose tissue., (© 2011 British HIV Association.)

Background: Highly active antiretroviral therapy (HAART) is reported to cause insulin resistance among adults, but effects on children are less clear. We attempted to describe the prevalence of insulin resistance among HIV-infected children receiving HAART., Methods: Insulin resistance was assessed at 96 weeks of treatment with nonnucleoside reverse transcriptase inhibitor (NNRTI)-based HAART (nevirapine or efavirenz with stavudine and lamivudine) among children in Chiang Mai, Thailand. Insulin resistance was defined as homeostasis model assessment for insulin resistance (HOMA-IR) >/=3.16, fasting c-peptide >/=4.40 ng/mL or fasting insulin >/=25.0 muU/mL. Impaired fasting glucose (IFG) was defined as glucose >/=110 mg/dL. Measurements were analysed for associations with age, lipodystrophy, treatment regimen and clinical data., Results: The prevalence of insulin resistance was 6.5%; no child had IFG. Those with insulin resistance were older with higher body mass index. Children >/=10 years had higher HOMA-IR, c-peptide and insulin, but no difference was seen in the frequency of insulin resistance. No associations between insulin resistance and lipodystrophy or treatment regimen were detected., Conclusions: Insulin resistance is uncommon among children receiving NNRTI-based HAART and is unrelated to lipodystrophy.

Objective: We evaluated hyperhomocysteinaemia (HHcy) in a cohort of HIV-infected patients in order to assess its relation to cardiovascular risk (CVR) and identify determinants of HHcy variability., Methods: Cross-sectional observational study. HIV-infected patients on stable highly active antiretroviral therapy (ART) were evaluated for the presence of the metabolic syndrome, lipodystrophy and traditional CVR factors. Plasma homocysteine levels were measured using high-performance liquid chromatography., Results: Five hundred and sixty-seven patients (38% female) with a median age of 44 years were included in the study. Homocysteine (Hcy) was significantly higher in patients with the metabolic syndrome and lipodystrophy. No significant association was found between Hcy levels and the use of ART. However, Hcy was associated with higher blood pressure, waist circumference and waist-to-hip ratio, total lean body mass, visceral adipose tissue (VAT), VAT/total adipose tissue, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides, high-density lipoprotein cholesterol, apolipoprotein A1, B, and creatinine. All 10-year CVR assessment scores were significantly associated with Hcy. In a multivariate regression model, systolic blood pressure, vitamin supplementation and HOMA-IR were significantly and independently related to Hcy., Conclusions: Hcy is elevated in HIV-infected patients and is significantly associated with increased CVR. Measurement of Hcy might be useful in identifying particularly high-risk populations at whom therapeutic interventions could be targeted.

Objectives: We compared androgen and gonadotropin values in HIV-infected men who did and did not develop lipoatrophy on combination antiretroviral therapy (cART)., Methods: From a population of 136 treatment-naïve male Caucasians under successful zidovudine/lamivudine-based cART, the 10 patients developing lipoatrophy (cases) were compared with 87 randomly chosen controls. Plasma levels of free testosterone (fT), dehydroepiandrosterone (DHEA), follicle-stimulating hormone and luteinizing hormone (LH) were measured at baseline and after 2 years of cART., Results: At baseline, 60% of the cases and 71% of the controls showed abnormally low fT values. LH levels were normal or low in 67 and 94% of the patients, respectively, indicating a disturbance of the hypothalamic-pituitary-gonadal axis. fT levels did not significantly change after 2 years of cART. Cases showed a significant increase in LH levels, while controls showed a significant increase in DHEA levels. In a multivariate logistic regression model, lipoatrophy was associated with higher baseline DHEA levels (P=0.04), an increase in LH levels during cART (P=0.001), a lower body mass index and greater age., Conclusions: Hypogonadism is present in the majority of HIV-infected patients. The development of cART-related lipoatrophy is associated with an increase in LH and a lack of increase in DHEA levels.

Objectives: We examined whether insulin-resistant lipodystrophic HIV-infected patients with known high fasting prehepatic insulin secretion rates (FISRs) displayed alterations in first-phase prehepatic insulin response to intravenous glucose (ISREG0-10 min)., Methods: Eighteen normoglycaemic lipodystrophic HIV-infected (LIPO) patients and 25 normoglycaemic nonlipodystrophic HIV-infected patients (controls) were included in the study. The prehepatic insulin secretion rate was estimated by deconvolution of C-peptide concentrations, and insulin sensitivity (SIRd) was estimated by the glucose clamp technique. The disposition index (Di=ISREG0-10 min x SIRd) was calculated to estimate the beta-cell response relative to insulin sensitivity., Results: FISR was increased by 69% (P<0.001), whereas median Di was decreased by 75% (P<0.01), primarily as a result of a reduction of SI(Rd) by 60% (P<0.001) in LIPO patients compared with controls. Three LIPO groups were identified arbitrarily according to their FISR and ISREG0-10 min values relative to those of controls. Four LIPO patients displayed high FISR [+3 standard deviations (SD), P<0.001], high ISREG0-10 min (+3 SD, P<0.001) and low SIRd (P<0.01), suggesting an intact B-cell capacity to compensate insulin resistance; six LIPO patients exhibited high FISR (+3SD, P<0.001), low ISREG0-10min (-1 SD, P=0.01), and low SIRd (P<0.01), suggesting depletion of readily releasable insulin stores; the remaining eight LIPO patients and controls displayed identical FISR and ISREG0-10 min. Increased concentrations of the nonglucose insulin secretagogues triglyceride (+124%), alanine (+35%) and glucagon (+88%), and also lactate (+96%) and tumour necrosis factor (TNF)-alpha (+62%) were observed in the 10 LIPO patients with aberrations in FISR and ISREG0-10 min compared with the remaining HIV-infected patients (all P<0.05)., Conclusion: Plasma triglyceride, alanine, glucagon, lactate and TNF-alpha may be associated with alterations in the first-phase prehepatic insulin secretion response to intravenous glucose in normoglycaemic lipodystrophic HIV-infected patients.

