Postprandial effects of the phosphodiesterase‐5 inhibitor tadalafil in people with well‐controlled Type 2 diabetes mellitus: a randomized controlled trial

The overall aim of this thesis was to investigate the microcirculation in insulin resistance, with focus on the expression of endothelin-1, through a translational approach. Specific aims: 1) Investigate if circulating endothelin-1 levels predicts incident coronary heart disease events. 2) To assess if sex differences modify endothelin-1 as a predictor of type 2 diabetes. 3) To investigate if microvascular insulin resistance impairs insulin delivery to the subcutaneous adipose tissue and skeletal muscle. 4) To investigate if acute administration of the PDE-5 inhibitor tadalafil induces positive vascular, metabolic and anti-inflammatory effects in type 2 diabetes. 5) To further elucidate the molecular action of tadalafil in tumour necrosis factor-α (TNF-α) stimulated human endothelial cells. Principal findings: The population-based cohort in Vara-Skövde was investigated for paper I-II. During baseline cardiovascular risk factors and endothelin-1 were assessed and incident coronary heart disease (CHD) was followed-up during a 10-year period (paper I). Endothelin-1 levels had a predictive value for incident CHD in women, but not in men. A randomly selected subgroup was investigated in a follow-up after 10 years, and impaired glucose tolerance (IGT) and T2D was documented for paper II. Here, higher quartiles of endothelin-1 at baseline were associated with IGT/T2D at follow-up in women. Paper III investigates microvascular aspects of insulin resistance using microdialyis; participants with T2D and age-matched healthy controls were studied after an oral glucose load. Participants with T2D had decreased delivery of insulin to adipose tissue, and a blunted subcutaneous adipose tissue blood flow compared with controls. In paper IV, T2D participants received either placebo or tadalafil (20 mg) before a mixed meal in a randomized controlled trial. Tadalafil increased forearm blood flow, glucose uptake and capillary recruitment, and blunted a postprandial increase of endothelin-1. In paper V, the effects of tadalafil were studied in an experimental setting using TNF-α stimulated endothelial cells. Tadalafil treatment decreased expression of c-Jun N-terminal kinase (JNK) phosphorylation as well as reduced gene expression and secretion of endothelin-1. Conclusions: This thesis shows that (i) endothelial dysfunction precedes IGT/T2D and CHD, and that endothelin-1 may pose as a risk factor for women, (ii) delivery of insulin from the circulation to subcutaneous adipose tissue is impaired in participants with T2D, and that participants with T2D exhibit a blunted postprandial blood flow response, (iii) acute administration of tadalafil induces positive vascular and metabolic effects in the postprandial state in T2D, and tadalafil decrease gene expression of endothelin-1 in cultured endothelial cells by decreasing activation of JNK