Abstract
The clinical characteristics of type 2 diabetes (T2D) differ between the sexes. For example, the risk of T2D is higher in males than in premenopausal females, whereas the risk of T2D-associated cardiovascular disease is higher in females. Notwithstanding, the sex-dependent mechanisms of T2D pathogenesis remain incompletely understood. Publicly available human islet datasets, such as HPAP and Humanislets.com, are valuable tools for uncovering the impact of biological sex on islet structure, gene expression, and function at a scale that was not previously possible. We performed integrated analyses of data from public sources to identify sex differences in baseline islet characteristics in donors without diabetes and also in donors who lived with T2D. Among donors without diabetes, female islets had a greater proportion of alpha-cells compared with male islets and showed enriched expression of ribosomal and mitochondrial pathways in both beta-cells and alpha-cells. Measurements of mitochondrial function in female islets revealed lower spare respiratory capacity compared with male islets. Male and female islets had distinct changes in gene and protein expression in the context of T2D with female islets having greater preservation of insulin content and fewer defects in islet function. Together, these data show female islets have fewer impairments in T2D. This highlights the need for detailed mechanistic studies in both sexes to support effective and sex-informed interventions for T2D.