Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice

Julio E. Ayala, Deanna P. Bracy, Brianna M. Julien, Jeffrey N. Rottman, Patrick T. Fueger, David H. Wasserman

Research output: Contribution to journalArticle

161 Scopus citations

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 hyperinsulinemic (4 mU·kg-1·min-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.

Original languageEnglish (US)
Pages (from-to)1025-1033
Number of pages9
JournalDiabetes
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2007

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Ayala, J. E., Bracy, D. P., Julien, B. M., Rottman, J. N., Fueger, P. T., & Wasserman, D. H. (2007). Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes, 56(4), 1025-1033. https://doi.org/10.2337/db06-0883