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Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism

Lizhi Fu1, Fenfen Li1, Antje Bruckbauer2

  • 1Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, USA.

Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy
|May 23, 2015
PubMed
Abstract

Insights

Combining leucine with phosphodiesterase 5 inhibitors (PDE5i) shows promise for metabolic health. This synergy improved insulin sensitivity, glycemic control, and lipid metabolism in obese mice, suggesting therapeutic potential.

Area of Science:

  • Metabolic signaling pathways
  • Nutrient-sensing mechanisms
  • Pharmacological interventions for metabolic disease

Background:

  • Leucine activates SIRT1/AMPK signaling, enhancing insulin sensitivity and lipid metabolism.
  • Phosphodiesterase 5 inhibitors (PDE5i) modulate nitric oxide-cGMP signaling, creating a positive feedback loop with SIRT1 and AMPK.
  • This interaction amplifies peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects, crucial for metabolic regulation.

Purpose of the Study:

  • To evaluate the synergistic effects of leucine and PDE5 inhibitors on insulin sensitivity and lipid metabolism.
  • To investigate these effects in vitro and in diet-induced obese (DIO) mouse models.

Main Methods:

  • In vitro studies utilized hepatocytes, adipocytes, and myotubes to assess synergy between leucine and subtherapeutic PDE5 inhibitor doses.
  • Diet-induced obese (DIO) mice were used to evaluate the combined effects on glycemic control, insulin sensitivity, and hepatic lipid metabolism.
  • Key metabolic parameters including glucose, insulin, fat oxidation, lipogenesis, and inflammation were measured.

Main Results:

  • Leucine synergized with subtherapeutic PDE5 inhibitors (sildenafil, icariin) in vitro, enhancing fat oxidation, nitric oxide production, and mitochondrial biogenesis.
  • In DIO mice, leucine alone did not improve metabolic parameters.
  • The combination of leucine and icariin significantly reduced fasting glucose and insulin, improved glucose tolerance, restored insulin response, inhibited hepatic lipogenesis, stimulated fatty acid oxidation, and reversed hepatic steatosis.

Conclusions:

  • Leucine-PDE5 inhibitor combinations demonstrate robust improvements in insulin sensitivity, glycemic control, and lipid metabolism.
  • These findings suggest significant therapeutic potential for combined leucine and PDE5 inhibitor treatments in metabolic disorders.
Keywords:
AMPKPDE5SIRT1diabetesicariinsildenafilsteatosis

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