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Lipodystrophy and Insulin Resistance in Combination Antiretroviral Treated HIV-1–Infected Patients: Implication of Resistin

Escoté, Xavier PhD*†; Miranda, Merce PhD*†; Veloso, Sergi MD*; Domingo, Pere MD, PhD; Alonso-Villaverde, Carlos MD, PhD§; Peraire, Joaquim MD, PhD*; Viladés, Consuelo MD, PhD*; Alba, Verónica*; Olona, Montserrat MD*; Castro, Antoni MD, PhD§; López-Dupla, Miguel MD, PhD*; Sirvent, Joan-Josep MD, PhD*; Vicente, Vicente MD, PhD*; Vendrell, Joan MD, PhD*†; Richart, Cristóbal MD, PhD*; Vidal, Francesc MD, PhD*for the HIV-1 Lipodystrophy Study Group

JAIDS Journal of Acquired Immune Deficiency Syndromes: May 1st, 2011 - Volume 57 - Issue 1 - p 16-23
doi: 10.1097/QAI.0b013e318213312c
Basic and Translational Science

Background: Little information is available with respect to the involvement of resistin in lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with combination antiretroviral therapy (cART). We determined whether the resistin (rest) −420C>G single-nucleotide polymorphism and plasma resistin are associated with the development of lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with cART.

Methods: The study group comprised 299 HIV-1-infected patients treated with a stable cART for at least 1 year (143 with lipodystrophy and 156 without) and 175 uninfected controls. Anthropometric, clinical, and metabolic variables were determined. Homeostasis model assessment for insulin resistance was used to evaluate insulin resistance. Plasma resistin levels were determined by enzyme-linked immunosorbent assay. The rest −420C>G was assessed using restriction fragment length polymorphism. Student t test, 1-way and 2-way analysis of variance, χ2 test, and Pearson and Spearman correlations were performed for statistical analysis.

Results: Genotypes containing the rest −420G variant allele were significantly more common in HIV-1-infected patients without lipodystrophy compared with those with lipodystrophy (P = 0.037). Infected patients had significantly greater plasma resistin levels than uninfected controls (P < 0.001). Among infected patients, plasma resistin levels were significantly lower in patients with lipodystrophy with respect to those without (P = 0.034). In infected patients, plasma resistin levels had a significant positive correlation with insulin and homeostasis model assessment for insulin resistance: P < 0.001 and P = 0.002 in the lipodystrophy subset and P = 0.002 and P = 0.03 in the nonlipodystrophy subset, respectively.

Conclusions: In our cohort of white Spaniards, the rest −420C>G single-nucleotide polymorphism may be associated with cART-related lipodystrophy. Plasma resistin correlates with insulin resistance in infected patients with and without lipodystrophy.

From the *Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain; †CIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Barcelona, Spain; ‡Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; and §Hospital Universitari de Sant Joan, Reus, IISPV, Universitat Rovira i Virgili, Reus, Spain.

Received for publication October 16, 2010; accepted January 28, 2011.

This work was partially financed by grants from the Fondo de Investigacion Sanitaria (07/0976, 08/1032, 08/1195, 10/2635); Fondos para el Desarrollo Europeo Regional (FEDER); Fundación para la Investigación y Prevención del Sida en España (FIPSE 06/36572, 06/30610 and 36-0998-10); SAF2008-02278, Ministerio de Ciencia e Innovación; Programa de Suport als Grups de Recerca AGAUR (2009 SGR 959, 1061 and 1257); and Red de Investigación en Sida (RIS, RD06/006/0022 and RD06/0006/1004), ISCIII, Ministerio de Sanidad y Consumo, Spain.

X. Escoté is supported by a fellowship from the Juan de la Cierva (JDC) program (JDCI20071020).

X. Escoté, M. Miranda, and S. Veloso have contributed equally to this work.

The authors have no funding or conflicts of interest to disclose.

Correspondence to: Francesc Vidal, MD, PhD, Infectious Diseases and HIV/AIDS Section, Department of Internal Medicine, Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Mallafré Guasch, 4, 43007 Tarragona, Spain (e-mail:

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Resistin, also known as FIZZ-3 (found in inflammatory zone 3), is a pleiotropic cytokine that acts as an immune and inflammatory mediator. It is an adipocyte-secreted peptide and has been named in relation to the connection between obesity and diabetes.1 Reports elsewhere have involved resistin in lipid and glucose metabolism1,2 while other investigations failed to observe associations between adipose tissue resistin expression and insulin resistance.3,4 Moreover, increased systemic resistin levels have been reported in obese4 and diabetic subjects,5,6 although data are inconsistent.4,5,7-9 Hence, at present, the involvement of resistin in obesity and diabetes is still a matter of debate.1 Because the lipodystrophy syndrome developed by some of the HIV-1-infected patients treated with combination antiretroviral treatment (cART) is reminiscent of obesity and its associated metabolic disorders, the involvement of resistin has been assessed. In a recent study, plasma resistin levels were increased in adult patients with cART-induced metabolic syndrome and the short-term administration of rosiglitazone diminished them.10 Other investigators, however, found no correlation between plasma resistin and markers of inflammation, and insulin resistance and the type of lipodystrophy in adult HIV-1-infected patients treated with cART.11 These discrepancies have also been observed in children.12,13

