Nrf2: The Master and Captain of Beta Cell Fate

Abstract

Prolonged hyperglycemia is toxic to pancreatic β cells, generating excessive reactive oxygen species, defective glucose-stimulated insulin secretion, decreased insulin production, and eventually β cell death and diabetes. Nrf2 is a master regulator of cellular responses to counteract dangerous levels of oxidative stress. Maintenance of β cell mass depends on Nrf2 to promote the survival, function, and proliferation of β cells. Indeed, Nrf2 activation decreases inflammation, increases insulin sensitivity, reduces body weight, and preserves β cell mass. Therefore, numerous pharmacological activators of Nrf2 are being tested in clinical trials for the treatment of diabetes and diabetic complications. Modulating Nrf2 activity in β cells is a promising therapeutic approach for the treatment of diabetes.

Keywords: Nrf2; diabetes; metabolic stress; oxidative stress; pancreatic beta cell; proliferation.

Figure 1 (Key Figure):. Nrf2 Activation under normal or diabetic conditions.

A. Quiescent β-cells produce a small, but important amount of Nrf2. Nrf2 levels are set by a fine balance between Nrf2 synthesis and Nrf2 proteasomal degradation using the Keap1-Cullin3-E3 ubiquitin ligase system. B. β-cells secret insulin in response to acute changes in extracellular glucose. Insulin secretion is coupled to glucose metabolism, which generates ROS, activating Nrf2 by preventing proteosomal degradation. Nrf2 enters the nucleus, binds to antioxidant response elements (AREs), and activates a program of gene expression including antioxidant enzyme genes, genes involved in mitochondrial biogenesis and function, and enzyme genes that produce NADPH. The production of NADPH restores the reduced state of antioxidant enzymes, promotes insulin secretion, and provides adaptively proliferating β-cells with reducing equivalents for nucleotide and membrane synthesis. C. In diabetes, ROS production outpaces antioxidant protection; too much ROS inhibits insulin secretion, proliferation and promotes apoptosis. Illustration by Jill Gregory. Used with permission of ©Mount Sinai Health System.

Figure 2:. Activation of Nrf2.

Nrf2, under basal conditions, remains inactive via proteosomal degradation. Glucose metabolism produces ROS, which oxidizes Keap1 cysteines, particularly C151, leading to disruption of Keap1-Keap1 homodimerization and Keap1-Cullin3 interaction, As a result, Keap1’s ability to target Nrf2 for degradation is impaired. Nrf2 is then phosphorylated at Serine 40 (Ser40) by PKC and translocates to the nucleus, where it forms a complex with small Maf proteins and binds to antioxidant response elements (ARE) that are found in regulatory regions of Nrf2 target genes. Nrf2 is also regulated by its interactions with Hrd1 and β-TrCP, both of which result in proteosomal degradation unless that interaction is disrupted. Hrd1 is an E3 ubiquitin ligase that interacts with Nrf2. In the case of β-TrCP, phosphorylation of Nrf2 by Gsk3β allows for the interaction to continue. Upon inhibition of Gsk3 β by the indicated signaling pathways, Nrf2 is spared proteasomal degradation. In addition, Keap1 can be targeted for autophagy by mTORC1-zctiated p62, resulting in stabilized Nrf2. Illustration by Jill Gregory. Used with permission of ©Mount Sinai Health System.