Effects of Glucagon-Like Peptide-1 on Oxidative Stress and Nrf2 Signaling

Abstract

Oxidative cellular damage caused by free radicals is known to contribute to the pathogenesis of various diseases such as cancer, diabetes, and neurodegenerative diseases, as well as to aging. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein1 (Keap1) signaling pathways play an important role in preventing stresses including oxidative and inflammatory stresses. Nrf2 is a master regulator of cellular stress responses, induces the expression of antioxidant and detoxification enzymes, and protects against oxidative stress-induced cell damage. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which was originally found to increase insulin synthesis and secretion. It is now widely accepted that GLP-1 has multiple functions beyond glucose control in various tissues and organs including brain, kidney, and heart. GLP-1 and GLP-1 receptor agonists are known to be effective in many chronic diseases, including diabetes, via antioxidative mechanisms. In this review, we summarize the current knowledge regarding the role of GLP-1 in the protection against oxidative damage and the activation of the Nrf2 signaling pathway.

Keywords: Nrf2 signaling; diabetes; glucagon-like peptide-1; oxidative stress; reactive oxygen species.

Figure 1

Schematic diagram of the Nrf2-Keap1-ARE signaling pathway. Under normal conditions, nuclear erythroid-2 like factor-2 (Nrf2) is constantly ubiquitinated through Kelch-like ECH-associated protein1 (Keap1) and degraded in the proteasome. After exposure to oxidative stress (ROS), Keap1 is inactivated and Nrf2 becomes phosphorylated. Phosphorylated Nrf2 (p-Nrf2) accumulates in the nucleus and binds to antioxidant response element (ARE) sites, subsequently activating many genes including antioxidants, detoxifying enzymes, and transport molecules.

Figure 2

Signaling pathways underlying the antioxidative effects of the GLP-1 receptor. GLP-1 and exendin-4 (a GLP-1 receptor agonist) bind to the GLP-1 receptor (GLP-1R) and stimulate cyclic adenosine monophosphate (cAMP), phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC)δ, subsequently activating a number of pathways including protein kinase A (PKA), exchange protein kinase activated by cAMP2 (Epac2) and protein kinase B (AKT). These pathways increase the antioxidant capacity in various tissues and reduce diabetes, diabetic complications, neurological disease, cardiac disease, and senescence. p, phosphorylation; ERK, extracellular signal-regulated kinase; CREB, cAMP response element binding protein; Src, sarcoma; eNOS, endothelial nitric oxide synthase 3.

Figure 3

Pleiotropic effects of GLP-1 based therapies on antioxidant defense mechanisms in several organs. GLP-1 receptor (GLP-1R)-mediated signaling blocks reactive oxygen species (ROS) generation induced by various oxidative stressors and regulates the physiological function of various organs including the pancreas, liver, brain, heart, muscle, and kidney. Red arrows, increase; blue arrows, decrease.