Background: PAI-1, an important inhibitor of fibrinolysis, is increased in obese subjects and has been shown to be an independent risk factor for cardiovascular disease. In the present study, we investigated the association between circulating levels of PAI-1 and locally produced PAI-1 in adipose tissue and body fat distribution and adipokines (TNF-alpha, TNF receptors, IL-6, IL-8) in patients with and without HIV-associated lipodystrophy syndrome (HALS)., Materials and Methods: Eighteen men with HALS and 18 men with HIV but without HALS were investigated. DEXA and computed tomography scan were performed to determine total body fat and visceral adipose tissue mass. Insulin sensitivity was determined by the euglycaemic clamp technique. Plasma levels of PAI-1 and cytokines were determined. In addition, PAI-1, TNF-alpha, IL-6 and IL-8 mRNA levels in subcutaneous adipose tissue were measured by real-time reverse transcriptase polymerase chain reaction., Results: HALS patients were characterized by a 3-fold increased visceral adipose tissue (P < 0.001) and reduced limb fat (P < 0.01) as compared with non-HALS patients but with no difference in total fat mass between the groups. Plasma PAI-1 was increased in HALS patients (16.7 ng mL(-1) vs. 8.2 ng mL(-1), P < 0.05). Plasma PAI-1 was positively correlated with BMI (r = 0.74, P < 0.01), plasma TNF-alpha level (r = 0.64, P < 0.01), sTNFR-I (r = 0.38, P < 0.05), and visceral fat (r = 0.67, P < 0.01). Moreover, plasma PAI-1 was negatively associated with insulin sensitivity (r = -0.57, P < 0.01) and the percentage of limb fat (r = -0.57, P < 0.01). A positive correlation was found between plasma PAI-1 and TNF-alpha mRNA level. No association was, however, found between plasma PAI-1 and PAI-1 mRNA level in adipose tissue., Conclusion: Plasma PAI-1 is increased in HALS patients and it is suggested that dysregulation of the TNF-system (high TNFalpha and high sTNFR1) may play a role in up-regulating PAI-1 in HALS.

Background: Treatment with high doses (2-6 mg day(-1)) of human growth hormone (hGH) in patients with human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) has been shown to increase concentrations of total insulin-like growth-factor-I (IGF-I) more than twofold greater than the normal upper range and is accompanied by adverse effects such as joint pain and glucose intolerance., Materials and Methods: We performed a 16-week open-labelled prospective pilot study in six male HALS patients using a s.c. low-dose hGH, 0.7 mg day(-1), aiming to examine the impact on total and free IGF-I and fat distribution. Glucose metabolism was examined by oral glucose tolerance tests and hyperinsulinaemic euglycaemic clamps., Results: Total IGF-I increased twofold (P < 0.01) and free IGF-I increased 2.5-fold (P < 0.01) to the level of the normal upper range. HDL-cholesterol increased (P = 0.01). Patients reported improvements of lipodystrophy, which was supported by a decreased waist-to-thigh ratio (P = 0.01), and waist-to-hip ratio (P = 0.06). Ratio of peripheral to trunk soft tissue mass increased (P = 0.01, measured by dual-energy X-ray absorptiometry scans) and a trend towards reduction in percentage of trunk fat was suggested (P = 0.12). Total fat mass, exercise capacity, glucose tolerance, glucose disposal rate and immune status, respectively, did not change (all P > 0.5). The patients did not complain of arthralgia or other known GH-related side-effects., Conclusions: Sixteen weeks' treatment of lipodystrophic HIV-infected patients with hGH, 0.7 mg day(-1), increased total and free IGF-I twofold and appeared safe and tolerable. The potential of low-dose hGH in the treatment of HIV-lipodystrophy awaits examination by placebo-controlled, randomized trials., (Copyright 2004 Blackwell Publishing Ltd)

Patients with HIV taking protease inhibitors were selected for the presence (five subjects) or absence (five subjects) of lipoatrophy. Following an overnight fast, subjects were given oral (2)H(2)O in divided doses (5 mL/kg body water), [U-(13)C(3)] propionate (10 mg/kg), and acetaminophen (1000 mg). Glucose (from plasma) or acetaminophen glucuronide (from urine) were converted to monoacetone glucose for (2)H NMR and (13)C NMR analysis. The fraction of plasma glucose derived from gluconeogenesis was not significantly different between groups. However, flux from glycerol into gluconeogenesis relative to glucose production was increased from 0.20 +/- 0.13 among subjects without lipoatrophy to 0.42 +/- 0.12 (P < 0.05) among subjects with lipoatrophy, and the TCA cycle contribution was reduced. Lipoatrophy was associated with an abnormal profile of glucose production as assessed by (13)C and (2)H NMR of plasma and urine.