Biological sex affects human islet gene expression and mitochondrial function in type 2 diabetes

Area of Science:

• Endocrinology
• Metabolic Diseases
• Human Genetics

Background:

• Type 2 diabetes (T2D) exhibits sex-specific clinical characteristics and pathogenesis.
• Understanding biological sex's impact on human islets is crucial for developing effective T2D treatments.
• Existing research has not fully elucidated the sex-dependent mechanisms underlying T2D.

Purpose of the Study:

• To investigate sex differences in human islet characteristics in individuals without and with type 2 diabetes.
• To identify how biological sex influences islet structure, gene expression, and function in the context of T2D.
• To compare islet alterations between males and females living with T2D.

Main Methods:

• Integrated analysis of publicly available human islet datasets (HPAP, Humanislets.com).
• Comparative analysis of islet cell composition, gene expression (ribosomal, mitochondrial pathways), and protein expression between sexes.
• Assessment of mitochondrial function, including spare respiratory capacity, in male and female islets.

Main Results:

• In donors without diabetes, female islets had more alpha-cells and enriched ribosomal/mitochondrial pathways.
• Female islets exhibited lower spare respiratory capacity compared to male islets.
• In T2D, female islets showed better preservation of insulin content and fewer functional defects than male islets.

Conclusions:

• Female islets demonstrate greater resilience and fewer impairments in type 2 diabetes compared to male islets.
• Significant sex-based differences exist in islet biology and response to T2D.
• Further mechanistic studies are needed to inform sex-specific T2D interventions.