As for many other proinflammatory cytokines, resistin production is to some extent genetically determined. Several functional single-nucleotide polymorphisms (SNP) have been identified within the resistin gene cluster and the most widely studied is a G to C transition at position −420 in the promoter (rest −420C>G).14-17 Carriage of some genetic variants may influence its circulating systemic levels.14 Recently, a substudy of the ACTG5005 reported that genetic variation in resistin is associated with metabolic disturbances in patients treated with cART.18

To gain further insight into the role of the resistin system in HIV-1 infection and in the cART-related lipodystrophy syndrome and its associated metabolic disorders, we undertook this study performed in a cohort of white Spanish HIV-1-infected patients treated with cART with and without lipodystrophy and in an uninfected control (UC) group. Our objectives were to assess whether the rest −420G>C SNP is associated with lipodystrophy and its associated metabolic complications and to evaluate plasma resistin levels. We also assessed the possible associations between the rest −420G>C SNP and the vulnerability to HIV-1 infection.

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Design, Setting, and Participants

This was a multicenter, cross-sectional, case-control study. We studied 474 adults: 299 HIV-1-infected patients and 175 UC. Patients were recruited within a prospectively collected cohort of 1700 HIV-1-infected individuals receiving cART, defined as the combination of 2 nucleoside reverse transcriptase inhibitors (NRTI) plus either a nonnucleoside reverse transcriptase inhibitor or protease inhibitor(s) (PI). Patients were followed at the HIV outpatient clinic of the 3 participating hospitals. Inclusion criteria were older than 18 years, presence of HIV-1 infection, stable cART regimen for at least 1 year, and presence or absence of lipodystrophy according to a clinical assessment (see below). We calculated the sample size of each category of patients (lipodystrophy and nonlipodystrophy) with a power of 80%, an alpha risk of 5%, a GG frequency of 15% in the nonlipodystrophy group, and an odds ratio = 2, and there was 125 patients per group. We recruited 143 patients who fulfilled the criteria of lipodystrophy (LD+) and agreed to participate in the study in addition to a randomly selected group of patients without lipodystrophy (LD−) (n = 156) whose age (±5 years), sex, and time of exposure to cART (±3 months) were comparable to those of patients with lipodystrophy. The control group comprised uninfected healthy persons comparable to the patients as regards age (±5years) and sex. The presence of cachexia, active opportunistic infections, current inflammatory diseases or conditions, consumption of drugs with known metabolic effects, such as corticosteroids and hormones, and plasma C reactive protein >1 mg/dL were exclusion criteria for both patients and controls. All subjects were white Spaniards; immigrants and their descendants (including those from other European countries) were excluded. All participants gave informed consent. The project was approved by the local ethics committee.

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Clinical Assessment of Lipodystrophy

All HIV-1-infected patients were given a full physical examination to assess the type (lipoatrophy, lipohypertrophy, or mixed) and degree (slight, moderate, or severe) of lipodystrophy. Waist and hip diameter, height, weight, and body mass index (BMI) were measured. Criteria for lipoatrophy were 1 or more of the following: loss of fat from the face, arms, and legs, prominent veins in the arms and legs, and a thin bottom. Lipohypertrophy was defined by the presence of 1 or more of the following criteria: increase in abdominal perimeter, breast and/or neck fat deposition. We defined mixed lipodystrophy as being when at least 1 characteristic of lipoatrophy and 1 of lipohypertrophy were concomitantly present in a given patient. Lipodystrophy was categorized in accordance with the scale proposed by Carr et al.19: nil {0}, slight (1), moderate (2), and severe (3). Doubtful cases were excluded. This categorization was evaluated in the face, arms, legs, buttocks, abdomen, neck, and breasts. The sum of the values corresponding to each body area indicated the degree of lipodystrophy: nil (0), slight (1-6), moderate (7-12), and severe (13-18).19,20 In this study, we included only moderate and severe cases to avoid superposition between groups.

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Computed Tomography Scan

To assess the distribution of visceral adipose tissue and subcutaneous adipose tissue, a single-slice computed tomography scan (CT helicoidal, ELSCINT Model TWIN, Haifa, Israel) was performed at the level of L4 in all HIV-1-infected patients. The surface of adipose tissue was measured in square centimeter.

