Phosphodiesterase 5 Inhibition Improves β-Cell Function in Metabolic Syndrome

Abstract

OBJECTIVE -This study tested the hypothesis that phosphodiesterase 5 inhibition alone or in combination with ACE inhibition improves glucose homeostasis and fibrinolysis in individuals with metabolic syndrome.RESEARCH DESIGN AND METHODS -Insulin sensitivity, ␤-cell function, and fibrinolytic parameters were measured in 18 adults with metabolic syndrome on 4 separate days after a randomized, crossover, double-blind, 3-week treatment with placebo, ramipril (10 mg/ day), tadalafil (10 mg o.d.), and ramipril plus tadalafil.RESULTS -Ramipril decreased systolic and diastolic blood pressure, ACE activity, and angiotensin II and increased plasma renin activity. Ramipril did not affect insulin sensitivity or ␤-cell function. In contrast, tadalafil improved ␤-cell function (P ϭ 0.01). This effect was observed in women (331.9 Ϯ 209.3 vs. 154.4 Ϯ 48.0 32 ⅐ mmol Ϫ1 ⅐ l Ϫ1 , respectively, for tadalafil treatment vs. placebo; P ϭ 0.01) but not in men. There was no effect of any treatment on fibrinolysis.CONCLUSIONS -Phosphodiesterase 5 inhibition may represent a novel strategy for improving ␤-cell function in metabolic syndrome.

A Common CD36 Variant Influences Endothelial Function and Response to Treatment with Phosphodiesterase 5 Inhibition

“…Second, a more prolonged treatment might be needed to reverse the vascular and metabolic abnormalities. However, arguing against this is that no trend towards improvement was observed in any of the cardiovascular and metabolic parameters after four-week treatment while previously DI was shown to improve after three-week treatment with tadalafil in patients with MetS (37). The interaction we observed between the rs3211938 genotype and the efficacy of sildenafil treatment highlights clinical importance of considering genotype in therapeutic interventions.…”

“…Two previous studies showed a beneficial effect of the PDE-5 inhibitor, tadalafil, on glucose disposition index after three weeks (37) and three months of treatment (38) in women with MetS and morbidly obese patients, respectively. Recently, we showed in a primarily Caucasian cohort that 3-month treatment with sildenafil improved insulin sensitivity in subjects with prediabetes (25).…”

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

“…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. In addition, a large set of preclinical studies conducted in animal models of diabetic and nondiabetic kidney disease have demonstrated the beneficial effect of PDE5 inhibition on pathophysiological pathways implicated in albuminuria, glomerulosclerosis, and tubulointerstitial injury.…”

Relation of Visceral Adiposity to Circulating Natriuretic Peptides in Ambulatory Individuals

“…There is accumulating evidence that the natriuretic peptides themselves have effects on glucose and insulin related pathways, including the ability to facilitate glucose transport via cyclic-GMP 23,24 and stimulate lipolysis. 25 Experimental models suggest that natriuretic peptides increase expression of PGC-1α, 26 a transcriptional coactivator that plays a central role in maintaining glucose, lipid, and energy homeostasis.…”