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Purpose: Combined antiretroviral therapy (cART) for the treatment of HIV-1 infection has been associated with complications, including lipodystrophy. Several interleukins have been implicated in the pathology and physiology of lipodystrophy. The present study aimed to compare the levels of IL-4 and IL-6 in HIV-1 patients under cART with and without, clinically and fat mass ratio defined, lipodystrophy and in four different groups of fat distribution: (1) no lipodystrophy; (2) isolated central fat accumulation; (3) isolated lipoatrophy and (4) mixed forms of lipodystrophy., Methods: In the present cross-sectional study we evaluated IL-4 and IL-6 levels, insulin resistance and insulin sensitivity indexes in 86 HIV-infected adults under cART., Results: No significant differences in IL-4 and IL-6 levels between the four groups of body composition were observed. Patients with HOMA-IR >4 presented higher levels of IL-6 and lower levels of IL-4, although without statistical significance. No correlation between IL-6, or IL-4, HOMA-IR and quantitative body fat mass distribution was found., Conclusion: Although there was a tendency for patients with isolated lipoatrophy and isolated fat accumulation to present higher IL-6 levels, these differences were not statistically significant. No differences were found relating IL-4 levels.

Background: Lipodystrophies are characterized by adipose tissue redistribution, insulin resistance (IR) and metabolic complications. Adipokines and hormones related to body composition may play an important role linking these alterations. Our aim was to evaluate adipocyte-derived hormones (adiponectin, leptin, resistin, TNF-α, PAI-1) and ghrelin plasma levels and their relationship with IR in HIV-infected patients according to the presence of lipodystrophy and fat redistribution., Methods: Anthropometric and metabolic parameters, HOMA-IR, body composition by DXA and CT, and adipokines were evaluated in 217 HIV-infected patients on cART and 74 controls. Fat mass ratio defined lipodystrophy (L-FMR) was defined as the ratio of the percentage of the trunk fat mass to the percentage of the lower limb fat mass by DXA. Patient's fat redistribution was classified into 4 different groups according the presence or absence of either clinical lipoatrophy or abdominal prominence: no lipodystrophy, isolated central fat accumulation (ICFA), isolated lipoatrophy and mixed forms (MXF). The associations between adipokines levels and anthropometric, metabolic and body composition were estimated by Spearman correlation., Results: Leptin levels were lower in patients with FMR-L and isolated lipoatrophy, and higher in those with ICFA and MXF. Positive correlations were found between leptin and body fat (total, trunk, leg, arm fat evaluated by DXA, and total, visceral (VAT), subcutaneous adipose tissue (SAT), and VAT/SAT ratio evaluated by CT) regardless of FMR-L, and with HOMA-IR only in patients with FMR-L. Adiponectin correlated negatively with VAT, and its mean levels were lower in patients with ICFA and higher in those with no lipodystrophy. Resistin was not correlated with adipose tissue but positively correlated with HOMA-IR in FMR-L patients. PAI-1 levels were higher in MXF-patients and their levels were positively correlated with VAT in those with FMR-L. Ghrelin was higher in HIV-infected patients than controls despite BMI-matching., Conclusion: The overall body fat reduction in HIV lipoatrophy was associated with low leptin plasma levels, and visceral fat accumulation was mainly associated with decreased plasma levels of adiponectin.

Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptin's contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes.