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Laboratory Methods

Collection of Blood Samples

After an overnight fast, 20 mL of blood obtained from a peripheral vein was collected in Vacutainer EDTA tubes. Five milliliters of whole blood were used to determine CD4+ T-cell count. Five hundred microliters were used for DNA isolation by a MagNa Pure LC Instrument (Roche Diagnostics, Basel, Switzerland). Plasma and serum were obtained by centrifugation at 3500g for 15 minutes at 4°C and stored at −80°C until use.

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HIV-1 Infection

This was diagnosed by a positive enzyme-linked immunosorbent assay and confirmed by a positive Western blot test.

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Plasma HIV Viral Load

This was determined by the Cobas Amplicor HIV-1 Monitor Test v 1.5 using the COBAS AMPLICOR system (Roche Diagnostics).

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CD4+ T-Cell Count Assessment

Samples were analyzed in a flow cytometer FAC Scan (Becton Dickinson Immunocytometry Systems, San Jose, CA). Data acquired were analyzed using the Multiset program.

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Blood Chemistry

Serum glucose was measured by the glucose oxidase method (Hitachi 737; Boehringer Mannheim, Marburg, Germany). Lipid profile [serum total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides] was measured by the usual enzymatic methods. Hyperglycemia was defined as a blood glucose level of ≥6.1 mmol/L, hypertriglyceridemia was defined as a triglyceride level of ≥2.2 mmol/L, hypercholesterolemia was defined as a total cholesterol level of ≥5.2 mmol/L, low-HDL cholesterol was defined as a level of ≤0.9 mmol/L, and high-LDL cholesterol was defined as a level of ≥3.4 mmol/L.21 Hyperinsulinemia was considered when insulin levels were ≥18 μU/mL.22 Insulin resistance was calculated according to the homeostasis model assessment for insulin resistance (HOMA-IR) method from fasting glucose and insulin concentrations, according to the following formula: insulin (μIU/mL) × glucose (mmol/L)/22.5.23 Plasma resistin levels were measured by enzyme-linked immunosorbent assay (BioVendor Laboratory Medicine, Inc, Palackeho, Czech Republic). Sensitivity was 0.2 ng/mL. The intra- and interassay coefficients of variation were 5.8% and 14.7% respectively. Plasma IL-6 and sTNFR1 levels and sTNFR2 levels were assessed as we have previously reported.24,25

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Rest −420 C>G Genotype

This was assessed by polymerase chain reaction (PCR) restriction fragment length polymorphism using the following oligonucleotides rest-420F 5′-TGTCATTCTCACCCAGAGACA-3′ and rest-420R 5′-TGGGCTCAGCTAACCAAATC-3′. The PCR was performed in a total volume of 20 μL containing 2 μL of 1 × 0 PCR buffer, 2 mM of MgCl2, 0.1 mM of dNTPs, 0.25 μM of each primer, 200 ng of genomic DNA, and 1 U of Taq DNA polymerase (MBI Fermentas, Vilnius, Lithuania). The amplification cycle was as follows: denaturation at 95°C for 7 minutes, preannealing at 64°C for 1 minute, and elongation at 72°C for 2 minutes followed by 35 cycles for 30 seconds at 95°C, 30 seconds at 64°C, and 1 minute 15 seconds at 72°C and, finally, elongation at 72°C for 10 minutes. An aliquot of 15 μL of PCR products was digested with 0.5U BbsI restriction endonuclease (New England BioLabs, Waltham, MA) in a reaction containing 3 μL of 10× New England Biolab buffer 2 (50 mM of NaCl, 10 mM of Tris-HCl, 10 mM of MgCl2 and 1 mM of dithiothreitol) in a total volume of 30 μL and incubated at 37°C for 12 hours. The 534-bp PCR product was cleaved into 2 fragments of 327 and 207 bp in the presence of the C allele, 3 fragments of 534, 327, and 207 bp for the heterozygote (CG), while the G homozygote remained nondigested, showing the 534-bp PCR product. The digestion products were separated by 2% agarose gel electrophoresis. In addition, 30% of the samples were selected randomly to perform the repeated assays, and the results were 100% concordant.

