Synergistic effects of leucine with phosphodiesterase 5 inhibition on insulin sensitivity (1035.4)

Abstract

Leucine activates Sirt1 signaling and markedly potentiates the effects of other activators on sirtuin signaling and downstream effects, including insulin signaling. PDE5 inhibition increases NO‐cGMP signaling, converging with sirtuins on PGC‐1 and mitochondrial biogenesis and thereby modulating insulin sensitivity. We confirmed this synergy in vitro, demonstrating synergy between leucine (0.5 mM) and two PDE5 inhibitors, sildenafil and the natural flavonol icariin (0.1‐10 nM) on aerobic metabolism, mitochondrial biogenesis and insulin sensitivity in myotubes and adipocytes. Effects on insulin sensitivity and glycemic control were then assessed in diet‐induced obese mice. High fat diet (HFD) for six weeks induced pronounced fasting and post‐prandial hyperglycemia and insulin resistance which was not significantly affected by addition of leucine (24 g/kg) or icariin to the diet. However, adding icariin at a level that produces no independent effect (25 mg/kg diet) to the high leucine HFD for 6 weeks reduced fasting glucose (38%, p<0.002), insulin (37%, p<0.05) and area under the glucose tolerance curve (20%, p<0.01). In addition, glucose response to an insulin challenge was impaired by HFD and fully restored by addition of leucine+icariin. These robust improvements in glycemic control and insulin sensitivity indicate therapeutic potential for this combination.Grant Funding Source: Supported by NuSirt Sciences, Inc.