Adipose tissue dysfunction is central to the heightened cardiovascular risk observed in people with type 2 diabetes mellitus (T2DM), yet the biological mechanisms underpinning this remain poorly defined. This thesis presents a series of epidemiological and translational studies suggesting that the microvascular biology of subcutaneous adipose tissue (SAT), particularly endothelial senescence, is critical in driving adverse cardiometabolic phenotype and outcomes.
Using data from half a million people from the UK Biobank, I demonstrate that obesity and diabetes are independently and additively associated with more advanced cardiovascular disease and increased incidence of major adverse cardiovascular events. These outcomes only weakly correlate with conventional risk markers, underscoring the need for deeper mechanistic insights. To explore this, I perform detailed phenotyping of SAT and primary human SAT microvascular endothelial cells (hSATMVECs) from individuals with heart failure and/or T2DM. These studies show that SAT in this population is fibrotic with impaired angiogenesis and characterised by pronounced endothelial senescence. I go on to show that senescent hSATMVECs exhibit dysfunctional crosstalk with adipocytes, likely mediated by the senescence associated secretory phenotype which induces a pro-inflammatory adipocyte phenotype resistant to glucose uptake.
Finally, I demonstrate that the cardiac glycoside digoxin, at a clinically therapeutic concentration, reduces hSATMVEC senescence, improves healthy hSATMVEC–adipocyte crosstalk, and improves adipocyte function. These findings provide a strong foundation for the further investigation of SAT microvascular senescence as a therapeutic target in T2DM and suggest potential utility for repurposing digoxin as a novel senolytic therapy in this context.