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Statistical Analyses

Before the statistical analyses, normal distribution and homogeneity of the variances were tested. Normally distributed data were expressed as mean ± SD, whereas variables with a skew distribution were represented as the median (interquartile range). Categorical variables were reported by number (percentages). Spearman rank or Pearson correlation test was used to assess the relationship between 2 continuous variables. Student t test and 1-way analysis of variance with post hoc Bonferroni test were used to compare continuous variables between 2 groups and more than 2 groups, respectively. Qualitative variables, including genotype and allele frequencies, were analyzed by the χ2 test. Hardy-Weinberg equilibrium was assessed by the χ2 goodness-of-fit test. The association between plasma resistin levels and the rest −420C>G SNP was explored by multiple lineal regression for adjusting of confounding factors. The dependent variable was plasma resistin level logarithm. The association between potential factors and the presence of lipodystrophy and metabolic abnormalities was examined by forward stepwise logistic regression analysis, and the model was adequately fitted by Hosmer and Lemeshow goodness-of-fit test. Variables included in the multivariate analysis were those that had presented a P value of less than 0.2 in the univariate analysis and those biologically plausible. All analyses were performed using the SPSS/PC+ statistical package (V. 11.01 for Windows; SPSS, Chicago, IL). A P value of less than 0.05 was considered significant.

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Characteristics of the Participants

Table 1 shows the main characteristics of the HIV-1-infected patients studied, categorized according to the presence or absence of lipodystrophy. Of the 299 HIV-1-infected subjects, 143 had lipodystrophy (47.8%), whereas 156 (52.2%) had not. Among patients with lipodystrophy, 33 (23%) had pure lipoatrophy and 110 (77%) had a mixed form (lipoatrophy plus lipohypertrophy). No cases of pure lipohypertrophy were observed. HIV-1-infected patients and UC were comparable in age (P = 0.206) and sex (P = 0.168). HIV-1-infected patients with lipodystrophy had a significantly higher BMI, significantly less subcutaneous adipose tissue mass, and more visceral adipose tissue mass compared with those without lipodystrophy (Table 1). Lipodystrophy patients had more advanced disease defined by the Centers for Disease Control and Prevention classification and greater CD4+ T-cell gain due to cART, compared with those without lipodystrophy. In addition, patients with lipodystrophy had consumed a higher number of PI and NRTI and had a more prolonged exposure to NRTI as a whole and, particularly, to stavudine (d4T) (Table 1).



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Biochemical Data

The main biochemical data of the HIV-1-infected patients categorized according to the presence or absence of lipodystrophy are shown in Table 2. No biochemical data were available from the UC cohort. Hyperglycemia, insulin, HOMA-IR, triglyceride, total cholesterol, and LDL cholesterol in plasma were significantly increased in patients with lipodystrophy compared with those without, whereas HDL cholesterol was significantly decreased. In addition, the proportion of carbohydrate and lipid metabolic abnormalities was significantly greater in patients with lipodystrophy compared with those of patients without lipodystrophy. Plasma TNFR1 levels were not significantly different in HIV-1-infected patients compared with UCs or among infected patients. In contrast, HIV-1-infected patients had significantly higher plasma levels of TNFR2 and IL-6 (P < 0.001, for both) compared with UCs. Among infected patients, plasma IL-6 and TNFR2 levels were nonsignificantly different in the lipodystrophy and nonlipodystrophy subsets (P = 0.983 for TNFR2 and P = 0.758 for IL-6). Among the patients with lipodystrophy, plasma metabolic and cytokine parameters assessed were nonsignificantly different between patients with pure lipoatrophy and patients with mixed lipodystrophy (data not shown).



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Plasma Resistin Levels

HIV-1-infected patients had significantly higher plasma resistin levels [median (interquartile range): 3.95 (2.77-5.40)] compared with UCs [2.74 (2.12-4.19); P < 0.001]. Among infected patients, plasma resistin levels were significantly lower in patients with lipodystrophy compared with those without (P = 0.034) (Table 2). Among patients with lipodystrophy, individuals with pure lipoatrophy had significantly greater plasma resistin levels than subjects with mixed lipodystrophy [4.64 (3.5-5.2) vs. 3.27 (2.5-4.4); P = 0.004].

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Relationship Between Plasma Resistin Levels and Metabolic and Inflammatory Parameters

Correlation analyses indicated that plasma resistin levels had a significant positive correlation with some immune and inflammatory parameters when we analyzed the HIV-1-infected and uninfected subjects separately: TNFR1 (r = 0.294; P < 0.001) in the infected patients and IL-6 in both the infected (r = 0.163; P = 0.006) and uninfected subsets (r = 0.83; P = 0.025). Moreover, when the infected subjects were categorized according to the presence or absence of lipodystrophy, plasma resistin levels significantly correlated with TNFR1, CD4 T-cell count, insulin, HOMA-IR, and LDL cholesterol in the nonlipodystrophy subset, whereas in the lipodystrophy subgroup, significant correlations were observed with TNFR1, insulin, and HOMA-IR (Table 3). Patients with lipodystrophy were further categorized according the type of fat redistribution. In subjects with pure lipoatrophy, plasma resistin levels correlated positively with insulin (r = 0.435; P = 0.018) and HOMA-IR (r = 0.382; P = 0.041). In patients with mixed lipodystrophy, significant correlations were observed with TNFR1 (r = 0.323; P = 0.001), insulin (r = 0.351; P < 0.001), and HOMA-IR (r = 0.313; P = 0.002).



