Insulin resistance is a central feature of metabolic syndrome and a powerful driver of type 2 diabetes and cardiovascular disease. In the modern antiretroviral therapy era, people living with HIV increasingly face a heightened burden of metabolic disorders, often at younger ages than the general population. While the shift to integrase strand transfer inhibitor-based regimens has dramatically improved viral suppression and drug tolerability, these regimens have also been linked to disproportionate weight gain and metabolic dysfunction, particularly among women. Understanding how sex, HIV, and related biological pathways interact to influence insulin resistance is therefore a pressing question for populations shouldering a dual burden of infectious and non-communicable diseases.

The research team recruited participants from the medical outpatient clinic between August 2023 and April 2024. People living with HIV had to have been on antiretroviral therapy for at least six months and achieved viral suppression, defined as a viral load below 50 copies per milliliter. Participants with conditions that could distort metabolic or inflammatory measurements, such as pregnancy, active malignancy, acute infections, or severe renal or hepatic disease, were excluded. After an overnight fast of eight to twelve hours, blood samples were collected and processed within two hours, with plasma and serum aliquots stored at minus 80 degrees Celsius until analysis.

In the laboratory, fasting glucose and lipid profiles were measured with automated clinical chemistry analyzers, while fasting insulin was quantified by immunoassay. HOMA-IR was calculated from fasting insulin and glucose values, with participants classified as insulin resistant at a threshold of 1.9 or above. The team also measured high-sensitivity C-reactive protein and interleukin-17A, a pro-inflammatory cytokine linked to Th17 immune responses, as well as angiotensin II, the primary effector peptide of the renin-angiotensin system, which has been implicated in promoting insulin resistance by interfering with insulin signaling and inducing oxidative stress in skeletal muscle and adipose tissue. All enzyme-linked immunosorbent assays were performed in duplicate with intra-assay coefficients of variation below 8 percent.

The cohort comprised 79 men and 154 women, with comparable median ages of roughly 48 years. Women carried a less favorable adiposity profile, with a higher mean body mass index of 26.9 versus 23.5 kilograms per square meter and larger waist circumferences of 88.3 versus 83.2 centimeters, indicating greater central obesity. Women also showed higher fasting insulin levels and higher HOMA-IR scores, together with a higher prevalence of insulin resistance at 17.5 percent compared with 12.7 percent in men. Inflammatory markers trended higher among women, although the variability was substantial, while men exhibited markedly higher alanine aminotransferase levels, hinting at sex-specific hepatic or metabolic stress.

The adjusted regression analysis for the overall population delivered two striking results. Female sex was independently associated with higher HOMA-IR, with a beta coefficient of 0.95 and a p-value of 0.037, while HIV-positive status was independently associated with lower HOMA-IR, with a beta of minus 1.54 and a p-value of 0.046. Hypertension, triglycerides, estimated glomerular filtration rate, angiotensin II, and interleukin-17A were not independently associated with insulin resistance in the combined model. The inverse HIV association was particularly pronounced among women, where HIV-positive status remained significantly linked to lower HOMA-IR after adjustment, with a beta of minus 2.31 and a p-value of 0.049.

Sex-stratified analyses revealed further divergence. Among men, hypertension was independently associated with higher HOMA-IR, with a beta of 0.61 and a p-value of 0.019, while higher estimated glomerular filtration rate was linked to lower insulin resistance, with a beta of minus 0.01 and a p-value of 0.029. This supports the well-established bidirectional relationship between hypertension and insulin resistance, in which insulin resistance promotes endothelial dysfunction, sympathetic nervous system activity, and oxidative stress, all of which can elevate blood pressure. The kidney finding suggests that impaired renal function, increasingly recognized as both a consequence and a contributor to insulin resistance through chronic inflammation, oxidative stress, and altered insulin clearance, may be an important metabolic correlate in men but not in women.

The authors caution that several findings warrant careful interpretation. Neither angiotensin II nor interleukin-17A was independently associated with HOMA-IR, a result that contrasts with experimental evidence implicating renin-angiotensin system activation and inflammatory pathways in insulin resistance. The researchers note that circulating biomarker concentrations may not fully capture tissue-level activity, and the cross-sectional design precludes any inference about temporal relationships. They also emphasize that the apparent sex differences were not formally tested for interaction, so statistical significance in one sex but not the other does not confirm true effect modification. The relatively small male subgroup of 79 participants may have reduced statistical power and produced less stable regression estimates.

The relatively low mean HOMA-IR values observed in this Zambian cohort also merit attention. Similar findings have been reported in other sub-Saharan African populations and may reflect differences in body composition, dietary patterns, physical activity, and genetic background compared with Western populations, where HOMA-IR thresholds of 2.5 to 3.0 are commonly applied. The authors suggest that thresholds derived from European and North American populations may not be directly applicable to African populations, underscoring the need for population-specific reference values in metabolic risk assessment.

Despite these limitations, the study offers a valuable exploratory framework for understanding sex-specific metabolic risk in African populations affected by HIV. The absence of data on physical activity, dietary intake, and menopausal status, particularly important given the median female age of 48 years, leaves open the question of whether the observed patterns reflect biological sex differences, lifestyle factors, hormonal status, or their interactions. The authors call for larger, adequately powered studies integrating comprehensive lifestyle, hormonal, inflammatory, and treatment-related assessments. In the meantime, the findings argue for incorporating sex-specific considerations into the assessment and management of insulin resistance, particularly in populations living with HIV, where metabolic risk pathways may diverge sharply between men and women.

Subject of Research: Sex differences in insulin resistance and associated metabolic and inflammatory markers among adults with and without HIV in Zambia

Article Title: Sex differences in insulin resistance and associated metabolic and inflammatory markers among adults with and without HIV in Zambia

Article References: Sibbenga, F., Chisompola, D., Chipuma, M., Chakulya, M., Lwiindi, P., Liamba, M. A., Hamooya, B. M., Povia, J. P., Liweleya, S., & Masenga, S. K. (2026). Sex differences in insulin resistance and associated metabolic and inflammatory markers among adults with and without HIV in Zambia. Physiological Reports, 14(17), Article e71093. https://doi.org/10.14814/phy2.71093

Image Credits: AI Generated

DOI: 10.14814/phy2.71093

Keywords: insulin resistance, HOMA-IR, HIV, Zambia, sex differences, hypertension, kidney function, angiotensin II, interleukin-17A, antiretroviral therapy, metabolic syndrome, inflammation