title: Superior Glucose Tolerance and Metabolomic Profiles, Independent of Adiposity, in HIV-Infected Women Compared With Men on Antiretroviral Therapy.
abstract: In epidemiologic studies, human immunodeficiency virus (HIV)-infected men on antiretroviral therapy (ART) are at higher risk of incident diabetes mellitus compared with women with similar treatment histories. We used metabolomics to determine whether a sex difference in plasma amino acids, acylcarnitines, and organic acids predictive of diabetes and impaired energy metabolism is present in HIV-infected persons on long-term ART.We enrolled 70 HIV-infected adults (43% women) on efavirenz, tenofovir, and emtricitabine (Atripla) with HIV-1 RNA <50 copies/mL for over 2 years. Half of the HIV-infected subjects were obese, and these were matched with 30 obese HIV-negative controls. All subjects had no history of diabetes, statin use, or heavy alcohol use. Fasting insulin sensitivity was measured using homeostatic model assessment 2 (HOMA2), and adipose tissue was measured using dual-energy x-ray absorptiometry (DEXA). Liquid chromatography/mass spectrometry was used to quantitate fasting plasma branched chain and aromatic amino acids predictive of incident diabetes, and C3 and C5 acylcarnitinines and organic acids indicative of impaired energy metabolism.HIV-infected women had more baseline risk factors for insulin resistance: women were older (46 vs 44 years) and had a longer ART duration (8.4 vs 5.1 years, P < 0.05 for both) compared with men but had similar CD4+ count (median 701 cells/μL), smoking and hepatic C prevalence, and body mass index (BMI) (median 30.3 kg/m). However, women had higher insulin sensitivity compared with men (P < 0.01), and lower plasma levels of isoleucine, leucine, valine, phenylalanine, and tyrosine (P < 0.01 for all), and lower C3 and C5 acylcarnitines (P < 0.01 for all), in multivariable regression models after adjusting for DEXA fat mass index, age, race, CD4+ count, smoking, and ART duration. In the obese HIV-infected subjects and HIV-negative controls, the relationship of sex and plasma metabolite levels did not significantly differ according to HIV-status.HIV-infected women on non-nucleoside reverse transcriptase inhibitor-based ART had superior glucose tolerance and lower plasma metabolites associated with the development of diabetes compared with men with similar metabolic disease risk profiles. The relationship between sex and plasma metabolite levels did not significantly differ according to HIV-status among obese subjects, suggesting the observed sex-differences may not be specific to HIV infection.
authors.affiliation: From the Division of Infectious Diseases (JRK, TRS); Department of Biostatistics (CAJ, BES), Vanderbilt University School of Medicine, Nashville, TN; and Sanford Burnham Prebys Metabolomics Core at the Southeast Center for Integrated Metabolomics, University of Florida (CP, JC), Gainesville, FL.
authors.forename: John R
authors.initials: JR
authors.lastname: Koethe
authors.forename: Cathy A
authors.initials: CA
authors.lastname: Jenkins
authors.forename: Christopher
authors.initials: C
authors.lastname: Petucci
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Culver
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Shepherd
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Sterling
mesh_terms: D015502:Absorptiometry, Photon; D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity; D000328:Adult; D000597:Amino Acids, Branched-Chain / Q000097:blood; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism*; D018791:CD4 Lymphocyte Count; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D016022:Case-Control Studies; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000821:virology; D005215:Fasting / Q000097:blood; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D018023:HIV Seronegativity; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D055442:Metabolome; D008875:Middle Aged; D009765:Obesity / Q000150:complications; D012044:Regression Analysis; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors
chemical_list: D000597:Amino Acids, Branched-Chain; D044966:Anti-Retroviral Agents; D001786:Blood Glucose; D018894:Reverse Transcriptase Inhibitors; C116917:acylcarnitine; D002331:Carnitine