SGLT2 inhibitors and mitochondrial function: a new avenue for an existing drug

Dr Elina Akalestou, Dr Luke Baker

Applications accepted all year round

Self-Funded PhD Students Only

About the Project

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are an established class of antidiabetic drugs that have demonstrated additional benefits beyond glycaemic control, including cardiovascular and renal protection. Despite growing clinical evidence of their multi-system effects, the underlying cellular and molecular mechanisms remain incompletely understood. Emerging evidence suggests that improvements in mitochondrial health may represent a key pathway through which SGLT2 inhibitors exert their protective actions. However, this hypothesis remains underexplored and poorly characterised, particularly in non-diabetic disease contexts.

Our preliminary data on SGLT2 inhibitor-treated mice indicate that suppression of SGLT2 expression reduces pro-inflammatory cytokines, independent of body weight and glycemia status (Brisnovali et al, 2025, Diabetologia), while tissue proteomics showed significant changes in mitochondrial function pathways. These findings suggest that SGLT2 inhibitors may directly or indirectly influence mitochondrial biology, raising the possibility that mitochondrial modulation could contribute to their therapeutic effects in cardiometabolic disease. The mechanistic basis of these changes is currently unknown and represents a critical gap in understanding the broader impact of this drug class.

This PhD project aims to investigate the effects of SGLT2 inhibitors on mitochondrial function and identify the molecular mechanisms underlying these changes. The central hypothesis is that SGLT2 inhibition improves mitochondrial efficiency and reduces oxidative stress through alterations in energy metabolism, redox signalling, and mitochondrial biogenesis pathways. To address this, the project will combine in vivo and in vitro approaches, including mitochondrial respiration assays, analysis of reactive oxygen species production, assessment of mitochondrial DNA content, and investigation of key regulatory pathways involved in mitochondrial dynamics and quality control. In addition, the project will explore whether observed mitochondrial changes are tissue-specific and whether they correlate with improvements in metabolic and inflammatory markers. By integrating functional, molecular, and biochemical analyses, the study aims to build a comprehensive understanding of how SGLT2 inhibitors interact with mitochondrial processes. This research has the potential to uncover a novel mechanism of action for a widely used drug class and provide important insights into how mitochondrial modulation may contribute to disease prevention and treatment. A clearer understanding of this mechanism could inform drug repurposing strategies and support the development of targeted therapies for conditions associated with mitochondrial dysfunction. Ultimately, the findings may help redefine the therapeutic potential of SGLT2 inhibitors beyond glucose lowering and contribute to improved treatment strategies for complex chronic diseases.

Training opportunities

The PhD student will receive structured training in essential laboratory including cell culture and drug treatment protocols, basic molecular biology methods such as RNA extraction, qPCR, and Western blotting. Training will also cover mitochondrial function assays, including measurement of respiration and oxidative stress markers. The student will be trained in tissue processing, histology, and immunostaining, alongside practical instruction in good laboratory practice, experimental design, and data recording. Additional training will include proteomics analysis, coding, statistical analysis, data interpretation, and the use of relevant software packages to ensure rigorous and reproducible research practice. Potential In vivo animal handling and dosing (subject to Home Office training and certification) and clinical trial involvement will also be available as part of the project.

Supervisor contact details:

Dr Elina Akalestou - ea355@le.ac.uk

Dr Luke Baker - lab69@le.ac.uk