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

Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, Wasserman DH
Diabetes. 2007 56 (4): 1025-33

PMID: 17229936 · DOI:10.2337/db06-0883

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 x kg(-1) x 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.

MeSH Terms (21)

Animal Feed Animals Arginine Blood Glucose Blood Pressure Body Composition Dietary Fats Echocardiography Energy Metabolism Feeding Behavior Glucose Clamp Technique Insulin Male Mice Mice, Inbred C57BL Mitochondria, Muscle Piperazines Purines Sildenafil Citrate Sulfones Vasodilator Agents

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