Alterations of fat distribution and insulin resistance are associated with increased risk of metabolic derangements and cardiovascular disease. HIV-infected adult patients on antiretroviral treatment often show lipodystrophy, insulin resistance and hypoadiponectinemia, but data in children are controversial. We investigated serum adiponectin concentration in a cohort of HIV-infected youths, and we assessed the relationships with lipodystrophy and insulin resistance. We studied 36 HIV-infected patients (aged 5.0 - 19.4 years), and 171 healthy subjects (aged 4.9 - 17.9 years) for adiponectin measurements. All patients underwent body composition assessment by dual-energy x-ray absorptiometry, and an oral glucose tolerance test to determine the fasting insulin concentration, the insulin area under the curve (AUC), and the HOMA index. Adiponectin serum concentration was measured by an immunoenzymatic assay. Sixteen patients had central fat accumulation, 6 had peripheral lipoatrophy, 5 had a mixed phenotype, and the remaining 9 were non-lipodystrophic. Fasting insulin, insulin AUC, and HOMA index were significantly higher in patients with central fat adiposity and mixed phenotype than in the other two groups. The patients of the former two groups had adiponectin concentration much lower than healthy controls, and patients with peripheral lipoatrophy or normal phenotype had normal concentration. Low adiponectin concentration is associated to central fat and mixed lipohypertrophy, and to signs of insulin resistance in HIV-infected youths. Strict monitoring of metabolic and cardiovascular evolution should be performed in these patients.

Objective: HIV-1-infected patients with lipodystrophy show insulin resistance, dyslipidemia and other signs of metabolic syndrome. Fibroblast growth factor-21 (FGF21) is a novel metabolic regulator that has been suggested to exert beneficial effects on metabolic homeostasis and insulin sensitivity. Our goal was to determine the relationship between FGF21 levels and metabolic alterations in these patients., Research Design and Methods: Serum FGF21 levels were analyzed in 179 individuals belonging to four groups: HIV-1-infected, antiretroviral-treated patients that have developed lipodystrophy (n = 59); HIV-1-infected, antiretroviral-treated patients without lipodystrophy (n = 45); untreated (naive) HIV-1-infected patients (n = 41); and healthy control individuals (n = 34). Serum FGF21 levels were correlated with parameters indicative of altered fat distribution, metabolic and cardiovascular risk, and in relation to HIV-1 infection and antiretroviral treatment regimens., Results: Serum FGF21 levels were increased in all HIV-1-infected patients, but the increases were most marked in those with lipodystrophy. FGF21 levels showed a strong positive correlation with indicators of lipodystrophy (trunk/apendicular fat ratio, waist-to-hip ratio), insulin resistance (fasting glucose, HOMA-R), dyslipidemia (low-density lipoprotein cholesterol), and liver injury (γ-glutamyltransferase)., Conclusions: FGF21 levels are increased in HIV-1-infected patients, especially in those with lipodystrophy, and this increase is closely associated with insulin resistance, metabolic syndrome and makers of liver damage. Further research will be required to determine whether the increase in FGF21 levels is caused by a compensatory response or resistance to FGF21, and to establish the potential of FGF21 as a biomarker of altered metabolism in HIV-1-infected, antiretroviral-treated patients.

Context: HIV-infected patients on antiretroviral therapy are at increased risk for excess visceral adiposity and insulin resistance. Treatment with GH decreases visceral adiposity but worsens glucose metabolism. IGF-I, which mediates many of the effects of GH, improves insulin sensitivity in HIV-negative individuals., Objective: Our objective was to determine whether IGF-I, complexed to its major binding protein, IGF-binding protein-3 (IGFBP-3), improves glucose metabolism and alters body fat distribution in HIV-infected patients with abdominal obesity and insulin resistance., Methods: We conducted a pilot, open-label study in 13 HIV-infected men with excess abdominal adiposity and insulin resistance to assess the effect of 3 months of treatment with IGF-I/IGFBP-3 on glucose metabolism and fat distribution. Glucose metabolism was assessed by oral glucose tolerance test and hyperinsulinemic-euglycemic clamp. Endogenous glucose production (EGP), gluconeogenesis, whole-body lipolysis, and de novo lipogenesis (DNL) were measured with stable isotope infusions. Body composition was assessed by dual-energy x-ray absorptiometry and abdominal computed tomography scan., Results: Glucose tolerance improved and insulin-mediated glucose uptake increased significantly during treatment. EGP increased under fasting conditions, and suppression of EGP by insulin was blunted. Fasting triglycerides decreased significantly in association with a decrease in hepatic DNL. Lean body mass increased and total body fat decreased, whereas visceral adipose tissue did not change., Conclusions: Treatment with IGF-I/IGFBP-3 improved whole-body glucose uptake and glucose tolerance, while increasing hepatic glucose production. Fasting triglycerides improved, reflecting decreased DNL, and visceral adiposity was unchanged.

