Tadalafil increases muscle capillary recruitment and forearm glucose uptake in women with type 2 diabetes

Abstract

Aims/hypothesisRecent evidence suggests that reduced synthesis of nitric oxide in endothelial cells, i.e. endothelial dysfunction, contributes to the impaired action of insulin in the vasculature of patients with type 2 diabetes. We investigated whether selective inhibition of phosphodiesterase-5 by tadalafil has beneficial effects on peripheral microcirculation and glucose uptake in these patients.MethodsWe enrolled seven postmenopausal women with type 2 diabetes and ten age-matched healthy women as controls in a placebo-controlled study to evaluate the acute metabolic effects of tadalafil. We performed microdialysis and blood flow measurements in muscle, and sampled arterial and deep venous blood before and after a single dose of tadalafil 20 mg or placebo. Circulating glucose and insulin levels, muscle capillary recruitment as reflected by permeability surface area for glucose (PSglu) and forearm glucose uptake were measured.ResultsIn women with type 2 diabetes, but not in the control group, tadalafil induced increases in the incremental AUC for PSglu (tadalafil vs placebo 41 ± 11 vs 4 ± 2 ml [100 g]−1 min−1, p < 0.05) and forearm glucose uptake (46 ± 9 vs 8 ± 4 µmol [100 g]−1 min−1, p < 0.05). The variable that best predicted forearm glucose uptake was PSglu, which explained 70% of its variance. However, fasting glucose and insulin concentrations were similar following treatment with placebo or tadalafil in the two groups.Conclusions/interpretationThis study suggests that tadalafil evokes positive metabolic effects in insulin-resistant women with type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-010-1819-4) contains supplementary material, which is available to authorised users.

Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy

“…Consistent with data reported in the pilot study conducted by Grover-Páez et al 20 with sildenafil, a lowering of HbA 1c upon treatment with PF-00489791 was also observed in the present study. Although the precise mechanism of HbA 1c reduction upon inhibition of PDE5 is unclear, preclinical and clinical studies suggest that PDE5 inhibition may favorably impact glucose metabolism in T2DM by mediating enhanced glucose uptake in skeletal muscle 22,23 improving b-cell function and decreasing insulin resistance. [24][25][26] Such mechanisms may eventually contribute to the improvement in microvascular disease and subsequent reduction of albuminuria in studies of longer treatment duration with PF-0048971.…”

Decreased Permeability Surface Area for Glucose in Obese Women with Postprandial Hyperglycemia: No Effect of Phosphodiesterase-5 (PDE-5) Inhibition

“…However, we were unable to demonstrate any acute eff ect on either vascular function or glucose uptake of the phosphodiesterase-5 (PDE-5) inhibitor tadalafi l. because NO promotes vasorelaxation by increasing the levels of cyclic guanosine monophosphate, that is normally degraded by PDE-5. We showed that tadalafi l increases permeability surface area for glucose, as well as forearm glucose uptake in type 2 diabetes patients [ 15 ] , suggesting PDE-5 inhibition as a novel candidate for treatment of type 2 diabetes. Interestingly, that study was performed after fasting overnight and not in states of moderately elevated glucose and insulin levels as usually observed following a meal.…”

“…Recent work from our laboratory showed that an intrabrachial infusion of methacholine, a potent stimulator of NO, improves forearm PS glu and glucose uptake in obese insulin-resistant subjects after an OGTT [ 14 ] , although forearm muscle blood fl ow was unchanged. Further, aiming to evaluate the metabolic eff ects of an amplifi ed NO-signal, the phosphodiesterase-5 (PDE-5)-inhibitor tadalafi l was tested in type 2 diabetes patients [ 15 ] . Inhibition of PDE-5 may result in improved microvascular function Introduction ▼ Type 2 diabetes is characterized by a combination of insulin resistance and impaired insulin secretion [ 1 ] .…”

Tadalafil once daily: Narrative review of a treatment option for female sexual dysfunctions (FSD) in midlife and older women

“…It is degraded by phosphodiesterase (PDE) isoenzymes, a heterogeneous group of hydrolytic enzymes. PDE5 inhibition should thus result in an increased NO signal and improved vascular function (23). To date, eleven different PDE families have been identified, each typically having several different isoforms and splice variants.…”

“…Treatment with tadalafil in elderly women for its metabolic and micro-vascular effects on skeletal muscle and adipose tissue in type 2 diabetic patients (23), for the treatment of pulmonary hypertension (30). Little evidence is reported on its efficacy in the treatment of FSD, specially in particular populations such as women treated with antidepressant drugs (31) or women affected by type 1 Diabetes Mellitus (DM) with sexual arousal disorders (28).…”