Activation of Nrf2 signaling by natural products-can it alleviate diabetes?

Abstract

Type 2 diabetes mellitus (DM) has reached pandemic proportions and effective prevention strategies are wanted. Its onset is accompanied by cellular distress, the nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor boosting cytoprotective responses, and many phytochemicals activate Nrf2 signaling. Thus, Nrf2 activation by natural products could presumably alleviate DM. We summarize function, regulation and exogenous activation of Nrf2, as well as diabetes-linked and Nrf2-susceptible forms of cellular stress. The reported amelioration of insulin resistance, β-cell dysfunction and diabetic complications by activated Nrf2 as well as the status quo of Nrf2 in precision medicine for DM are reviewed.

Keywords: Nrf2; cellular stress; hyperglycemia; insulin sensitivity; natural products; type 2 diabetes; vascular complications; β-cell function.

Fig. 1

Domain structure of Nrf2 and Keap1. (A) The different functional domains Neh1 -7 of Nrf2, involved in DNA-, Keap 1-, coactivator-, βTrcP and RXRα-binding, are depicted. (B) The functional domains of Keap 1: The Broad complex, Tramtrack and Bric-a-Brac (BTB) domain and the double-glycine repeat (DGR) domain are responsible for protein – protein interactions. The intervening region (IVR) separates those domains and the N terminal part is, together with the BTB domain, responsible for dimerization to Cul3. In the region of the Kelch domain it can interact with Nrf2 (Neh2 domain).

Fig. 2

Control of transcription and transactivation of Nrf2 target genes. Possible mechanisms impinging on Nrf2 target gene expression are depicted. They include (i) altered chromatin structure via histone (de)acetylation, (ii) altered nuclear abundance of Nrf2 (via PTM of Nrf2) (iii) an altered transactivation activity based on interaction partners and PTM of Nrf2 or (iv) promoter silencing of Nrf2 target genes.

Fig. 3

Control of Nrf2 abundance. Possible mechanisms impinging on cellular Nrf2 levels are depicted. They include (i) altered transcription of Nrf2 mRNA (ii) altered translation of Nrf2 mRNA via miRNA or translational repression and (iii) altered degradation of Nrf2 protein via direct interference with Keap1, βTrcP1, Hrd1-mediated proteasomal degradation as well as reduction of the Nrf2/Keap1 complexes via p62-mediated autophagic degradation of Keap1 or competitive binding of Nrf2.

Fig. 4

Biochemical routes of ROS production under hyperglycemia. High cellular glucose levels lead to an overwhelmed electron transport chain in the mitochondrial membrane, resulting in superoxide production and finally in activation of alternative metabolic pathways which further aggravate the cellular redox load.

Fig. 5

Potential cellular stress relief by Nrf2 activation in diabetes. Hyperglycemia and obesity as encountered in (type 2) DM disturb the cellular redox balance and proteostasis as well as elevate the inflammatory status. Nrf2 and its various target genes may counteract these insults and successfully increase the cellular detoxification, repair and survival capacities.

Fig. 6

Structure of prominent natural activators of Nrf2 signaling (with particular relevance for this review). (A) Stilbenes (B) flavonoids (e.g. apigenin, luteolin, rutin,) and catechins (EGCG) (C) other relevant natural compounds (e.g. cinnamic aldehyde, curcumin, sulforaphane).

Fig. 7

Diabetes-associated vascular complications. Chronic hyperglycemia is especially harmful for endothelial and nerve cells. Their dysfunction mainly accounts for the increased risk for the depicted micro-and macrovascular complications experienced by diabetic patients.