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.

The aim was to study the mechanisms involved in the dyslipidemia associated with lipodystrophy in HIV infected patients on antiretroviral therapy (ART). We investigated the in vivo kinetics of apolipoprotein B100 (apoB) containing lipoproteins using a 14 h primed constant infusion of [5,5,5, (2)H(3)] leucine and compartmental modelling in normolipidemic without lipodystrophy (7 patients, NLD) or dyslipidemic with lipodystrophy (7 patients, LD) treated with ART. Subjects in group LD showed higher plasma triglycerides (5.73+/-3.58 vs 1.29+/-0.54 g/L, p<0.005), total cholesterol (2.98+/-0.95 vs 1.74+/-0.26 g/L, p<0.05), apoB (1.49+/-1.11 vs 0.51+/-0.11 g/L, p<0.005) and apolipoprotein CIII in apoB containing lipoproteins (117.7+/-42.2 vs 22.6+/-23.9 g/L, p<0.005). LD subjects exhibited an insulin resistant as observed by higher HOMA (3.44+/-1.62 vs 1.60+/-0.61, p<0.05). They exhibited an increase in VLDL (1.24+/-0.33 vs 0.80+/-0.21 mg/kg/h, p<0.05), decrease in IDL (0.20+/-0.10 vs 0.48+/-0.24 mg/kg/h, p<0.05) and no difference in LDL (0.38+/-0.19 vs 0.45+/-0.25 mg/kg/h) production rate. LD subject also showed a dramatic decrease in transformation of VLDL to IDL (0.013+/-0.010 vs 0.258+/-0.206 h(-1), p<0.005) and IDL to LDL (0.088+/-0.093 vs 0.366+/-0.189 h(-1), p<0.05) and a decrease in fractional catabolic rate (FCR) of VLDL (0.199+/-0.132 vs 0.555+/-0.398 h(-1), p<0.05), IDL (0.110+/-0.08 vs 0.523+/-0.275 h(-1), p<0.05) and LDL (0.010+/-0.005 vs 0.025+/-0.014 h(-1), p<0.05). These disturbances, overproduction and an overall delayed catabolism of apoB, are similar to those observed using the same protocol in insulin resistant subjects. Our study suggests that metabolic disturbance of apoB100 observed in lipodystrophic HIV in combined antiretroviral therapy are consecutive to insulin resistance induced by the treatment.

HIV-associated insulin resistance frequently presents as relative lack of peripheral adipose tissue storage associated with dyslipidemia. This review discusses explanations for the links between acute and subacute abnormalities in glucose metabolism and chronic changes in adipose tissue distribution. Specifically, the molecular mechanisms by which the HIV protease inhibitor class of drugs may affect the normal stimulatory effect of insulin on glucose and fat storage are reviewed. It is proposed that both chronic inflammation from HIV infection and treatment with some drugs in this class trigger cellular homeostatic stress responses with adverse effects on glucose metabolism. The physiologic outcome is such that total energy storage in the adipocytes is decreased, and the remaining adipocytes resist further energy storage. The excess circulating and dietary lipid metabolites, normally "absorbed" by adipose tissue, are deposited ectopically in lean (muscle and liver) tissue where they impair insulin action. This leads to a pathologic cycle of insulin resistance, lipotoxicity and lipoatrophy and a clinical phenotype of body fat distribution with elevated waist-to-hip ratio similar to the metabolic syndrome.

