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

Type 2 diabetes mellitus is a serious global health problem that is hard to treat in the long term, prompting great efforts to find new drug targets. Little attention has been paid, however, to the metabolic significance of the microcirculation in insulin-sensitive tissues, despite the fact that microvascular insulin resistance and endothelial dysfunction are closely associated and have been shown to precede Type 2 diabetes [1]. Endothelial nitric oxide plays a major role in mediating the beneficial effects of insulin on capillary recruitment and muscle glucose uptake [2] and in suppression of inflammatory pathways, including those activated by a high-fat diet [3]. Nitric oxide acts by increasing intracellular levels of cyclic guanosine monophosphate (cGMP), and treatments that amplify nitric oxide-cGMP signalling could thus be expected to improve peripheral microcirculation and glucose uptake. cGMP is hydrolysed by phosphodiesterase-5, and evidence from animal models and men with erectile dysfunction suggests that phosphodiesterase-5 inhibition may promote metabolic benefits [4]. We previously showed that acute treatment with the phosphodiesterase-5 inhibitor tadalafil induces increased capillary recruitment and muscle glucose uptake in people with Type 2 diabetes in the fasting state [5]. In the present study, we investigated whether tadalafil induces positive vascular, metabolic and antiinflammatory effects in the hyperinsulinaemic state after a mixed meal in people with Type 2 diabetes. Between 2008 and 2011, we recruited men and women with well-controlled Type 2 diabetes. Participants were randomized to receive either placebo (n = 10) or 20 mg tadalafil (n = 10) 30 min before they received a mixed meal (Fig. S1). We followed the participants before (baseline) and for up to 180 min after the meal using plethysmography for blood flow measurements, intramuscular microdialysis for interstitial glucose concentrations, and venous and arterial blood sampling for circulating concentrations of glucose,