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Implication of Rest −420C>G SNP in HIV-1 Infection and in Lipodystrophy

Genotype distribution and allele frequencies in the complete cohort were in accordance with the expected Hardy-Weinberg equilibrium. Table 4 shows the results of the association studies performed among the risk of infection, risk of lipodystrophy, and rest −420C>G polymorphism. Genotype distribution showed nonsignificant differences between UC and HIV-1-infected subjects categorized as a whole (P = 0.1 for genotype analyses; P = 0.27 for allele analyses). Among the infected group, the distribution of the rest −420G>C SNP was significantly different between LD+ and LD− patients (P = 0.037 for genotypes containing the variant G allele); allele analyses showed, however, nonsignificant differences (P = 0.28). We also assessed associations between the rest −420C>G and several different metabolic outcomes (see Table 2 for categorization), and a significant association was observed between carriage of genotypes containing the rest-420C variant allele and hyperinsulinemia (P = 0.017). Genotype distribution by other metabolic end points showed nonsignificant associations (data not shown).



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Effect of the Rest −420 C>G Genotype and Other Determinants on Plasma Resistin Levels

The association between the rest -420 C>G genotype and plasma resistin levels was first evaluated in the full study group (UC+HIV-1 infected). We included in the model the variables that were available in all 474 individuals studied: resistin, rest -420 C>G genotype, age, sex, HIV-1 infection, TNFR1, TNFR2, and IL-6. Univariate analysis showed a significant association between plasma resistin and the rest -420 C>G genotype (P = 0.001) but, when adjusting for confounding factors, the association was no longer significant (P = 0.48). In fact, in the multivariate analysis, the variables significantly associated with plasma resistin levels were plasma levels of TNFR1 (P < 0.0001) and TNFR2 (P = 0.024) and the presence of HIV-1 infection (P = 0.001).

We also explored assessed the association between the rest -420 C>G genotype and plasma resistin levels in the infected subset. The model included all clinical and analytical variables reflected in Table 1 and in Table 2. In the univariate analysis, the association between the rest -420 C>G genotype and plasma resistin levels was near-significant (P = 0.08), but after adjusting for confounding, this association was nonsignificant (P = 0.48). In the multivariate analysis in the HIV-1-infected subset, plasma resistin levels were significantly associated with CD4 T-cell count (P = 0.046), plasma TNFR1 (P < 0.0001) and TNFR2 (P = 0.025) levels, cumulative time on stavudine (P = 0.009), and presence of lipodystrophy (P < 0.0001).

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Factors Associated With Lipodystrophy

The independent predictors of lipodystrophy in the infected subset were assessed. Variables included in the multivariate analysis were age, BMI more than 25, waist-to-hip circumference ratio, AIDS stage, risk factor for HIV infection, duration of HIV-1 infection, CD4+ T-cell gain, duration of cART, consumption of NRTI before cART, consumption and cumulative time of PI, NRTI, nonnucleoside reverse transcriptase inhibitor, d4T, and AZT, HCV infection, plasma resistin levels, and resistin genotype. The consumption and cumulative time of each antiretroviral drug were expressed in intervals of time. The length of time of d4T exposure was the only independent factor associated with lipodystrophy [for more of 48 months, odds ratio (95% confidence interval): 32.6 (4.3-250.6); P = 0.001). This result did not change when plasma resistin levels, and resistin genotyping were not included in the analysis.

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This is the first report to assess the involvement of both circulating resistin and resistin gene polymorphism together in cART-treated HIV-1-infected patients with lipodystrophy and metabolic disturbances. We found that the rest −420C>G SNP may be implicated in the development of lipodystrophy in HIV-1-infected subjects treated with cART but not in the vulnerability to HIV-1 infection. The rest −420G>C SNP genotype is not an independent modulator of plasma resistin levels in HIV-1-infected subjects either with or without lipodystrophy. We have also revealed that there is a systemic excess production of resistin in infected patients under cART, which is greater in patients without lipodystrophy. Among patients with lipodystrophy, plasma resistin levels are greater in patients with pure lipoatrophy. In infected subjects, resistin correlates with abnormal carbohydrate metabolism parameters, both in patients with and without lipodystrophy. We have shown that in HIV-1-infection, the duration of stavudine exposure, plasma tumor necrosis factor, and lipodystrophy are the strongest independent determinants of plasma resistin levels. We have confirmed the high prevalence of metabolic disturbances in lipodystrophy.21,26 Finally, our study agrees with previous reports that related lipodystrophy in HIV-1-infected subjects under cART with more advanced disease defined by Centers for Disease Control and Prevention classification, with a robust CD4+ T-cell gain and with the amount of d4T exposure.26