Context: Highly active antiretroviral therapy (HAART) for HIV-1 infection has been associated with a metabolic syndrome characterized by insulin resistance, hyperlipidemia, and redistribution of body fat (lipodystrophy). A subset of patients with predominant lipoatrophy has low levels of the adipocyte-secreted hormone leptin., Objective: The objective of the study was to assess whether administration of recombinant methionyl human leptin (r-metHuLeptin) improves insulin resistance and other metabolic abnormalities in HIV+ leptin-deficient subjects with HAART-induced lipoatrophy., Design, Setting, Patients, and Intervention: We conducted a randomized, placebo-controlled, double-blinded, crossover study from 2002 to 2004 in seven HIV+ men with HAART-induced lipoatrophy, serum leptin level less than 3 ng/ml, and fasting triglyceride level greater than 300 mg/dl, who were administered placebo for 2 months before or after administration of r-metHuLeptin at physiological doses for an additional 2 months., Main Outcome Measures: Insulin resistance, lipid levels, inflammatory markers, body composition, and HIV control were measured., Results: Compared with placebo, r-metHuLeptin therapy improved fasting insulin levels, insulin resistance (as expressed by the homeostasis model assessment index and an insulin suppression test), and high-density lipoprotein. Body weight and fat mass decreased on r-metHuLeptin, mainly due to a decrease in truncal fat but not peripheral fat or lean body mass. r-metHuLeptin was well tolerated, and HIV control was not adversely affected., Conclusions: r-metHuLeptin replacement at physiological doses in HIV+ leptin-deficient patients with HAART-induced lipoatrophy improves insulin resistance, high-density lipoprotein, and truncal fat mass. Future larger and more long-term studies in HAART-induced lipoatrophy, including patients with more severe metabolic abnormalities, are warranted to evaluate the physiological and potentially therapeutic role of r-metHuLeptin for this condition and to fully clarify the underlying mechanisms of action.

Acquired fat redistribution, that is, peripheral fat loss often accompanied by central fat accumulation in patients with HIV infection is the most common form of lipodystrophy in man. Approximately 30 - 50% of HIV-infected individuals after > or = 12 months on highly active antiretroviral therapy (HAART) may encounter the HIV-associated lipodystrophy syndrome (HALS), which attenuates patient compliance to this treatment. HALS is characterised by impaired glucose and lipid metabolism and other risk factors for cardiovascular disease. This review depicts the metabolic abnormalities associated with HAART by describing the key cell and organ systems that are involved, emphasising the role of insulin resistance. An opinion on the remedies available to treat the metabolic abnormalities and phenotype of HALS is provided.

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: HIV-infected patients with HAART-related lipodystrophy are frequently insulin resistant and at risk of non-alcoholic fatty liver disease (NAFLD) with steatohepatitis (NASH). The transcription factors, peroxisome proliferator activated receptors (PPARalpha, PPARgamma1/PPARgamma2) and sterol regulatory element binding proteins (SREBP-1) regulate liver lipid metabolism. Here, we examined whether their expression was modified and related to liver injury in HIV-infected patients., Methods: Fourteen HAART-treated HIV patients (nine with and five without insulin resistance) who had liver biopsy because of unexplained elevated transaminases were compared with nine non-HIV age-and body mass index-matched patients with NAFLD and 10 controls without steatosis. Hepatic expression of PPARs and SREBP-1 was assessed by real time reverse transcriptase-polymerase chain reaction., Results: Liver histology showed NASH in six of nine insulin-resistant lipodystrophic and two of five non-insulin-resistant HIV patients. Compared with NAFLD or control subjects, expression of SREBP-1 was significantly higher only in HIV-insulin-resistant patients (P = 0.04 and P = 0.02) whereas, compared to controls, HIV-insulin-resistant, HIV-non-insulin-resistant and NAFLD patients had lower expressions of PPARgamma1 (P = 0.03, P = 0.05 and P = 0.01) and PPARgamma2 (P = 0.04, P = 0.05 and P = 0.01). Among HIV patients, the percentage of steatosis was positively correlated with SREBP-1 expression (r = 0.62, P = 0.04) whereas the score of fibrosis was inversely correlated with PPARgamma1 and PPARgamma2 expression (r = -0.57, P = 0.03 and r = -0.6, P = 0.02, respectively)., Conclusion: Insulin-resistant lipodystrophic HIV-infected patients may develop NASH. Steatosis is associated with overexpression of SREBP-1 and fibrosis with decreased expression of PPARgamma1 and PPARgamma2. These results suggest that altered expression of SREBP-1 and PPARgamma could contribute to the pathogenesis of steatosis and fibronecrotic changes in insulin-resistant lipodystrophic patients.

