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.

HIV-infected patients have metabolic abnormalities that put them at increased risk of cardiovascular disease (CVD), including abnormalities associated with HIV infection itself, antiretroviral treatment, restoration to health, and body composition changes. The 2 major components of dyslipidemia in HIV-infected patients are hypertriglyceridemia and reduction in high-density lipoprotein (HDL) cholesterol (with likely altered function of HDL cholesterol); these abnormalities contribute to increased atherosclerotic risk. Adverse effects of antiretroviral drugs on lipids are not class specific but rather are associated with particular drugs. Thus, practitioners need to be cognizant of the risks of metabolic abnormalities posed by individual drugs. HIV infection increases CVD risk independent of the effects of traditional risk factors. The relative risk of CVD in HIV-infected patients has decreased in recent years with increasing use of lipid-lowering therapy. However, use of lipid-lowering therapy is complicated by numerous potential drug interactions with antiretroviral drugs that practitioners need to consider when prescribing lipid-lowering therapy. This article summarizes a presentation made by Carl Grunfeld, MD, PhD, at the International AIDS Society-USA continuing medical education program in Los Angeles in March 2010. The original presentation is available as a Webcast at www.iasusa.org.

Phospholipids are required for epidermal lamellar body formation. Glycerol 3-phosphate acyltransferases (GPATs) catalyze the initial step in the biosynthesis of glycerolipids. Little is known about the expression and regulation of GPATs in epidermis/keratinocytes. Here, we demonstrate that GPAT 1, 3, and 4 are expressed in epidermis/keratinocytes, whereas GPAT2 is not detected. In mouse epidermis, GPAT 3 and 4 are mainly localized to the upper layers whereas GPAT1 is found in both the upper and lower layers. GPAT1 and 3 mRNA increase during fetal rat epidermal development. No change in GPAT expression was observed in adult mice following acute permeability barrier disruption. Calcium-induced human keratinocyte differentiation increased GPAT3 mRNA whereas both GPAT1 and 4 mRNA levels decreased. In parallel, total GPAT activity increased 2-fold in differentiated keratinocytes attributable to an increase in N-ethylmaleimide (NEM) sensitive GPAT activity localized to microsomes with little change in NEM resistant activity, consistent with an increase in GPAT3. Furthermore, PPARγ or PPARδ activators increased GPAT3 mRNA, microsomal GPAT activity, and glycerol lipid synthesis without affecting the expression of GPAT1 or 4. Finally, both PPARγ and PPARδ activators increased GPAT3 mRNA via increasing its transcription. Thus, multiple isoforms of GPAT are expressed and differentially regulated in epidermis/keratinocytes.

BACKGROUND

Some HIV protease inhibitors (PIs), including full-dose ritonavir (800 mg) and ritonavir-boosted lopinavir, acutely induce insulin resistance in the absence of HIV infection and changes in body composition. Boosting dose ritonavir (100-200 mg) is the most commonly prescribed PI, yet its effects on glucose metabolism have not been described in the absence of another PI.

METHODS

In this randomized, double-blind, cross-over study, a single dose of ritonavir 200 mg or placebo was given to healthy HIV-seronegative volunteers before assessment of insulin sensitivity by euglycemic hyperinsulinemic clamp.

RESULTS

Boosting dose ritonavir had no effect on insulin-mediated glucose disposal (M/I, placebo: 8.59 ± 0.83 vs. ritonavir: 8.51 ± 0.64 mg/kg per minute per μU/mL insulin, P = 0.89).

CONCLUSIONS

A single boosting dose of ritonavir does not alter insulin sensitivity, suggesting lopinavir is likely responsible for the induction of insulin resistance demonstrated in prior short-term studies of lopinavir/ritonavir. There is a dose-dependent effect of ritonavir on insulin sensitivity.

OBJECTIVE

to assess the associations between nucleoside reverse transcriptase inhibitors (NRTIs) and change in lipid levels among a large cohort of HIV-infected patients in routine clinical care initiating their first potent antiretroviral regimen.

DESIGN

longitudinal observational cohort study from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort.

METHODS

we used generalized estimating equations to examine the association between NRTIs and lipids accounting for within-patient correlations between repeated measures and key clinical and demographic characteristics including other antiretroviral medications.

RESULTS

among 2267 individuals who started their first antiretroviral regimen, tenofovir with emtricitabine or lamivudine was associated with lower levels for total cholesterol, low-density lipoprotein (LDL), triglycerides, non-high-density lipoprotein (HDL), and HDL, compared with other NRTI pairs in adjusted analyses. LDL levels were highest among patients receiving didanosine/lamivudine. Triglyceride levels were highest in stavudine/lamivudine users. HDL levels were highest among patients receiving didanosine/stavudine. Hepatitis C infection and younger age were also associated with lower lipid levels.

CONCLUSION

we found clinically important heterogeneity within the NRTI class of antiretroviral medications regarding their effect on lipid levels over time. Although the lipid profile of tenofovir with emtricitabine or lamivudine appeared to be less pro-atherogenic in this large longitudinal study of HIV-infected patients in routine clinical care, there was no association with beneficial HDL levels. In general, the change in lipid levels associated with most antiretroviral agents, particularly those NRTI combinations currently in common use, are relatively modest. Additional studies are needed to understand the long-term implications of these findings on cardiovascular disease risk.

OBJECTIVE

Patients with RA have systemic inflammation and increased risk of cardiovascular (CV) events, including thrombosis. Levels of fibrinogen, a pro-thrombotic protein with predictive value for CV disease (CVD), are elevated during systemic inflammation. We compared circulating fibrinogen levels in patients with RA with healthy controls and evaluated the relationship with measures of disease activity.

