Title

Interaction Between Leucine and Phosphodiesterase 5 Inhibition in Modulating Insulin Sensitivity and Lipid Metabolism

Authors

Lizhi Fu, Georgia State UniversityFollow
Fenfen Li, Georgia State UniversityFollow
Antje BruckbauerFollow
Qiang Cao, Georgia State UniversityFollow
Xin Cui, Georgia State UniversityFollow
Rui Wu, Georgia State University
Hang Shi, Georgia State UniversityFollow
Bingzhong Xue, Georgia State UniversityFollow
Michael B. Zemel, University of Tennessee, KnoxvilleFollow

Document Type

Article

Publication Date

2015

Abstract

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.

Comments

Originally Published in:

Diabetes Metab Syndr Obes, 8 227-39. DOI: 10.2147/dmso.s82338

Recommended Citation

Zemel, Michael, Lizhi Fu, Fenfen Li, Antje Bruckbauer, Qiang Cao, Rui Wu, Hang Shi, Bingzhong Xue, and Xin Cui. 2015. “Interaction between Leucine and Phosphodiesterase 5 Inhibition in Modulating Insulin Sensitivity and Lipid Metabolism.” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, May, 227. doi:10.2147/DMSO.S82338.

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