Altered fat distribution is associated with insulin resistance in HIV, but little is known about regional glucose metabolism in fat and muscle depots in this patient population. The aim of the present study was to quantify regional fat, muscle, and whole body glucose disposal in HIV-infected men with lipoatrophy. Whole body glucose disposal was determined by hyperinsulinemic clamp technique (80 mU x m(-2) x min(-1)) in 6 HIV-infected men and 5 age/weight-matched healthy volunteers. Regional glucose uptake in muscle and subcutaneous (SAT) and visceral adipose tissue (VAT) was quantified in fasting and insulin-stimulated states using 2-deoxy-[18F]fluoro-D-glucose positron emission tomography. HIV-infected subjects with lipoatrophy had significantly increased glucose uptake into SAT (3.8 +/- 0.4 vs. 2.3 +/- 0.5 micromol x kg tissue(-1) x min(-1), P < 0.05) in the fasted state. Glucose uptake into VAT did not differ between groups. VAT area was inversely related with whole body glucose disposal, insulin sensitivity, and muscle glucose uptake during insulin stimulation. VAT area was highly predictive of whole body glucose disposal (r2 = 0.94, P < 0.0001). This may be mediated by adiponectin, which was significantly associated with VAT area (r = -0.75, P = 0.008), and whole body glucose disposal (r = 0.80, P = 0.003). This is the first study to directly demonstrate increased glucose uptake in subcutaneous fat of lipoatrophic patients, which may partially compensate for loss of SAT. Furthermore, we demonstrate a clear relationship between VAT and glucose metabolism in multiple fat and muscle depots, suggesting the critical importance of this depot in the regulation of glucose and highlighting the significant potential role of adiponectin in this process.

We examined whether plasma concentrations of nonglucose insulin secretagogues are associated with prehepatic insulin secretion rates (ISR) in nondiabetic, insulin-resistant, human immunodeficiency virus (HIV)-infected, lipodystrophic patients (LIPO). Additionally, the negative feedback of insulin on ISR was evaluated. ISR were estimated by deconvolution of plasma C-peptide concentrations during fasting (basal) and during the last 30 min of a 120-min euglycemic insulin clamp (40 mU.m(-2).min(-1)). Eighteen normoglycemic LIPO were compared with 25 normoglycemic HIV-infected patients without lipodystrophy (controls). Thirty minutes before start of the clamp, a bolus of glucose was injected intravenously to stimulate endogenous insulin secretion. Insulin sensitivity index (SiRd) was estimated from glucose tracer analysis. LIPO displayed increased basal ISR (69%), clamp ISR (114%), basal insulin (130%), and clamp insulin (32%), all P < or = 0.001, whereas SiRd was decreased (57%, P < 0.001). In LIPO, ISRbasal correlated significantly with basal insulin, alanine, and glucagon (all r > 0.65, P < 0.01), but not with glucose. In control subjects, ISR(basal) correlated significantly with insulin, glucagon, and glucose (all r > 0.41, P < 0.05), but not with alanine. In LIPO, ISRclamp correlated significantly with clamp free fatty acids (FFA), alanine, triglyceride, and glucagon (all r > 0.51, P < 0.05). In control subjects, ISRclamp correlated with clamp triglyceride (r = 0.45, P < 0.05). Paradoxically, in LIPO, ISRclamp correlated positively with clamp insulin (r = 0.68, P < 0.01), which suggests an absent negative feedback of insulin on ISR. Our data support evidence that lipodystrophic, nondiabetic, HIV-infected patients exhibit increased ISR, which can be partially explained by an impaired negative feedback of insulin on beta-cells and an increased stimulation of ISR by FFA, alanine, triglyceride, and glucagon.

