Abstract
Testosterone deficiency is prevalent in men with type 2 diabetes (T2D) and is associated with greatly elevated risk of cardiovascular mortality. Testosterone replacement has beneficial effects on surrogate markers and risk factors of atherosclerosis including inflammation, cholesterol and insulin resistance improving survival in men with T2D. The underlying mechanisms of this action remain poorly understood. Inflammation is a central feature to both T2D and atherosclerosis and is driven by monocyte/macrophages, placing these immune cells at the crossroads of disease pathology. The recruitment of immune cells to atherosclerosis-prone areas of the vasculature is influenced by many factors including the inflammatory status of the circulating monocytes. The present study investigates the influence of testosterone replacement on monocyte inflammatory markers in a randomised double blinded placebo controlled clinical trial. 65 men with poorly controlled diabetes (HbA1c between 53 and 80 mmol/mol) and confirmed hypogonadism via early morning [0800−1200h] total testosterone ≤12 nmol/L or calculated free testosterone ≤255 pmol/L on two occasions ≥1 week apart, with at least two symptoms of hypogonadism were included in the study. Patients were randomly assigned to either placebo or treatment (depot testosterone undecanoate, 6 weekly followed by 3 monthly intramuscular injections) for 6 months. Monocytes were isolated from whole blood collected at baseline, 3 and 6 month visits followed by gene expression of key inflammatory targets IL-1β, IL-6, IL-10, TNFα, ICAM1, TLR2, TLR4, SCARB1 and MCP1 assessed via qPCR. Pro-inflammatory targets TNFα and MCP1 were significantly reduced over time in monocytes from patients treated with testosterone between 3 and 6 months (1.39±0.39 Vs 0.68±0.09, P<0.01; 15.36±7.79 Vs 1.88±0.93, P<0.01 respectively) and TNFα at 6 months compared to the start of the study (1.00±0.00 Vs 0.68±0.09, P<0.001) when normalised to baseline. TNFα expression was also significantly reduced compared to placebo treated patient monocytes at 6 months (0.68±0.09 Vs 3.45±1.50, P<0.01). Other targets were not significantly altered over time or between treatment groups. These findings importantly indicate for the first time that testosterone influences monocyte inflammatory activation in type 2 diabetic men by altering expression of the most potent atherogenic chemokine MCP1 and potent pro-inflammatory cytokine TNFα, as a potential mechanism to protect against atherosclerotic plaque development in hypogonadism.
Computational modeling of epiphany learning
