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Context: Sex hormone–binding globulin (SHBG) and testosterone are differentially associated with type 2 diabetes (T2D) risk.

Objective: This work aimed to investigate whether the associations between SHBG, testosterone, and T2D risk differ by HIV and menopausal status in Black African women living with HIV (WH) and without HIV (WOH).

Methods: This cross-sectional observational study took place at the Health Research Unit in Soweto, Johannesburg, South Africa. A total of 81 premenopausal (57 WOH, 24 WH) and 280 postmenopausal (236 WOH, 44 WH) women from the Middle-Aged Soweto Cohort (MASC) participated. Main outcome measures included circulating SHBG and sex hormones, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (Matsuda index), secretion (insulinogenic index) and clearance, and β-cell function (disposition index, DI). Dysglycemia was defined as either impaired fasting or postprandial glucose or T2D.

Results: SHBG was higher and total and free testosterone were lower in postmenopausal WH than WOH (all P ≤ .023). Irrespective of HIV serostatus, SHBG was positively associated with Matsuda index, insulin clearance, and DI and inversely with HOMA-IR (all P < .011). The association between SHBG and Matsuda index was stronger in premenopausal than postmenopausal women (P = .043 for interaction). Free testosterone (and not total testosterone) was only negatively associated with basal insulin clearance (P = .021) and positively associated with HOMA-IR (homeostatic model assessment of insulin resistance) in premenopausal and not postmenopausal women (P = .015 for interaction).

Conclusion: We show for the first time that midlife African WH have higher SHBG and lower total and free testosterone than WOH, which corresponded to their higher β-cell function, suggesting a putative protective effect of SHBG on T2D risk in WH.