Objective: To achieve a better understand of the pathophysiology of HIV-related lipoatrophy, we compared the mRNA expression of adipocytokines in fat samples from patients and healthy HIV-seronegative controls together with fat morphology and we studied the relationship between changes in fat morphology, adipocytokine expression, markers of adipose tissue differentiation and whole body insulin sensitivity., Design: Cross-sectional analytical study., Subjects and Methods: The mRNA expression of adipocytokines and transcriptional factors in fat samples from 26 patients with peripheral lipoatrophy (all under anti-retroviral therapy associating protease inhibitor and nucleoside-analogue reverse transcriptase inhibitors) and from 16 non-HIV-infected controls was measured by real time quantitative RT-PCR. Fat morphology was assessed histologically on a subgroup of 10 patients and six controls: collagen fibres by Sirius Red staining, apoptosis by the TUNEL technique, vessels by smooth muscle alpha-actin staining and macrophages by CD68 staining. Insulin resistance was assessed by using the homeostasis model assessment., Results: The patients' fat showed higher values of apoptosis (P=0.005), fibrosis (P<0.05), vessel density (P=0.001) and macrophage infiltration (P<0.05) than the controls' fat, together with lower adiponectin and leptin mRNA levels and higher interleukin (IL)-6 and tumour necrosis factor (TNF)alpha mRNA levels. TNFa and IL-6 expression correlated positively with the level of apoptosis (P=0.05 and P<0.05, respectively) and negatively with CCAAT-enhancer binding protein (C/EBP)alpha (P<0.001 and P<0.05, respectively). Apoptosis correlated negatively with the expression level of sterol-regulatory-element-binding-protein-1c (SREBP1c) (P=0.01) and C/EBPalpha (P=0.01) whilst the vessel density correlated negatively with SREBP1c (P<0.005), C/EBPalpha (P=0.001) and beta (P=0.001). Adiponectin and leptin expression correlated positively with each other, and also with adipogenic marker expression and overall insulin sensitivity. These relationships were also present when the patient group was studied separately. Finally, fat morphological abnormalities correlated positively with whole body insulin resistance., Conclusions: Adipose tissue from patients with HIV-1-related lipoatrophy shows increased apoptosis, together with decreased adipocyte differentiation. Increased TNFalpha and IL-6 expression could be a major phenomenon linking these alterations. Decreased adiponectin and leptin expression, which may result from decreased adipocyte differentiation, could be involved in the observed whole body insulin resistance.

