Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism
Authors Fu L, Li F, Bruckbauer A, Cao Q, Cui X, Wu R, Shi H, Xue B, Zemel M
Received 6 February 2015
Accepted for publication 23 March 2015
Published 6 May 2015 Volume 2015:8 Pages 227—239
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Professor Ming-Hui Zou
Lizhi Fu,1 Fenfen Li,1 Antje Bruckbauer,2 Qiang Cao,1 Xin Cui,1 Rui Wu,1 Hang Shi,1 Bingzhong Xue,1 Michael B Zemel2
1Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, 2NuSirt Biopharma Inc., Nashville, TN, USA
Purpose: Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide–cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects.
Methods: We evaluated potential synergy between leucine and PDE5i on insulin sensitivity and lipid metabolism in vitro and in diet-induced obese (DIO) mice.
Results: Leucine (0.5 mM) exhibited significant synergy with subtherapeutic doses (0.1–10 nM) of PDE5-inhibitors (sildenafil and icariin) on fat oxidation, nitric oxide production, and mitochondrial biogenesis in hepatocytes, adipocytes, and myotubes. Effects on insulin sensitivity, glycemic control, and lipid metabolism were then assessed in DIO-mice. DIO-mice exhibited fasting and postprandial hyperglycemia, insulin resistance, and hepatic steatosis, which were not affected by the addition of leucine (24 g/kg diet). However, the combination of leucine and a subtherapeutic dose of icariin (25 mg/kg diet) for 6 weeks reduced fasting glucose (38%, P<0.002), insulin (37%, P<0.05), area under the glucose tolerance curve (20%, P<0.01), and fully restored glucose response to exogenous insulin challenge. The combination also inhibited hepatic lipogenesis, stimulated hepatic and muscle fatty acid oxidation, suppressed hepatic inflammation, and reversed high-fat diet-induced steatosis.
Conclusion: These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine–PDE5 inhibitor combinations.
Keywords: AMPK, diabetes, icariin, PDE5, sildenafil, SIRT1, steatosis
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