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- Title
Chronic Treatment With Sildenafil Improves Energy Balance and Insulin Action in High Fat-Fed Conscious Mice.
- Authors
Ayala, Julio E.; Bracy, Deanna P.; Julien, Brianna M.; Rottman, Jeffrey N.; Fueger, Patrick T.; Wasserman, David H.
- Abstract
Stimulation of nitric oxide--cGMP signaling results in vascular relaxation and increased muscle glucose uptake. We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 inhibitor sildenafil improves energy balance and enhances in vivo insulin action in a mouse model of diet-induced insulin resistance. High-fat-fed mice treated with sildenafil plus L-arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, uncoupling protein-1 levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil plus L-arginine or sildenafil alone increased arterial cGMP levels but did not adversely affect blood pressure or cardiac morphology. Sildenafil treatment, with or without L-arginine, resulted in lower fasting insulin and glucose levels and enhanced rates of glucose infusion, disappearance, and muscle glucose uptake during a hyperiusulinemic (4 mU ⋅ kg[sup -1] ⋅ min[sup -1])-euglycemic clamp in conscious mice. These effects occurred without an increase in activation of muscle insulin signaling. An acute treatment of high fat-fed mice with sildenafil plus L-arginine did not improve insulin action. These results show that phosphodiesterase-5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance. Diabetes 56:1025-1033, 2007
- Subjects
NITRIC oxide; CYCLIC guanylic acid; HYDROLYSIS; INSULIN; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, Issue 4, p1025
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db06-0883