Recent advances in the development of three different types of antiviral drugs, the nucleotide and non-nucleotide analogues acting as reverse transcriptase inhibitors (NRTIs) and the nonpeptidic viral protease inhibitors (PI), and their introduction in the management of patients with AIDS, either alone or in combination, have dramatically improved the clinical course of the disease and prolonged life expectancy in patients with AIDS. The increase in life expectancy in association with the long-term use of the above antiviral agents, however, have generated novel morbidities and complications. Central among them is the quite common AIDS-related insulin resistance and lipodystrophy syndrome, which is characterized by a striking phenotype and marked metabolic disturbances. To look for the pathologic causes of this particular syndrome, we focused on one of the HIV-1 accessory proteins, Vpr, which has multiple functions, such as virion incorporation, nuclear translocation of the HIV-1 preintegration complex, nucleo-cytoplasmic shuttling, transcriptional activation, and induction of apoptosis. Vpr may also act like a hormone, which is secreted into the extracellular space and affects the function of distant organs. Vpr functions as a coactivator of the glucocorticoid receptor and potentiates the action of glucocorticoid hormones, thereby inducing tissue glucocorticoid hypersensitivity. Vpr also arrests host cells at the G2/M phase of the cell cycle by interacting with novel 14-3-3 proteins. Vpr facilitates the interaction of 14-3-3 and its partner protein Cdc25C, which is critical for the transition of G2/M checkpoint in the cell cycle, and suppresses its activity by segregating it into the cytoplasm. The same Vpr protein also suppresses the association of 14-3-3 with other partner molecules, the Foxo transcription factors. Since the Foxo proteins function as negative transcription factors for insulin, Vpr may cause resistance of tissues to insulin. Through these two newly identified functions of Vpr, namely, coactivation of glucocorticoid receptor activity and inhibition of insulin effects on Foxo proteins, Vpr may participate in the development of AIDS-related insulin resistance/lipodystrophy syndrome.

Obesity is a risk factor for type 2 diabetes and cardiovascular diseases. The hypothesis that cytokines could play a role in the pathophysiology of obesity and insulin resistance is suggested in the last few years. We showed a positive correlation between circulating interleukin (IL-6) levels and obesity and insulin resistance suggesting that IL-6 could be involved in insulin resistance in humans. We showed a decrease of both circulating and adipose tissue IL-6 levels in non-diabetic obese subjects after a very low calorie diet program inducing weight loss. This suggests that adipose tissue could be involved in the regulation of circulating IL-6 levels in these subjects. Adipose tissue is also involved in lipodystrophies particularly in HIV patients on antiviral therapy. We showed an alteration of the SREBP-1 transcription step in subcutaneous abdominal adipose tissue from HIV patients. We found an inverse correlation between circulating adiponectin levels and both insulin resistance and cardiovascular risk factors such as CRP levels and apolipoprotein B/A1 ratio. These findings suggest that adipose tissue is involved in insulin resistance in humans particularly via adipocytokine secretion., (Copyright John Libbey Eurotext 20003.)

The recent development of highly active antiretroviral therapy (HAART) has drastically improved the life expectancy of AIDS patients, by reducing infection-related mortality. However, the prolongation of the lives of HIV-1-infected patients and/or the long-term use of novel, potent antiviral agents have generated a score of new problems and complications. Among them is the AIDS-related insulin resistance and lipodystrophy syndrome, which is observed in 30-80% of AIDS patients who are well controlled by HAART. This syndrome is associated with severe metabolic disturbances, such as carbohydrate intolerance/diabetes mellitus and dyslipidemia, which cause atherosclerotic cardiovascular disease. The etiology of this syndrome appears to be multi-factorial; other than the anti-viral drugs, hypercytokinemia and the HIV-1 infection itself, including the virally encoded molecules Vpr and Tat, could contribute to the development of these pathologic changes or increase the vulnerability of patients to the adverse effect of the therapeutic compounds. In this article, we review our current understanding of the pathogenesis and therapeutic approach of this newly emerging AIDS-associated metabolic syndrome.

Lipodystrophy (LD) associated with HIV infection is a syndrome of abnormal fat distribution observed in HIV-infected patients treated with various antiretroviral agents. In addition, insulin resistance and dyslipidemia can occur in HIV-infected patients with or without LD. The demonstration of the latter metabolic disorders in normal subjects using protease inhibitors suggests that these agents could play a causative role in their development independently of HIV status. Possible mechanisms whereby protease inhibitors can hinder insulin actions include inhibition of glucose transporter isoform Glut 4, and altered expression of leptin and tumor necrosis factor-a in adipose tissue. The presence of insulin resistance and dyslipidemia can potentially increase the risk of diabetes, cardiovascular disease, and death. However, short-term data in this regard are inconsistent. Treatment of HIV-related LD with metformin may ameliorate insulin resistance, but its impact on fat redistribution requires additional studies. Temporary cessation of antiretroviral therapy does not appear to reverse body fat changes or insulin resistance, but may partially improve the lipid profile. Further investigations are urgently needed to define the mechanisms and cardiovascular consequences of insulin resistance in HIV-related LD, and to find an effective treatment for this complex syndrome.