Because not all HIV-1-infected patients treated with cART develop lipodystrophy and/or metabolic perturbations, a host genetic individual vulnerability has been proposed. Among candidate genes, IL-6,24 TNF-α,25,27-29 APOE,29 APOC3,29 β3-Adrenergic receptor,30 PPARγ,31 and resistin,18 among others, have been investigated. In this study, we have assessed the effect of a resistin promoter genetic variant. The rationale behind this study is the convincingly demonstrated modulator effect that the rest −420C>G SNP and resistin exert in obesity, hyperglycemia, insulin resistance, and dyslipidemia in uninfected subjects.15,32-37 Our data indicate that the rest −420C>G SNP may be implicated in the development of lipodystrophy in HIV-1-infected patients on cART. This confirms the results provided in a previous study by Ranade et al18 who reported that variability within the resistin gene was implicated in HIV-1-related lipodystrophy, but in their study, this was due to a genetic variation at position +156 (C>T, rs3219177), whereas in our cohort, the association was with polymorphism at position −420 (C>G, rs1862513). However, our positive association findings are based in a single contrast only (genotype analyses, allele analyses found no such association) and, as pointed out elsewhere,38 genetic associations based in a single contrasts are less likely to be further replicated than those based in double contrasts.

An additional finding in our study was that the distribution of resistin genetic variants was nonsignificantly differently distributed between the infected and uninfected population. Our data hence suggest that the rest −420C>G SNP is not involved in the vulnerability of HIV-1 infection. The rationale behind this assessment comes from recent reports that have shown that immune cells may be targets for resistin39 and that resistin may be involved in innate immunity.40,41 Because both innate and acquired immune responses are involved in the initial steps of HIV-1 infection, it is biologically plausible to investigate the possible modulating effects of resistin polymorphisms on the vulnerability to HIV-1 infection. However, our data indicate that the rest −420C>G SNP is not implicated in the vulnerability to HIV-1 infection.

Few reports have assessed whether resistin is involved in body fat and metabolic disturbances that occur in HIV-1-infected patients.10-13 A seminal study by Kamin et al10 showed that resistin production was increased in patients with cART-related lipoatrophy and metabolic abnormalities. In this study, plasma resistin levels decreased after a 12-week course of rosiglitazone, together with an improvement in the metabolic disorders.10 These findings, however, were not further replicated in another study, which failed to find significant correlations among plasma resistin levels, inflammatory markers, lipodystrophy, and metabolic abnormalities.11 Hence, whether resistin is involved in this issue is controversial. In this respect, our data show that there is a systemic excess production of resistin in HIV-1-infected patients treated with cART. Because we have not assessed untreated patients, it is not possible to ascertain whether this is a result of the inflammatory environment that accompanies HIV-1 infection or the antiretroviral drugs used, or both. We also observed a weak but a significant increase in plasma resistin levels in patients without lipodystrophy, compared with those with lipodystrophy. Metabolic abnormalities do not explain this difference because they were less prevalent in the nonlipodystrophic subset. Nor the explanation can be sought in immunovirologic data because both viral load and CD4+ T-cell count were nonsignificantly different in patients with and without lipodystrophy. In addition, we observed no correlations between plasma resistin and viral load and CD4+ T-cell count. Hence, this was a surprising and unexpected observation in our study, and we have no clear explanation for this finding. We found a significant positive correlation among plasma resistin, insulin, and insulin resistance; the more resistin, the more insulin and insulin resistance. Because this was observed in the lipodystrophy subset of patients (as well as in patients without lipodystrophy), we confirm here the relationship between resistin and carbohydrate metabolic abnormalities provided by Kamin et al10 in lipoatrophy patients. Note that all 143 patients with lipodystrophy assessed in our study had the lipoatrophy component of the syndrome.

In our study, lipodystrophy patients had higher values of insulin, HOMA, and lipids, but resistin was lower compared with nonlipodystrophy subjects. When we divided the lipodystrophy subset according to the presence of lipoatrophy and/or lipohypertrophy, patients with pure lipoatrophy had significantly higher plasma resistin values than patients with mixed lipodystrophy (lipoatrophy plus lipohypertrophy), whereas metabolic and inflammatory parameters did not differ between these 2 groups. This contrasts with what was recently reported in other studies in uninfected patients, in which resistin correlated with obesity (reminiscent of lipohypertrophy) and insulin resistance.15,42 Although it is difficult to ascertain the reason of this apparent paradoxical behavior of resistin in lipohypertrophy, it could be hypothesized that the overproduction of resistin in treated HIV-1-infected patients may overshadow the effect of the different lipodystrophy phenotypes on circulating resistin.

