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

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

A Combination of Leucine, Metformin, and Sildenafil Treats Nonalcoholic Fatty Liver Disease and Steatohepatitis in Mice

Sirt1, AMPK, and eNOS modulate hepatic energy metabolism and inflammation and are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses of metformin or sildenafil on the AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD in preclinical mouse models. Here we tested a possible multicomponent synergy to yield greater therapeutic efficacy in NAFLD/NASH. Liver cells and macrophages or an atherogenic diet induced NASH mouse model was treated with two-way and three-way combinations. The three-way combination Sild-Met-Leu increased hepatic fatty acid oxidation and reduced lipogenic gene expression and inflammatory marker in vitro. In mice, Sild-Met-Leu reduced the diet induced increases of ALT, TGFβ, PAI-1, IL1β, and TNFα, hepatic collagen expression, and nearly completely reversed hepatocyte ballooning and triglyceride accumulation, while all two-way combinations had only modest effects. Therefore, these data provide preclinical evidence for therapeutic efficacy of Sild-Met-Leu in the treatment of NAFLD and NASH

Study of energetic particle physics with advanced ECEI system on the HL-2A tokamak

Understanding the physics of energetic particles (EP) is crucial for the burning plasmas in next generation fusion devices such as ITER. In this work, three types of internal kink modes (a saturated internal kink mode (SK), a resonant internal kink mode (RK), and a double e-fishbone) excited by energetic particles in the low density discharges during ECRH/ECCD heating have been studied by the newly developed 24(poloidal) × 16(radial) = 384 channel ECEI system on the HL-2A tokamak. The SK and RK rotate in the electron diamagnetic direction poloidally and are destabilized by the energetic trapped electrons. The SK is destabilized in the case of qmin > 1, while the RK is destabilized in the case of qmin < 1. The double e-fishbone, which has two m/n = 1/1 modes propagating in the opposite directions poloidally, has been observed during plasma current ramp-up with counter-ECCD. Strong thermal transfer and mode coupling between the two m/n = 1/1 modes have been studied

Study of energetic particle physics with advanced ECEI system on the HL-2A tokamak

Understanding the physics of energetic particles (EP) is crucial for the burning plasmas in next generation fusion devices such as ITER. In this work, three types of internal kink modes (a saturated internal kink mode (SK), a resonant internal kink mode (RK), and a double e-fishbone) excited by energetic particles in the low density discharges during ECRH/ECCD heating have been studied by the newly developed 24(poloidal) × 16(radial) = 384 channel ECEI system on the HL-2A tokamak. The SK and RK rotate in the electron diamagnetic direction poloidally and are destabilized by the energetic trapped electrons. The SK is destabilized in the case of qmin > 1, while the RK is destabilized in the case of qmin < 1. The double e-fishbone, which has two m/n = 1/1 modes propagating in the opposite directions poloidally, has been observed during plasma current ramp-up with counter-ECCD. Strong thermal transfer and mode coupling between the two m/n = 1/1 modes have been studied