Background: The HIV-associated lipodystrophic syndrome (HIV-LDS) combines redistribution of fat mass with insulin resistance and hyperlipidemia. We have previously reported that HIV-LDS prevails in children in a comparable pattern as in adults. The metabolic activity itself of the lipodystrophic adipose tissue in HIV infection has been poorly studied., Aim and Methods: To assess in situ the insulin sensitivity of the lipohypertrophic subcutaneous abdominal adipose tissue using the microdialysis technique in HIV-infected children. Insulin sensitivity, assessed by the inhibition of glycerol release, was measured in the abdominal subcutaneous adipose tissue during a standard oral glucose tolerance test (OGTT) in six HIV-infected children under multi-therapy with abdominal lipohypertrophy (supra-iliac skinfold thickness >97th percentile) (HIV/LH+), in six obese children (obese group) and in eight HIV-infected children without lipodystrophy (HIV/LH-)., Results: Glucose tolerance was normal in all subjects. Mean insulin areas under the curve (IAUC) were significantly higher in the obese and HIV/LH+ groups than in HIV/LH- (8769+/-5429, 8161+/-4552 and 3618+/-2222 mU min l(-1), respectively; P=0.04 for the three groups comparison by the Kruskal-Wallis test), reflecting insulin resistance in the two former groups independent of a significant difference in percentage fat mass (37.2+/-4.7, 22.8+/-10.9 and 20.7+/-7.1%, respectively; P= 0.006). The crude inhibition of glycerol release, expressed as the relative change in dialysate glycerol concentration between baseline and 120 min, was not statistically different between the three groups (14% in obese, -38+/-14% in HIV/LH+ and -51+/-17% in HIV/LH- groups; P=0.3). The inhibition of glycerol release with respect to the circulating insulin level (expressed by IAUC) was similar in HIV/LH+ and obese groups (-6+/-5 x 10(-3) and -7+/-5 x 10(-3) l mU(-1) min(-1), respectively, P=0.4 for two-groups comparison by the U-Mann-Whitney test) and four-fold less than in the HIV/LH- group (-24+/-25 x 10(-3) l mU(-1) min(-1); P=0.02)., Conclusion: These data argue in favor of insulin resistance in the adipose tissue of lipohypertrophies associated with HIV infection.

Protease inhibitors used as therapy for HIV-1 infection have been associated with metabolic side-effects such as peripheral fat wasting, central adiposity, hyperlipidaemia and insulin resistance. This metabolic disorder is known as the lipodystrophy syndrome. This syndrome can be recognized by the early appearance of an increase in serum triglyceride, cholesterol and plasma-free fatty acid levels. Here, we describe an HIV-1 positive patient with the lipodystrophy syndrome in whom a decline in serum triglycerides was seen along with a significant improvement in glucose uptake following treatment with bezafibrate for 3 months. This improvement may be a consequence of the Randle effect, i.e. increased availability of plasma-free fatty acids is negatively correlated to glucose uptake. We also noted a significant improvement in endothelial-dependent flow-mediated dilatation after treatment with bezafibrate. This effect could result from the increased glucose uptake observed and a decrease in insulin resistance secondary to the lowered triglyceride levels by bezafibrate. We conclude that bezafibrate may be of clinical utility in the lipodystrophy syndrome, through its beneficial effects on insulin resistance, glucose uptake and endothelial dysfunction.