Our study has some limitations. First, the cross-sectional nature of our design provides associations, not causality. Further studies are warranted to elucidate the mechanisms by which resistin exerts its effects with respect to HIV-1 infection. Second, our positive genetic association findings have been found in genotype analyses and not in allele analyses; hence, they have less chance to be replicated in subsequent studies. Finally, the fact that our control group comprised individuals with no known risk factors for HIV-1 infection means that our findings should be interpreted with great caution. The best control group to assess this issue would have been composed of exposed uninfected individuals.

In summary, when taken together, our data suggest that genetic variability within the resistin gene may be associated with cART-related lipodystrophy in HIV-1-infected patients. The vulnerability to HIV-1 infection is not modulated by the resistin genetic background. HIV-1 infection and/or cART carry an increased systemic resistin production. Carbohydrate metabolism disturbances in HIV-1-infected patients treated with cART, either with or without lipodystrophy, correlate with resistin.

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The authors thank other members of the HIV Lipodystrophy Study Group and contributors to this article: Alba Aguilar, Teresa Auguet, Matilde R. Chacón, Anna Megia, Merce Miranda, Carles Olona, Montserrat Vargas, Ignacio Velasco (Hospital Universitari Joan XXIII, IISPV and Universitat Rovira i Virgili, Tarragona, Spain); Pedro Pardo, Gerard Aragonés, Sandra Parra (Hospital Universitari de Sant Joan, IISPV and Universitat Rovira i Virgili, Reus, Spain); Àngels Fontanet, Mar Gutiérrez, Gràcia Mateo, Jessica Muñoz, Ma Antònia Sambeat (Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona, Barcelona, Spain). They greatly appreciate the comments and criticisms of the anonymous reviewers that greatly helped them to improve the manuscript.