METHODS

Patients with RA and controls were recruited at the University of California, San Francisco (UCSF). Disease activity was evaluated using standard composite indices. Fibrinogen, ESR, serum CRP, acute-phase serum amyloid A and levels of selected cytokines were quantified.

RESULTS

A total of 105 RA patients and 62 controls were studied. Among patients with RA, disease activity ranged from quiescent to highly active disease. Circulating fibrinogen levels were significantly higher in RA than in controls [median (interquartile range) 466 (391-575) vs 367 (309-419) mg/dl, respectively, P < 0.0001]. This difference remained highly statistically significant after adjustment for demographic variables and BMI. Although fibrinogen correlated significantly with clinical measures of disease activity, significantly elevated levels were observed at low levels of activity, even in RA patients with no detectable swollen or tender joints. In multivariable models, ~ 80% of the increased fibrinogen in RA was accounted for by increases in CRP and ESR.

CONCLUSION

Circulating levels of fibrinogen are elevated in RA and correlated with markers of inflammation, but only modestly correlate with clinical assessments of disease activity. Even RA patients with excellent clinical disease control exhibit elevated levels compared with controls.

Inhibition of adipocyte triglyceride biosynthesis is required for fatty acid mobilization during inflammation. Triglyceride biosynthesis requires glycerol 3-phosphate and phosphoenolpyruvate carboxykinase (PEPCK) plays a key role. We demonstrate that LPS, zymosan, and TNF-α decrease PEPCK in liver and fat. Turpentine decreases PEPCK in liver, but not in fat. The LPS-induced decrease in PEPCK does not occur in TLR4 deficient animals, indicating that this receptor is required. The LPS-induced decrease in hepatic PEPCK does not occur in TNF receptor/IL-1 receptor knockout mice, but occurs in fat, indicating that TNF-α/IL-1 is essential for the decrease in liver but not fat. In 3T3-L1 adipocytes TNF-α, IL-1, IL-6, and IFNγ inhibit PEPCK indicating that there are multiple pathways by which PEPCK is decreased in adipocytes. The binding of PPARγ and RXRα to the PPARγ response element in the PEPCK promoter is markedly decreased in adipose tissue nuclear extracts from LPS treated animals. Lipopolysaccharide and zymosan reduce PPARγ and RXRα expression in fat, suggesting that a decrease in PPARγ and RXRα accounts for the decrease in PEPCK. Thus, there are multiple cytokine pathways by which inflammation inhibits PEPCK expression in adipose tissue which could contribute to the increased mobilization of fatty acids during inflammation.

OBJECTIVE AND DESIGN

The aim of this study was to examine the expression of G protein-coupled receptor 81 (GPR81) in mouse adipose tissue in response to inflammatory stimuli. GPR81 is activated by lactate resulting in the inhibition of lipolysis.

MATERIALS AND TREATMENT

Mice were injected with saline, lipopolysaccharide (LPS), zymosan, or turpentine, N = 5 per group. 3T3-L1 adipocytes were treated with tumor necrosis factor alpha, interleukin (IL)-l beta, IL-6, or interferon gamma.

METHODS

GPR81 expression levels were measured by real-time PCR and statistical significance was determined by Student's t test.

RESULTS

LPS resulted in a marked decrease in GPR81 mRNA level in mouse adipose tissue in C57BL/6 and OuJ mice, an effect that was not observed in HeJ mice, which have a mutation in TLR4. Zymosan and turpentine also decreased adipose tissue GPR81 expression. Cytokine treatment of 3T3-L1 adipocytes had no effect on GPR81 expression. GPR81 expression was decreased in ob/ob mice, an animal model of type 2 diabetes that is characterized by inflammation.

CONCLUSION

Inflammation decreases the expression of GPR81 in adipose tissue.

OBJECTIVE

Genetic studies may help explain abnormalities of fat distribution in HIV-infected patients treated with antiretroviral therapy (ARV).

METHODS

Subcutaneous adipose tissue (SAT) volume measured by MRI in the leg, the lower trunk, the upper trunk, and the arm was examined in 192 HIV-infected White men, ARV-treated from the Fat Redistribution and Metabolic Change in HIV infection study. Single-nucleotide polymorphisms were assayed using the Illumina Human CNV370-quad beadchip. Multivariate and univariate genome-wide association analyses of the four SAT depots were implemented in PLINK software adjusted for age and ARV duration. Functional annotation analysis using Ingenuity Systems Pathway Analysis tool was carried out for markers with P lower than 10(-3) near known genes identified by multivariate analysis.

RESULTS

Loci (rs10504906, rs13267998, rs921231) in or near the anion exchanger solute carrier family 26, member 7 isoform a (SLC26A7) were strongly associated with the upper trunk and the arm SAT (9.8×10(-7) ≤P<7.8×10(-6)). Loci (rs193139, rs7523050, rs1761621) in and near a gene-rich region including G-protein-signaling modulator 2 (GPSM2) and syntaxin-binding protein 3 (STXBP3) were significantly associated with the lower body SAT depots (9.9×10(-7) ≤P<9.5×10(-6)). GPSM2 is associated with cell division and cancer whereas STXBP3 is associated with glucose metabolism in adipoctyes. Ingenuity Systems Pathway Analysis identified atherosclerosis, mitochondrial function, and T-cell-mediated apoptosis as processes related to SAT volume in HIV-infected individuals (P<5×10(-3)).

CONCLUSION

Our results are limited by the small sample size and replication is needed; however, this genomic scan uncovered new genes associated with metabolism and inflammatory pathways that may affect SAT volume in ARV-treated HIV-infected patients.