Metabolic reprogramming and redox imbalance of innate immune cells in T1D: G6PD and immune dysfunction

Redox balance is essential for monocyte survival and function, ensuring pathogen clearance while preventing oxidative stress-induced damage. In people living with T1D (plwT1D), immune and metabolic dysregulation contribute to increased susceptibility to infections and tissue injury, potentially contributing to the emergence of T1D-associated complications. With funding from Diabetes UK we performed an ex vivo profiling of monocytes in T1D and identified a diminished glucose-6-phosphate dehydrogenase (G6PD) protein expression in plwT1D compared to people without diabetes, while other major metabolic enzymes remained unchanged. G6PD is the rate-limiting enzyme of the pentose phosphate pathway, a major source of NADPH, which is essential in maintaining redox homeostasis. Given than NADPH production underpins antioxidant defenses, in this studentship we hypothesize that decreased G6PD activity in T1D monocytes impairs redox balance, leading to oxidative stress and functional defects. To test this, a battery of ex vivo and in vitro experiments will be carried out and the experimental results will be correlated with in vivo measurements of glucose variability and other clinical parameters. This work aims to uncover a novel mechanism linking redox imbalance to G6PD dysfunction to immune function impairments in T1D, providing a rationale for therapeutic strategies targeting G6PD activity and NADPH metabolism.