Lower Concentrations of Circulating Medium and Long-Chain Acylcarnitines Characterize Insulin Resistance in Persons with HIV

Abstract

In human immunodeficiency virus (HIV)-negative individuals, a plasma metabolite profile, characterized by higher levels of branched-chain amino acids (BCAA), aromatic amino acids, and C3/C5 acylcarnitines, is associated with insulin resistance and increased risk of diabetes. We sought to characterize the metabolite profile accompanying insulin resistance in HIV-positive persons to assess whether the same or different bioenergetics pathways might be implicated. We performed an observational cohort study of 70 nondiabetic, HIV-positive individuals (50% with body mass index ≥30 kg/m²) on efavirenz, tenofovir, and emtricitabine with suppressed HIV-1 RNA levels (<50 copies/mL) for at least 2 years and a CD4⁺ count over 350 cells/μL. We measured fasting insulin resistance using the homeostatic model assessment 2, plasma free fatty acids (FFA) using gas chromatography, and amino acids, acylcarnitines, and organic acids using liquid chromatography/mass spectrometry. We assessed the relationship of plasma metabolites with insulin resistance using multivariable linear regression. The median age was 45 years, median CD4⁺ count was 701 cells/μL, and median hemoglobin A1c was 5.2%. Insulin resistance was associated with higher plasma C3 acylcarnitines (p = .01), but not BCAA or C5 acylcarnitines. However, insulin resistance was associated with lower plasma levels of C18, C16, C12, and C2 acylcarnitines (p ≤ .03 for all), and lower C18 and C16 acylcarnitine:FFA ratios (p = .002, and p = .03, respectively). In HIV-positive persons, lower levels of plasma acylcarnitines, including the C2 product of complete fatty acid oxidation, are a more prominent feature of insulin resistance than changes in BCAA, suggesting impaired fatty acid uptake and/or mitochondrial oxidation is a central aspect of glucose intolerance in this population.

Keywords: HIV; diabetes mellitus; insulin resistance; lipid metabolism; metabolomics.

FIG. 1.

Forest plot of multivariable regression coefficients for medium and long-chain acylcarnitines and insulin resistance. Model adjusted for age, sex, CD4⁺ count at enrollment (square root transformed), duration of antiretroviral treatment, smoking status, and fat mass index. The dependent variable (HOMA2) was log-transformed. HOMA, Homeostasis Model Assessment.

FIG. 2.

Forest plot of multivariable regression coefficients for C2, C3, and C5 acylcarnitines and insulin resistance. Model adjusted for age, sex, CD4⁺ count at enrollment (square root transformed), duration of antiretroviral treatment, smoking status, and fat mass index. The dependent variable (HOMA2) was log-transformed.