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1. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409:307-312.
2. Satoh H, Nguyen MT, Miles PD, et al. Adenovirus-mediated chronic “hyper-resistinemia” leads to in vivo insulin resistance in normal rats. J Clin Invest. 2004;114:224-231.
3. Way JM, Gorgun CZ, Tong Q, et al. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor agonists. J Biol Chem. 2001;276:25651-25653.
4. Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, et al. Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab. 2003;88:5452-5455.
5. Youn BS, Yu KY, Park HJ, et al. Plasma resistin concentrations measured by enzyme- linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004;89:150-156.
6. Silha JV, Krsek M, Skrha JV, et al. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol. 2003;149:331-335.
7. Lee JH, Chan JL, Yiannakouris N, et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab. 2003;88:4848-4856.
8. Heilbronn LK, Rood J, Janderova L, et al. Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J Clin Endocrinol Metab. 2004;89:1844-1848.
9. Vozarova de Court, Degawa-Yamauchi M, Considine RV, et al. High serum Resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians. Diabetes. 2004;53:1279-1284.
10. Kamin D, Hadigan C, Lehrke M, et al. Resistin levels in human immunodeficiency virus-infected patients with lipoatrophy decrease in response to rosiglitazone. J Clin Endocrinol Metab. 2005;90:3423-3426.
11. Barb D, Wadhwa SG, Kratzsch J, et al. Circulating resistin levels are not associated with fat redistribution, insulin resistance, or metabolic profile in patients with the highly active antiretroviral therapy-induced metabolic syndrome. J Clin Endocrinol Metab. 2005;90:5324-5328.
12. Spagnuolo MI, Bruzzese E, Vallone GF, et al. Is resistin a link between highly active antiretroviral therapy and fat redistribution in HIV-infected children? J Endocrinol Invest. 2008;31:592-596.
13. Resino S, Micheloud D, Lorente R, et al. Adipokine profiles and lipodystrophy in HIV-infected children during the first 4 years on highly active antiretroviral therapy. HIV Med. 2011;12:54-60.
14. Osawa H, Tabara Y, Kawamoto R, et al. Plasma resistin, associated with single nucleotide polymorphism -420 is correlated with insulin resistance, lower HDL cholesterol, and high-sensitivity C reactive protein in the Japanese general population. Diabetes Care. 2007;30:1501-1506.
15. Li M, Fisette A, Zhao XY, et al. Serum resistin correlates with central obesity but weakly with insulin resistance in Chinese children and adolescents. Int J Obes (Lond). 2009;33:424-439.
16. Manduteanu I, Dragomir I, Calin M, et al. Resistin up-regulates fractalkine expression in human endothelial cells: Lack of additive effect with TNF-α. Biochem Biophys Res Commun. 2009;381:96-101.
17. Tang NP, Wang LS, Yang L, et al. A polymorphism in the Resistin gene promoter and the risk of coronary artery disease in a Chinese population. Clin Endocrinol. 2008;68:82-87.
18. Ranade K, Geese WJ, Noor M, et al. Genetic analysis implicates resistin in HIV lipodystrophy. AIDS. 2008;22:1561-1568.
19. Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia and diabetes mellitus: a cohort study. Lancet. 1999;353:2093-2099.
20. Christeff N, Melchior JC, de Truchis P, et al. Lipodystrophy defined by a clinical score in HIV-infected men on highly active antiretroviral therapy: correlation between dyslipidaemia and steroid hormone alterations. AIDS. 1999;13:2251-2260.
21. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis. 2001;32:130-139.
22. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National health and Nutrition Examination. JAMA. 2002;287:356-359.
23. Mattews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419.
24. Saumoy M, López-Dupla M, Veloso S, et al. A study on the IL-6 system in HIV-1-infected patients. AIDS. 2008;22:893-896.
25. Auguet T, Vidal F, López-Dupla M, et al. A study on the TNF-α system in Caucasian Spanish patients with alcoholic liver disease. Drug Alcohol Depend. 2008;92:91-99.
26. HIV Lipodystrophy Case Definition Study Group. An objective case definition of lipodystrophy in HIV-infected adults: a case-control study. Lancet. 2003;361:726-735.
27. Maher B, Alfirevic A, Vilar FJ, et al. TNF-α promoter region gene polymorphisms in HIV-positive patients with lipodystrophy. AIDS. 2002;16:2013-2018.
28. Nolan D, Moore C, Castley A, et al. Tumor necrosis factor-alpha gene -238G/A promoter polymorphism associated with a more rapid onset of lipodystrophy. AIDS. 2003;17:121-122.
29. Tarr PE, Taffé P, Bleiber G, et al. Modeling the influence of APOC3, APOE and TNF polymorphisms on the risk of antiretroviral therapy-associated lipid disorders. J Infect Dis. 2005;191:1419-1426.
30. Vonkeman HE, Napel CHH, Oeveren-Dybicz AM, et al. β3-Adrenergic receptor polymorphism and the antiretroviral therapy-related lipodystrophy syndrome. AIDS. 2000;14:1463-1464.
31. Saumoy M, Veloso S, Alonso-Villaverde C, et al. PPARγ Pro12Ala polymorphism in HIV-1-infected patients with HAART-related lipodystrophy. Curr HIV Res. 2009;7:533-540.
32. Won JC, Park CY, Lee WY, et al. Association of plasma levels of resistin with subcutaneous fat mass and markers of inflammation but not with metabolic determinants or insulin resistance. J Korean Med Sci. 2009;4:695-700.
33. Makino H, Shimizu I, Murao S, et al. A pilot study suggests that the G/G genotype of resistin single nucleotide polymorphism at -420 may be an independent predictor of a reduction in fasting plasma glucose and insulin resistance by pioglitazone in type 2 diabetes. Endocr J. 2009;56:1049-1058.
34. Baba T, Endo T, Sata F, et al. The contributions of resistin and adiponectin gene single nucleotide polymorphisms to the genetic risk for polycystic ovary syndrome in a Japanese population. Gynecol Endocrinol. 2009;25:498-503.
35. Osawa H, Ochi M, Tabara Y, et al. Serum resistin is positively correlated with the accumulation of metabolic syndrome factors in type 2 diabetes. Clin Endocrinol (Oxf). 2008;1:74-80.
36. Ochi M, Osawa H, Hirota Y, et al. Frequency of the G/G genotype of resistin single nucleotide polymorphism at -420 appears to be increased in younger-onset type 2 diabetes. Diabetes. 2007;56:2834-2838.
37. Asano H, Izawa H, Nagata K, et al. Plasma resistin concentration determined by common variants in the resistin gene and associated with metabolic traits in an aged Japanese population. Diabetologia. 2010;53:234-246.
38. Ioannidis JP, Ntzani EE, Trikalinos TA, et al. Replication validity of genetic association studies. Nat Genet. 2001;29:306-309.
39. Nagaev I, Bokarewa M, Tarkowski A, et al. Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes. PLoS One. 2006;1:e31.
40. Anderson PD, Mehta NN, Wolfe ML, et al. Innate immunity modulates adipokines in humans. J Clin Endocrinol Metab. 2007;92:2272-2279.
41. Kopp A, Buechler C, Neumeier M, et al. Innate immunity and adipocyte function: ligand-specific activation of multiple Toll-like receptors modulates cytokine, adipokine, and chemokine secretion in adipocytes. Obesity (Silver Spring). 2009;17:648-656.
42. Gharibeh MY, Al Tawallbeh GM, Abboud MM, et al. Correlation of plasma resistin with obesity and insulin resistance in type 2 diabetic patients. Diabetes Metab. 2010;36:443-449.

HIV; combination antiretroviral therapy; lipodystrophy; resistin; insulin resistance

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